bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–11–17
53 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Molecular measurable residual disease monitoring and transplant indications in NPM1 mutated acute myeloid leukemia.
  2. RNA splicing as a therapeutic target in myelodysplastic syndromes.
  3. A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones.
  4. Paediatric bone marrow mesenchymal stem cells support acute myeloid leukaemia cell survival and enhance chemoresistance via contact-independent mechanism.
  5. Venetoclax in combination with hypomethylating agents in chronic myelomonocytic leukemia: a propensity score matched multicenter cohort study.
  6. Diagnosis of TP53-mutated myeloid disease by the ICC and WHO 5th Edition Classifications.
  7. A line in shifting sand: Can we define and target TP53 mutated MDS?
  8. The IL-1β inhibitor canakinumab in previously treated lower-risk myelodysplastic syndromes: a phase 2 clinical trial.
  9. GPR68 supports AML cells through the calcium/calcineurin pro-survival pathway and confers chemoresistance by mediating glucose metabolic symbiosis.
  10. Targeting DDX3X eliminates leukemia stem cells in chronic myeloid leukemia by blocking NT5DC2 mRNA translation.
  11. Methodology and clinical utility of longitudinal UBA1 tracking in VEXAS syndrome.
  12. Long-term tracking of haematopoietic clonal dynamics and mutations in non-human primate undergoing transplantation of lentivirally barcoded haematopoietic stem and progenitor cells.
  13. A simple score for clonal cytopenias.
  14. Redistribution of PU.1 partner transcription factor RUNX1 binding secures cell survival during leukemogenesis.
  15. Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia.
  16. IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy.
  17. In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy.
  18. Is age just a number? Intensive therapy for core binding factor acute myeloid leukemia in older adults.
  19. TET2 mutation in acute myeloid leukemia: biology, clinical significance, and therapeutic insights.
  20. Lenalidomide in Transfusion-Dependent IPSS Low- or Intermediate-1-Risk Myelodysplastic Syndromes and Isolated Del(5q): Results of a European Postauthorization Safety Surveillance Study.
  21. Hydroxy-wybutosine tRNA modifications as indicators of disease progression and therapeutic targets in leukaemia.
  22. CXCL8 secreted by immature granulocytes inhibits WT hematopoiesis in chronic myelomonocytic leukemia.
  23. Homoharringtonine Added to Venetoclax and Azacitidine Improves Outcome and Mitigates Genetic Impact in Relapsed/Refractory AML: A Multi-center Cohort Study.
  24. Longitudinal Assessment of Transfusion Intensity in Patients With JAK Inhibitor-Naive or -Experienced Myelofibrosis Treated With Momelotinib.
  25. Approaching a therapeutic inflection point for FLT3-mutated AML.
  26. Sustained benefits of imetelstat on patient-reported fatigue in patients with lower-risk myelodysplastic syndromes ineligible for, or relapsed/refractory to, erythropoiesis-stimulating agents and high transfusion burden in the phase 3 IMerge study.
  27. Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice.
  28. Allogeneic hematopoietic cell transplantation for therapy-related myeloid neoplasms arising following treatment for multiple myeloma: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.
  29. Predicting therapy-related myeloid neoplasms after CAR-T with the Clonal Haematopoiesis Risk Score (CHRS).
  30. Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD-positive AML.
  31. Germline genetics, disease, and exposure to medication influence longitudinal dynamics of clonal hematopoiesis.
  32. Perspectives on drug development in chronic myelomonocytic leukemia: changing the paradigm.
  33. Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation.
  34. Clonal hematopoiesis in patients with autoimmune thrombocytopenia: an international multicenter study.
  35. Dissecting the genomic traits and clinical course of secondary myelodysplastic syndrome following aplastic anaemia: A milestone.
  36. Causes of death in patients with myelodysplastic syndrome and spliceosome mutations.
  37. Post-transplant G-CSF impedes engraftment of gene-edited human hematopoietic stem cells by exacerbating p53-mediated DNA damage response.
  38. Unveiling the Genetic and Clinical Differences of Acute Myeloid Leukemia (AML) in Obese Patients.
  39. Revumenib Revises the Treatment Landscape for KMT2A-r Leukemia.
  40. When and how to transplant in myelofibrosis - recent trends.
  41. A glutamine metabolic switch supports erythropoiesis.
  42. How I approach the treatment of thrombotic complications in patients with myeloproliferative neoplasms.
  43. Imetelstat: A new addition to the Therapeutic Landscape of Lower-Risk MDS.
  44. Longitudinal ultra-sensitive mutation burden sequencing for precise minimal residual disease assessment in AML.
  45. Ruxolitinib REACHes FOR children with GVHD.
  46. Early mixed donor chimerism is a strong negative prognostic indicator in allogeneic stem cell transplant for AML and MDS.
  47. Inebilizumab for Treatment of IgG4-Related Disease.
  48. Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS.
  49. PP2A licenses the FANCD2/FANCI complex for chromosome loading.
  50. Increased exercise tolerance in humanized G6PD deficient mice.
  51. Adult skull bone marrow is an expanding and resilient haematopoietic reservoir.
  52. Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis.
  53. Endothelial heterogeneity in bone marrow: insights across development, adult life and leukemia.
  1. Bone Marrow Transplant. 2024 Nov 13.
    Molecular measurable residual disease monitoring and transplant indications in NPM1 mutated acute myeloid leukemia.
    Mary R Christopher, Mariam T Nawas, John L Reagan.
      NPM1 mutated acute myeloid leukemia (AML) comprises roughly 30% of all AML cases and is mainly classified as favorable or intermediate-risk according to the European Leukemia Net stratification. Some patients, however, either have a poor response to initial intensive chemotherapy or ultimately relapse. NPM1 mutations are common, generally stable at early relapse and AML specific, features which make them ideal targets for measurable residual disease (MRD) monitoring. MRD monitoring via molecular analysis during the course of treatment can inform the role of allogeneic stem cell transplantation (HCT) in first remission in patients with NPM1 mutated AML with high-risk co-occurring mutations, particularly FLT3-ITD, and in favorable risk patients who do not achieve defined molecular milestones. In this review, we evaluate the prognostic role of MRD monitoring in NPM1 mutated AML and its use as a predictive biomarker to refine risk stratification and inform decision making regarding treatment. We explore the impact of pre-HCT MRD positivity on post-HCT outcomes in this AML subset, and how HCT-related factors such as conditioning intensity may influence this risk.
    DOI:  https://doi.org/10.1038/s41409-024-02465-2
  2. Semin Hematol. 2024 Oct 23. pii: S0037-1963(24)00121-5. [Epub ahead of print]
    RNA splicing as a therapeutic target in myelodysplastic syndromes.
    Chun-Chih Tseng, Esther A Obeng.
      Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematological disorders and are more commonly found in people over the age of 60. MDS patients exhibit peripheral blood cytopenias and carry an increased risk of disease progression to acute myeloid leukemia (AML). Splicing factor mutations (including genes SF3B1, SRSF2, U2AF1, and ZRSR2) are early events identified in more than 50% of MDS cases. These mutations cause aberrant pre-mRNA splicing and impact MDS pathophysiology. Emerging evidence shows that splicing factor-mutant cells are more sensitive to perturbations targeting the spliceosome, aberrantly spliced genes and/or their regulated molecular pathways. This review summarizes current therapeutic strategies and ongoing efforts targeting splicing factor mutations for the treatment of MDS.
    Keywords:  Clinical trial; Myelodysplastic syndromes; Spliceosome; Splicing factor
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.10.005
  3. Leukemia. 2024 Nov 13.
    A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones.
    Raúl Sánchez-Lanzas, Justin Barclay, Alexandros Hardas, Foteini Kalampalika, Amanda Jiménez-Pompa, Paolo Gallipoli, Miguel Ganuza.
      Clonal hematopoiesis (CH) is nearly universal in the elderly. The molecular and cellular mechanisms driving CH and the clinical consequences of carrying clonally derived mutant mature blood cells are poorly understood. We recently identified a C223Y mutation in the extracellular domain (ECD) of NOTCH3 as a putative CH driver in mice. Provocatively, germline NOTCH3 ECD mutations perturbing cysteine numbers cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a type of vascular dementia, suggesting an unexpected link between CADASIL and CH. Here, we formally demonstrated that mouse hematopoietic stem and progenitor cells (HSPCs) expressing CADASIL-related NOTCH3C455R exhibit a proliferative advantage resulting in robust cellular expansion in vivo and in vitro. Co-expression of NOTCH3C455R and Dnmt3aR878H, homologous to a frequent human CH mutation, increased the fitness of NOTCH3C455R HSPCs, demonstrating their functional cooperation. Surprisingly, the presence of NOTCH3C455R hematopoietic cells supported the expansion of Dnmt3aR878H HSPCs in a non-cell autonomous fashion in vivo, strongly suggesting that CADASIL patients and asymptomatic carriers can be highly predisposed to DNMT3AR882H-driven CH. Considering that CADASIL-related NOTCH3 mutations are more frequent in the general population than anticipated (~1 carrier in 400 people), the effect of these NOTCH3 mutations on CH development should be considered.
    DOI:  https://doi.org/10.1038/s41375-024-02464-8
  4. Br J Haematol. 2024 Nov 10.
    Paediatric bone marrow mesenchymal stem cells support acute myeloid leukaemia cell survival and enhance chemoresistance via contact-independent mechanism.
    Alison Laing, Ahmed Elmarghany, Arwa A Alghaith, Aya Gouma, Thomas Stevens, Alexander Winton, Jennifer Cassels, Cassie J Clarke, Claire Schwab, Christine J Harrison, Brenda Gibson, Karen Keeshan.
      Children diagnosed with acute myeloid leukaemia (paediatric AML [pAML]) have limited treatment options and relapse rates due to chemoresistance and refractory disease are over 30%. Current treatment is cytotoxic and in itself has long-lasting harsh side effects. New, less toxic treatments are needed. The bone marrow microenvironment provides chemoprotection to leukaemic cells through cell communication and interaction with mesenchymal stem cells (MSCs), but this is not well defined in pAML. Using primary patient material, we identify a cell contact-independent mechanism of MSC-mediated chemoprotection involving extrinsic soluble factors that is abrogated through inhibition of the JAK/STAT and ERK pathways.
    Keywords:  AML; chemosensitivity; childhood leukaemia; mesenchymal cells
    DOI:  https://doi.org/10.1111/bjh.19884
  5. Leukemia. 2024 Nov 12.
    Venetoclax in combination with hypomethylating agents in chronic myelomonocytic leukemia: a propensity score matched multicenter cohort study.
    Douglas Tremblay, Clifford Csizmar, Courtney D DiNardo, Somedeb Ball, Noa Rippel, Danielle Hammond, Tapan M Kadia, Farhad Ravandi, Kelly Chien, Grace Van Hyfte, Madhu Mazumdar, Antoine Saliba, Abhishek Mangaonkar, Terra Lasho, Aref Al-Kali, Marina Kremyanskaya, Jonathan Feld, Lewis R Silverman, Rami Komrokji, John Mascarenhas, Eric Padron, Guillermo Garcia-Manero, David A Sallman, Mrinal M Patnaik, Guillermo Montalban-Bravo.
      
    DOI:  https://doi.org/10.1038/s41375-024-02466-6
  6. Blood Adv. 2024 Nov 13. pii: bloodadvances.2024014140. [Epub ahead of print]
    Diagnosis of TP53-mutated myeloid disease by the ICC and WHO 5th Edition Classifications.
    Stephanie A Hart, Laura Lee, Adam Seegmiller, Emily Ferguson Mason.
      The International Consensus (ICC) and World Health Organization 5th edition (WHO5) classifications introduced new but differing categories of myeloid disease defined by TP53 mutations. We reviewed a cohort of 188 cases of TP53-mutated myeloid disease to determine how diagnoses and outcomes differ between the two classifications. Overall, 120 (64%) cases were classified differently by the ICC and WHO5, including 24/80 (30%) cases with <20% blasts. These cases were discrepantly categorized primarily due to inclusion of complex karyotype (CK) as a surrogate for biallelic TP53 inactivation only in the ICC. However, there were no significant differences in clinicopathologic characteristics or overall survival between cases categorized as TP53-mutated disease by both classifications and those with a single TP53 mutation and CK, suggesting that CK reliably identifies TP53-mutated cases with biallelic TP53 inactivation. The majority of cases of AML (96/102; 94%) were discrepantly diagnosed between the ICC and WHO5 due to the introduction of AML with mutated TP53 as a distinct category only in the ICC. Nearly all of these were instead diagnosed as AML, myelodysplasia-related (AML, MR) by WHO5. However, when compared to a separate cohort of patients with AML, MR without TP53 mutations, patients with TP53-mutated AML showed a distinct genetic profile and significantly worse overall survival, supporting the inclusion of AML with mutated TP53 as a distinct disease category. Overall, our results show that a significant percentage of TP53-mutated myeloid disease is classified differently by the ICC and WHO5 and highlight areas to address in future classification systems.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014140
  7. Semin Hematol. 2024 Nov 06. pii: S0037-1963(24)00126-4. [Epub ahead of print]
    A line in shifting sand: Can we define and target TP53 mutated MDS?
    Sarah Skuli, Andrew Matthews, Martin Carroll, Catherine Lai.
      Mutations in the tumor suppressor protein, TP53, lead to dismal outcomes in myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Recent pathological reclassifications have integrated TP53 mutated MDS and AML under a unified category of TP53 mutated myeloid neoplasms, which allows for more flexibility in treatment approaches. Therapeutic strategies have predominantly mirrored those for AML, with allogeneic stem cell transplantation emerging as critical for long-term disease control. The question remains whether there are physiological distinctions within TP53 mutated myeloid neoplasms that will significantly impact prognosis and therapeutic considerations. This review explores the unique aspects of classically defined "TP53 mutated MDS", focusing on its distinct biological characteristics and outcomes. Our current understanding is that TP53 mutated MDS and AML are globally quite similar, but as a group have unique features compared to TP53 wildtype (WT) disease. Optimizing immunotherapy and targeting vulnerabilities due to co-mutations and/or chromosome abnormalities should be the focus of future research.
    Keywords:  AML; Biology; MDS; TP53; Treatment
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.10.009
  8. Nat Commun. 2024 Nov 13. 15(1): 9840
    The IL-1β inhibitor canakinumab in previously treated lower-risk myelodysplastic syndromes: a phase 2 clinical trial.
    Juan Jose Rodriguez-Sevilla, Vera Adema, Kelly S Chien, Sanam Loghavi, Feiyang Ma, Hui Yang, Guillermo Montalban-Bravo, Xuelin Huang, Xavier Calvo, Joby Joseph, Kristy Bodden, Guillermo Garcia-Manero, Simona Colla.
      In myelodysplastic syndromes (MDS), the IL-1β pathway is upregulated, and previous studies using mouse models of founder MDS mutations demonstrated that it enhances hematopoietic stem and progenitor cells' (HSPCs') aberrant differentiation towards the myeloid lineage at the expense of erythropoiesis. To evaluate whether targeting the IL-1β signaling pathway can rescue ineffective erythropoiesis in patients with MDS, we designed a phase 2 non-randomized single-arm clinical trial (NCT04239157) to assess the safety profile and efficacy of the IL-1β inhibitor canakinumab in previously treated lower-risk MDS patients. We enrolled 25 patients with a median age of 74 years; 60% were male, 16% had lower-risk MDS, 84% had intermediate-1 risk MDS according to the International Prognostic Scoring System score, and 80% failed hypomethylating agent therapy. The study met the primary endpoint of defining the clinical activity of canakinumab, and the secondary objective of determining the safety profile, including the rate of transfusion independence, the duration of response, progression-free survival, leukemia-free survival, and overall survival. The overall response rate was 17.4%, with all responses including hematological improvement. Sequential post-hoc prospective single-cell RNA sequencing analyses of HSPCs and bone marrow mononuclear cells at different time points during therapy showed that canakinumab's on-target effects in hematopoietic populations expressing the IL-1β receptor decreased the TNF-mediated inflammatory signaling pathway but rescued ineffective erythropoiesis only in the context of lower genetic complexity. This study demonstrates that better stratification strategies could target lower-risk MDS patients more effectively.
    DOI:  https://doi.org/10.1038/s41467-024-54290-2
  9. Biochim Biophys Acta Mol Basis Dis. 2024 Nov 08. pii: S0925-4439(24)00559-3. [Epub ahead of print] 167565
    GPR68 supports AML cells through the calcium/calcineurin pro-survival pathway and confers chemoresistance by mediating glucose metabolic symbiosis.
    Xiaofei He, Caleb Hawkins, Lauren Lawley, Tra Mi Phan, Isaac Park, Nicole Joven, Jiajia Zhang, Mark Wunderlich, Benjamin Mizukawa, Shanshan Pei, Amisha Patel, Jennifer VanOudenhove, Stephanie Halene, Jing Fang.
      Accumulating evidence demonstrates that the "Warburg effect" that glycolysis is enhanced even in the presence of oxygen existed in hematopoietic malignancies, contributing to extracellular acidosis. G-protein coupled receptor 68 (GPR68), as a proton sensing GPCR responding to extracellular acidosis, is expected to play a critical role in hematopoietic malignancies. In the present study, we found that GPR68 was overexpressed in acute myeloid leukemia (AML) cells, and GPR68 deficiency impaired AML cell survival in vitro and cell engraftment in vivo. Mechanistic studies revealed that unlike GPR68 regulates Calpain1 in myelodysplastic syndromes (MDS) cells, GPR68 deficiency reduced cytosolic Ca2+ levels and calcineurin (CaN) activity in AML cells through an NFAT-independent mechanism. Moreover, the decreased Ca2+ levels disturbed cellular respiration (i.e., oxidative phosphorylation, OxPhos) by inhibiting isocitrate dehydrogenase (IDH) activity; this was more pronounced when BCL2 was inhibited simultaneously. Interestingly, GPR68 inhibition also decreased aerobic glycolysis in AML cells in a Ca2+-independent manner, suggesting that GPR68 mediated glucose metabolic symbiosis. As glucose metabolic symbiosis and the heterogeneous dependencies on aerobic glycolysis and cellular respiration tremendously impact chemosensitivity, the inhibition of GPR68 potentiated the tumoricidal effect of first-line chemotherapeutic agents, including BCL-2 inhibitors targeting OxPhos and cytarabine (AraC) targeting glycolysis. Consistent with these in vitro observations, higher levels of GPR68 were associated with inferior clinical outcomes in AML patients who received chemotherapies. In short, GPR68 drives the Ca2+/CaN pro-survival pathway and mediates glucose metabolic pathways in AML cells. Targeting GPR68 eradicates AML cells and alleviates chemoresistance, which could be exploited as a therapeutic target. The overexpression of GPR68 drives a Ca2+/CaN pro-survival pathway and mediates glucose metabolic symbiosis in AML cells, suggesting the diagnostic and therapeutic potential of GPR68 in AML. (GPR68, G proton-coupled receptor 68; PLCβ, phospholipase C beta; CaN, Calcineurin; IDH, isocitrate dehydrogenase; HIF-1α, Hypoxia-inducible factor alpha subunit; GLUT1, Glucose transporter type 1; HK-1, Hexokinase 1).
    Keywords:  Calcineurin; Calcium; Chemoresistance; Glucose metabolic symbiosis; Proton-sensing GPR68
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167565
  10. Oncogene. 2024 Nov 08.
    Targeting DDX3X eliminates leukemia stem cells in chronic myeloid leukemia by blocking NT5DC2 mRNA translation.
    Chen Duan, Xiaoying Lin, Waiyi Zou, Qi He, Fen Wei, Jingxuan Pan, Chang Liu, Yanli Jin.
      Tyrosine kinase inhibitors (TKIs) are highly effective in the treatment of patients with chronic myeloid leukemia (CML), but fail to eliminate leukemia stem cells (LSCs), which can lead to disease relapse or progression. It is urgently need to identify the regulators specifically driving LSCs. In this study, we identified DEAD-box helicase 3 X-linked (DDX3X), a ubiquitously expressed RNA helicase, as a critical regulator for CML LSCs by using patient samples and BCR-ABL-driven CML mouse model. We found that DDX3X enhanced the survival, serially plating and long-term engraftment abilities of human primary CML CD34+ cells. Inhibition of DDX3X reduced leukemia burden, eradicated LSCs and extended the survival of CML mice. Mechanistically, we uncovered that DDX3X protein bound to 5'-Nucleotidase Domain Containing 2 (NT5DC2) mRNA and promoted its translation in CML cells. NT5DC2 was a functional mediator in DDX3X regulation of LSCs. Collectively, our findings provide new evidence for RNA helicase facilitating the translation of specific mRNA in LSCs. Targeting DDX3X may represent a promising therapeutic strategy for eradication of LSCs in CML patients.
    DOI:  https://doi.org/10.1038/s41388-024-03215-w
  11. Br J Haematol. 2024 Nov 13.
    Methodology and clinical utility of longitudinal UBA1 tracking in VEXAS syndrome.
    Carmelo Gurnari, Elisa Galossi, Eleonora Lumia, Alfonso Piciocchi, Mariadomenica Divona, Elisa Casciani, Francesca Romano, Elisa Diral, Alessandro Tomelleri, Federico Caroni, Antonio Vitale, Gregorio Maria Bergonzi, Annalisa Condorelli, Giorgia Battipaglia, Erika Morsia, Elena Crisà, Paola Triggianese, Arianna Savi, Chiara Cardamone, Matteo Dragani, Giulia Rivoli, Federica Pilo, Davide Firinu, Sara Plebani, Francesco D'Agostino, Alessandro D'Ambrosio, Katja Sockel, Cristina Papayannidis, Silvia Salmoiraghi, Fabrizio Pane, Monica Bocchia, Luca Cantarini, Marco Frigeni, Corrado Campochiaro, Lorenzo Dagna, Raffaella Greco, Fabio Ciceri, Orietta Spinelli, Christian Thiede, Maria Teresa Voso.
      Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) is a haemato-inflammatory syndrome genetically defined by somatic mutations in the X-linked UBA1 gene, typically Val/Thr/Leu substitutions at the Met41 hotspot. Clinical manifestations are heterogeneous and refractory to most haemato-rheumatological treatments. To date, no guidelines exist for the management of VEXAS, and scarce is the evidence on methodology and clinical significance of longitudinal UBA1 clonal burden evaluation upon therapy. Here, we validated a method to quantify UBA1 clonal burden and explored its applicability in patients with VEXAS. Given the different treatment interactions, droplet digital polymerase chain reaction (ddPCR) may allow for informed therapeutic decisions and implementation of personalized strategies.
    Keywords:  autoimmune disease; molecular diagnostics; mutation detection; myeloid neoplasia
    DOI:  https://doi.org/10.1111/bjh.19897
  12. Br J Haematol. 2024 Nov 10.
    Long-term tracking of haematopoietic clonal dynamics and mutations in non-human primate undergoing transplantation of lentivirally barcoded haematopoietic stem and progenitor cells.
    Rohan V Hosuru, Jack Yang, Yifan Zhou, Ashley Gin, Taha B Hayal, So Gun Hong, Cynthia E Dunbar, Chuanfeng Wu.
      Haematopoietic stem and progenitor cell (HSPC) autologous gene therapies are promising treatment for a variety of blood disorders. Investigation of the long-term HSPC clonal dynamics and other measures of safety and durability following lentiviral-mediated gene therapies in predictive models are crucial for assessing risks and benefits in order to inform decisions regarding wider utilization. We established an autologous lentivirally barcoded HSPC transplantation model in rhesus macaque (RM), a model offering insights into haematopoiesis and gene therapies with direct relevance to human. Healthy young adult RMs underwent total body irradiation, followed by transplantation of autologous HSPCs transduced with a lentiviral vector containing a diverse genetic barcode library, uniquely labelling individual HSPCs and their progeny. With up to 131 months of follow-up, we now report quantitative clonal dynamics, characterizing the number, diversity, stability and lineage bias of hundreds of thousands of HSPC clones tracked in five RMs. We documented long-term stable and multi-lineage output from a highly polyclonal pool of HSPCs. Clonal succession after stable haematopoietic reconstitution was minimal. There was no evidence for accelerated acquisition of acquired somatic mutations following autologous lentivirally transduced HSPC transplantation. Our results provide relevant insights into long-term HSPC behaviours in vivo following transplantation and gene therapies.
    Keywords:  clonal dynamics; haematopoietic stem and progenitor cell transplantation; lentiviral barcoding; mutation; non‐human primate
    DOI:  https://doi.org/10.1111/bjh.19889
  13. Blood. 2024 Nov 07. 144(19): 1981-1982
    A simple score for clonal cytopenias.
    Torsten Haferlach.
      
    DOI:  https://doi.org/10.1182/blood.2024026076
  14. EMBO J. 2024 Nov 14.
    Redistribution of PU.1 partner transcription factor RUNX1 binding secures cell survival during leukemogenesis.
    Alexander Bender, Füsun Boydere, Ashok Kumar Jayavelu, Alessia Tibello, Thorsten König, Hanna Aleth, Gerd Meyer Zu Hörste, Thomas Vogl, Frank Rosenbauer.
      Transcription factors (TFs) orchestrating lineage-development often control genes required for cellular survival. However, it is not well understood how cells survive when such TFs are lost, for example in cancer. PU.1 is an essential TF for myeloid fate, and mice with downregulated PU.1 levels develop acute myeloid leukemia (AML). Combining a multi-omics approach with a functional genetic screen, we reveal that PU.1-downregulated cells fundamentally change their survival control from cytokine-driven pathways to overexpression of an autophagy-predominated stem cell gene program, for which we also find evidence in human AML. Control of this program involves redirected chromatin occupancy of the PU.1 partner TF Runx1 to a lineage-inappropriate binding site repertoire. Hence, genomic reallocation of TF binding upon loss of a partner TF can act as a pro-oncogenic failsafe mechanism by sustaining cell survival during leukemogenesis.
    Keywords:  Myeloid Development; Myeloid Leukemia; PU.1; RUNX1
    DOI:  https://doi.org/10.1038/s44318-024-00295-y
  15. Cell Stem Cell. 2024 Nov 08. pii: S1934-5909(24)00374-6. [Epub ahead of print]
    Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia.
    Richard A Voit, Xiaotian Liao, Alexis Caulier, Mateusz Antoszewski, Blake Cohen, Myriam Armant, Henry Y Lu, Travis J Fleming, Elena Kamal, Lara Wahlster, Aoife M Roche, John K Everett, Angelina Petrichenko, Mei-Mei Huang, William Clarke, Kasiani C Myers, Craig Forester, Antonio Perez-Atayde, Frederic D Bushman, Danilo Pellin, Akiko Shimamura, David A Williams, Vijay G Sankaran.
      Gene therapy using hematopoietic stem and progenitor cells is altering the therapeutic landscape for patients with hematologic, immunologic, and metabolic disorders but has not yet been successfully developed for individuals with the bone marrow failure syndrome Diamond-Blackfan anemia (DBA). More than 30 mutations cause DBA through impaired ribosome function and lead to inefficient translation of the erythroid master regulator GATA1, providing a potential avenue for therapeutic intervention applicable to all patients with DBA, irrespective of the underlying genotype. Here, we report the development of a clinical-grade lentiviral gene therapy that achieves erythroid lineage-restricted expression of GATA1. We show that this vector is capable of augmenting erythropoiesis in DBA models and diverse patient samples without impacting hematopoietic stem cell function or demonstrating any signs of premalignant clonal expansion. These preclinical safety and efficacy data provide strong support for the first-in-human universal gene therapy trial for DBA through regulated GATA1 expression.
    Keywords:  Diamond-Blackfan anemia; GATA1; bone marrow failure; enhancer; erythropoiesis; gene therapy; hematopoiesis; hematopoietic stem cell; hypoplastic anemia; lentivirus
    DOI:  https://doi.org/10.1016/j.stem.2024.10.012
  16. Cell Rep Med. 2024 Nov 08. pii: S2666-3791(24)00597-4. [Epub ahead of print] 101826
    IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy.
    Viviana Rubino, Michelle Hüppi, Sabine Höpner, Luigi Tortola, Noah Schnüriger, Hugo Legenne, Lea Taylor, Svenja Voggensperger, Irene Keller, Remy Bruggman, Marie-Noëlle Kronig, Ulrike Bacher, Manfred Kopf, Adrian F Ochsenbein, Carsten Riether.
      Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4+ T cell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR T cell treatment on LSCs in vitro. Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML.
    Keywords:  AML; CD70-targeting CAR T cells; IL-21; cytarabine; leukemia stem cell; p38 MAPK; self-renewal; stemness
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101826
  17. Cancer Cell. 2024 Nov 11. pii: S1535-6108(24)00397-0. [Epub ahead of print]42(11): 1955-1969.e7
    In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy.
    Robert L Bowman, Andrew J Dunbar, Tanmay Mishra, Wenbin Xiao, Michael R Waarts, Inés Fernández Maestre, Shira E Eisman, Louise Cai, Shoron Mowla, Nisargbhai Shah, Angela Youn, Laura Bennett, Suean Fontenard, Shreeya Gounder, Anushka Gandhi, Michael Bowman, Kavi O'Connor, Zachary Zaroogian, Pablo Sánchez-Vela, Anthony R Martinez Benitez, Matthew Werewski, Young Park, Isabelle S Csete, Aishwarya Krishnan, Darren Lee, Nayla Boorady, Chad R Potts, Matthew T Jenkins, Sheng F Cai, Martin P Carroll, Sara E Meyer, Linde A Miles, P Brent Ferrell, Jennifer J Trowbridge, Ross L Levine.
      Cancer evolution is a multifaceted process leading to dysregulation of cellular expansion and differentiation through somatic mutations and epigenetic dysfunction. Clonal expansion and evolution is driven by cell-intrinsic and -extrinsic selective pressures, which can be captured with increasing resolution by single-cell and bulk DNA sequencing. Despite the extensive genomic alterations revealed in profiling studies, there remain limited experimental systems to model and perturb evolutionary processes. Here, we integrate multi-recombinase tools for reversible, sequential mutagenesis from premalignancy to leukemia. We demonstrate that inducible Flt3 mutations differentially cooperate with Dnmt3a, Idh2, and Npm1 mutant alleles, and that changing the order of mutations influences cellular and transcriptional landscapes. We next use a generalizable, reversible approach to demonstrate that mutation reversion results in rapid leukemic regression with distinct differentiation patterns depending upon co-occurring mutations. These studies provide a path to experimentally model sequential mutagenesis, investigate mechanisms of transformation and probe oncogenic dependency in disease evolution.
    Keywords:  genetically engineered mouse models; leukemia; oncogene dependency; sequential mutagenesis
    DOI:  https://doi.org/10.1016/j.ccell.2024.10.009
  18. Haematologica. 2024 Nov 14.
    Is age just a number? Intensive therapy for core binding factor acute myeloid leukemia in older adults.
    Benson M George, Marlise R Luskin.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.286640
  19. Clin Epigenetics. 2024 Nov 09. 16(1): 155
    TET2 mutation in acute myeloid leukemia: biology, clinical significance, and therapeutic insights.
    Qiang Gao, Kefeng Shen, Min Xiao.
      TET2 is a critical gene that regulates DNA methylation, encoding a dioxygenase protein that plays a vital role in the regulation of genomic methylation and other epigenetic modifications, as well as in hematopoiesis. Mutations in TET2 are present in 7%-28% of adult acute myeloid leukemia (AML) patients. Despite this, the precise mechanisms by which TET2 mutations contribute to malignant transformation and how these insights can be leveraged to enhance treatment strategies for AML patients with TET2 mutations remain unclear. In this review, we provide an overview of the functions of TET2, the effects of its mutations, its role in clonal hematopoiesis, and the possible mechanisms of leukemogenesis. Additionally, we explore the mutational landscape across different AML subtypes and present recent promising preclinical research findings.
    Keywords:   TET2 ; Acute myeloid leukemia; DNA methylation; Mechanisms; Therapeutic insights
    DOI:  https://doi.org/10.1186/s13148-024-01771-2
  20. Clin Lymphoma Myeloma Leuk. 2024 Oct 10. pii: S2152-2650(24)02365-6. [Epub ahead of print]
    Lenalidomide in Transfusion-Dependent IPSS Low- or Intermediate-1-Risk Myelodysplastic Syndromes and Isolated Del(5q): Results of a European Postauthorization Safety Surveillance Study.
    Antonella Poloni, Klas Raaschou-Jensen, Francisca Hernandez Mohedo, Stefania Paolini, Esther Natalie Oliva, Francesco Buccisano, Alberto Vasconcelos, Iris Kim, Aidan Makwana, David Bernasconi, Barbara Rosettani, Thomas Prebet, Valeria Santini.
       BACKGROUND: This noninterventional postauthorization safety study assessed the safety and effectiveness of lenalidomide in patients with transfusion-dependent, International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) associated with isolated deletion of 5q (del[5q]) who were treated in routine care.
    PATIENTS AND METHODS: Eligible adult patients in the lenalidomide cohort had transfusion-dependent, IPSS Low- or Int-1-risk MDS and isolated del(5q) and had received ≥ 1 dose of lenalidomide between 2014 and 2022. The primary endpoint was the 24-month cumulative incidence of acute myeloid leukemia (AML) progression. Overall survival (OS) was estimated by Kaplan-Meier analysis and safety data were collected.
    RESULTS: In total, 296 patients received ≥ 1 dose of lenalidomide (lenalidomide cohort, safety population) and 277 had received ≥ 1 complete cycle of lenalidomide (primary population). In the safety population, 44.3% of patients completed 3-year follow-up and 55.1% discontinued, with 33.1% discontinuing due to death. In the primary population, 24-month cumulative incidence of AML progression was 12.7% (95% confidence interval, 8.9%-17.1%) and estimated OS probability was 78.3% at 24 months and 63.9% at 36 months. Grade 3/4 treatment-emergent adverse events were experienced by 67.2% of the safety population, and these led to discontinuation in 35.5% of patients. There were no new safety signals.
    CONCLUSION: These real-world data support the established benefit-risk profile of lenalidomide in transfusion-dependent IPSS Low- or Int-1-risk MDS with isolated del(5q).
    Keywords:  Acute myeloid leukemia; Deletion 5q; immunomodulatory imide drug; noninterventional study; overall survival
    DOI:  https://doi.org/10.1016/j.clml.2024.10.007
  21. Br J Haematol. 2024 Nov 10.
    Hydroxy-wybutosine tRNA modifications as indicators of disease progression and therapeutic targets in leukaemia.
    Xu Chen, Rui-Ze Gong, Liu-Ying Mo, Ya-Ting Cheng, Yu Ma, Yi-Tao Qi, Tong-Meng Yan, Zhi-Hong Jiang.
      Therapeutic approaches for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) differ due to distinct diagnostic criteria and treatment strengths. However, reliable biomarkers to differentiate AML from MDS are needed. This study investigated transfer RNA (tRNA) modifications, particularly hydroxy-wybutosine (OHyW), in the transition from MDS to AML. We found a significant decrease in OHyW and its biosynthetic enzyme leucine carboxyl methyltransferase 2 (LCMT2, alias symbol is TYW4) levels in AML compared to MDS. Mass spectrometric analysis revealed distinct tRNA modification patterns, with AML showing decreased OHyW and increased precursor levels, indicating a disrupted biosynthetic pathway. Lower LCMT2 expression correlated with reduced drug sensitivity and limited differentiation potential in AML cell lines. The results highlight the pivotal role of tRNA modifications in the progression from MDS to AML and suggest that targeting LCMT2 may enhance therapeutic outcomes in AML. By understanding these molecular mechanisms, we can develop new diagnostic markers and therapeutic strategies, potentially transforming the clinical management of AML and improving patient outcomes.
    Keywords:  AML; LCMT2; MDS; OHyW; tRNA modification
    DOI:  https://doi.org/10.1111/bjh.19873
  22. J Clin Invest. 2024 Sep 17. pii: e180738. [Epub ahead of print]134(22):
    CXCL8 secreted by immature granulocytes inhibits WT hematopoiesis in chronic myelomonocytic leukemia.
    Paul Deschamps, Margaux Wacheux, Axel Gosseye, Margot Morabito, Arnaud Pagès, Anne-Marie Lyne, Alexia Alfaro, Philippe Rameau, Aygun Imanci, Rabie Chelbi, Valentine Marchand, Aline Renneville, Mrinal M Patnaik, Valerie Lapierre, Bouchra Badaoui, Orianne Wagner-Ballon, Céline Berthon, Thorsten Braun, Christophe Willekens, Raphael Itzykson, Pierre Fenaux, Sylvain Thépot, Gabriel Etienne, Emilie Elvira-Matelot, Francoise Porteu, Nathalie Droin, Leïla Perié, Lucie Laplane, Eric Solary, Dorothée Selimoglu-Buet.
      Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrates early clonal dominance with few residual WT hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokines they produce generate a deleterious inflammatory climate. Our hypothesis is that therapeutic control of the inflammatory component in CMML could contribute to stepping down disease progression. The present study explored the contribution of immature granulocytes (iGRANs) to CMML progression. iGRANs were detected and quantified in the peripheral blood of patients by spectral and conventional flow cytometry. Their accumulation was a potent and independent poor prognostic factor. These cells belong to the leukemic clone and behaved as myeloid-derived suppressor cells. Bulk and single-cell RNA-Seq revealed a proinflammatory status of iGRAN that secreted multiple cytokines of which CXCL8 was at the highest level. This cytokine inhibited the proliferation of WT but not CMML hematopoietic stem and progenitor cells (HSPCs) in which CXCL8 receptors were downregulated. CXCL8 receptor inhibitors and CXCL8 blockade restored WT HSPC proliferation, suggesting that relieving CXCL8 selective pressure on WT HSPCs is a potential strategy to slow CMML progression and restore some healthy hematopoiesis.
    Keywords:  Cytokines; Hematology; Leukemias; Neutrophils
    DOI:  https://doi.org/10.1172/JCI180738
  23. Clin Cancer Res. 2024 Nov 12.
    Homoharringtonine Added to Venetoclax and Azacitidine Improves Outcome and Mitigates Genetic Impact in Relapsed/Refractory AML: A Multi-center Cohort Study.
    Guopan Yu, Yu Zhang, Sijian Yu, Zhao Yin, Guangyang Weng, Na Xu, Xin Du, Dongjun Lin, Jie Xiao, Zhiqiang Sun, Hongyu Zhang, Xinquan Liang, Ziwen Guo, Weihua Zhao, Min Dai, Zhiping Fan, Li Xuan, Hui Liu, Dan Xu, Jieyu Ye, Xuejie Jiang, Pengcheng Shi, Hua Jin, Qifa Liu.
       PURPOSE: We investigated whether homoharringtonine (HHT) added to venetoclax (VEN) plus azacitidine (VA) could improve outcomes and counteract the negative effects of genetic patterns in patients with relapsed/refractory acute myeloid leukemia (RR-AML).
    EXPERIMENTAL DESIGN: A multi-center, retrospective, cohort study of the response and genetic patterns of response to the VA plus HHT (VAH) versus the VA regimens as salvage treatment in patients with RR-AML was performed. The endpoints were the rates of composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), and relapse between VAH and VA groups.
    RESULTS: A total of 321 patients (VAH, n=172; VA, n=149) were analyzed. Compared to VA, VAH significantly improved the rates of CRc (44.3% vs. 66.3%, P<0.001), MRD-negativity (34.8% vs. 59.3%, P=0.002), prolonged OS (median: 15.1 months vs. not reached, P <0.001), and EFS (median: 3.8 vs. 13.0 months, P<0.001). VAH significantly mitigated the negative impact on VA efficacy of mutated FLT3-ITD/TKD, N/KRAS, and t(8;21)/AML1-ETO, as well as the relatively unfavorable effects of the TET2 and DNMT3A mutations. VAH significantly enhanced the response of patients with non-adverse European LeukemiaNet (ELN) risk, with a trend towards improved response in those with adverse ELN risk, complex karyotype, and DNMT3A+FLT3+NPM1+. The incidence of grade 3 or higher adverse events was comparable between the two groups.
    CONCLUSIONS: Our findings suggest the addition of HHT to VA might enhance response and mitigate the negative impact of certain genetic patterns in RR-AML while being well tolerated.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-1332
  24. Clin Lymphoma Myeloma Leuk. 2024 Oct 16. pii: S2152-2650(24)02359-0. [Epub ahead of print]
    Longitudinal Assessment of Transfusion Intensity in Patients With JAK Inhibitor-Naive or -Experienced Myelofibrosis Treated With Momelotinib.
    Claire N Harrison, Ruben Mesa, Moshe Talpaz, Vikas Gupta, Aaron T Gerds, Andrew Perkins, Yeow Tee Goh, Maria Laura Fox, Donal McLornan, Jeanne Palmer, Lynda Foltz, Alessandro Vannucchi, Steffen Koschmieder, Francesco Passamonti, Sung-Eun Lee, Catherine Ellis, Bryan Strouse, Francisco J Gonzalez Carreras, Stephen T Oh.
       PURPOSE: Anemia is a cardinal feature of myelofibrosis often managed with red blood cell (RBC) transfusions, which may contribute to negative prognostic, quality-of-life, and healthcare-related economic impacts. The Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib was approved for the treatment of patients with myelofibrosis and anemia based on clinical trial evidence of anemia, spleen, and symptom benefits illustrated using binomial response/nonresponse endpoints. In the present post hoc, descriptive analyses, the impact of momelotinib on RBC transfusion burden over time was further characterized across JAK inhibitor-naive and -experienced patients.
    METHODS: All RBC units transfused were collected during the baseline and 24-week treatment periods, initially in a single-arm phase 2 study as proof-of-concept analysis, and then versus comparators (ruxolitinib, best available therapy [BAT], and danazol) in the phase 3 SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM studies, respectively.
    RESULTS: In the phase 2 study, mean transfusion requirement changed by -1.5 units/28 days, with 85% of patients (35/41) achieving numeric transfusion reduction. Across SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM, mean transfusion requirements decreased with momelotinib (-0.1, -0.36, and -0.86 units/28 days), while mean requirements with ruxolitinib, BAT, and danazol changed by +0.39, 0, and ‒0.28 units/28 days, respectively. Overall, 87% (185/213), 77% (79/103), and 85% (110/130) of patients had improved or stable transfusion intensities with momelotinib versus 54% (117/216), 62% (32/52), and 63% (41/65) with ruxolitinib, BAT, and danazol.
    CONCLUSION: These novel time-dependent transfusion burden analyses demonstrate that momelotinib is associated with anemia-related benefits in most patients and greater transfusion burden reduction versus comparators.
    TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02515630, NCT01969838, NCT02101268, NCT04173494.
    Keywords:  Anemia; Hemoglobin; Janus kinase inhibitor; Myeloproliferative neoplasm; Red blood cell transfusion
    DOI:  https://doi.org/10.1016/j.clml.2024.10.001
  25. Blood. 2024 Nov 14. pii: blood.2024024248. [Epub ahead of print]
    Approaching a therapeutic inflection point for FLT3-mutated AML.
    Alexander E Perl.
      Combining FLT3 inhibitors with intensive chemotherapy and transplant has substantially improved AML outcomes, prompting a recent re-evaluation of FLT3-ITD's historically negative prognostic effect. Treatment approaches may soon undergo major changes as emerging data suggest maximal intensity does not benefit all patients and MRD potentially can guide several treatment choices. Finally, recent data also suggest FLT3 inhibitors could transform outcomes in patients unsuitable for intensive therapy. If confirmed, this has important implications for fit patients and could revolutionize the treatment paradigm.
    DOI:  https://doi.org/10.1182/blood.2024024248
  26. Leuk Lymphoma. 2024 Nov 13. 1-6
    Sustained benefits of imetelstat on patient-reported fatigue in patients with lower-risk myelodysplastic syndromes ineligible for, or relapsed/refractory to, erythropoiesis-stimulating agents and high transfusion burden in the phase 3 IMerge study.
    Mikkael A Sekeres, Valeria Santini, Maria Díez-Campelo, Rami S Komrokji, Pierre Fenaux, Michael R Savona, Yazan F Madanat, David Valcárcel-Ferreiras, Esther Natalie Oliva, Antoine Regnault, Kristin Creel, Nishan Sengupta, Souria Dougherty, Sheetal Shah, Libo Sun, Ying Wan, Shyamala Navada, Amer M Zeidan, Uwe Platzbecker.
      
    DOI:  https://doi.org/10.1080/10428194.2024.2426057
  27. J Clin Invest. 2024 Nov 12. pii: e182939. [Epub ahead of print]
    Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice.
    Wenli Liu, Brian D Hardaway, Eunyoung Kim, Jessica Pauli, Justus Leonard Wettich, Mustafa Yalcinkaya, Cheng-Chieh Hsu, Tong Xiao, Muredach P Reilly, Ira Tabas, Lars Maegdefessel, Kai Schlepckow, Haass Christian, Nan Wang, Alan R Tall.
      Clonal hematopoiesis (CH) increases inflammasome-linked atherosclerosis but the mechanisms by which CH mutant cells transmit inflammatory signals to non-mutant cells are largely unknown. To address this question we transplanted 1.5% Jak2VF bone marrow (BM) cells with 98.5% WT BM cells into hyperlipidemic Ldlr-/- mice. Low allele burden (LAB) mice showed accelerated atherosclerosis with increased features of plaque instability, decreased levels of macrophage phagocytic receptors MERTK and TREM2, and increased neutrophil extracellular traps (NETs). These changes were reversed when Jak2VF BM was transplanted with Il1r1-/- BM. LAB mice with non-cleavable MERTK in WT BM showed improvements in necrotic core and fibrous cap formation and reduced NETs. An agonistic TREM2 antibody (4D9) markedly increased fibrous caps in both control and LAB mice eliminating the difference between groups. Mechanistically, 4D9 increased TREM2+PDGFB+ macrophages and PDGF receptor-α positive fibroblast-like cells in the cap region. TREM2 and PDGFB mRNA levels were positively correlated in human carotid plaques and co-expressed in macrophages. In summary, low frequency Jak2VF mutations promote atherosclerosis via IL-1 signaling from Jak2VF to WT macrophages and neutrophils promoting cleavage of phagocytic receptors and features of plaque instability. Therapeutic approaches that stabilize MERTK or TREM2 could promote plaque stabilization especially in CH- and inflammasome-driven atherosclerosis.
    Keywords:  Atherosclerosis; Vascular biology
    DOI:  https://doi.org/10.1172/JCI182939
  28. Bone Marrow Transplant. 2024 Nov 12.
    Allogeneic hematopoietic cell transplantation for therapy-related myeloid neoplasms arising following treatment for multiple myeloma: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.
    Kavita Raj, Diderik-Jan Eikema, Sarah Lawless, Linda Koster, Desiree Kunadt, Nicolaus Kröger, Uwe Platzbecker, Matthias Stelljes, Wolfgang Bethge, Tobias Holderried, Renato Fanin, Robert Zeiser, Jürgen Kuball, Véronique Leblond, Emma Nicholson, Jakob Passweg, Victoria Potter, Jacques-Olivier Bay, Ali Bazarbachi, Lucía López Corral, Carmelo Gurnari, Christof Scheid, Joanna Drozd-Sokolowska, Treen Curly Morris, Patrick Hayden, Ibrahim Yakoub-Agha, Marie Robin, Donal P McLornan.
      Therapy-related myeloid neoplasms (t-MN) are a complication of multiple myeloma (MM) treatment. Our retrospective, EBMT registry study included 157 such patients allografted (allo-HCT) between 2006 and 2018. Most patients (130) had a prior autologous HCT. Fifty-seven (36.4%) were transplanted for t-AML and 100 (63.6%) for t-MDS. Median times from MM and t-MN diagnoses to allo-HCT were 72.6 (interquartile range (IQR), 46.1-102.9) and 6.4 (IQR, 3.9-9.4) months. Fifty-eight (38.4%) t-MN patients were in complete remission (CR) at allo-HCT predominantly conditioned with reduced intensity (70.3%). With a median follow-up of 64.9 (95% CI: 39-76) months, relapse incidence (RI) from MM at 1 and 5 years was 4% (0-10%) and 12% (2-22%), respectively, with few deaths (n = 3) only due to MM disease progression, whereas t-MN RI and non-relapse mortality (NRM) at 1 and 5 years were 35% (95% CI 28-43%) and 45% (95% CI: 36-53%) and 20% (95% CI 13-26%) and 31% (95% CI: 23-39%). Overall survival (OS) and progression-free survival (PFS) estimates at 1 and 5 years were 55% (95% CI: 47-63%) and 27% (95% CI: 19-35%) and 45% (95% CI 36-53%) and 24% (95% CI 16-32%). Older (>65 years) t-MN patients with high-risk cytogenetics do not benefit from allo-HCT.
    DOI:  https://doi.org/10.1038/s41409-024-02462-5
  29. Br J Haematol. 2024 Nov 13.
    Predicting therapy-related myeloid neoplasms after CAR-T with the Clonal Haematopoiesis Risk Score (CHRS).
    Eugenio Galli, Monica Rossi, Ilaria Pansini, Marcello Viscovo, Tanja Malara, Maria Colangelo, Eleonora Alma, Caterina Giovanna Valentini, Luciana Teofili, Stefan Hohaus, Simona Sica, Federica Sorà, Patrizia Chiusolo.
      The clonal haematopoiesis risk score (CHRS) was proposed to predict the rate of progression from clonal haemopoiesis of indeterminate potential (CHIP)/clonal cytopenia with unknown significance (CCUS) to myeloid neoplasms in the general population. CHRS encompasses the type and VAF of the mutation, the presence of a single DNMT3A mutation, cytopenia, age, red cell distribution width (RDW) and mean corpuscular volume (MCV). We studied clonal haematopoiesis in a cohort of 55 consecutive patients treated with CD19-directed CAR-T cells: CHIP and CCUS were present in 7% and 33% of patients before CAR-T. Three therapy-related myeloid neoplasms (t-MN) were observed after treatment with CAR-T (2 MDS and 1 AML). Only patients with an intermediate-high baseline CHRS developed a t-MN. Patients with an intermediate-high CHRS had more than a twofold increased risk of developing a t-MN within the first 9 months after CAR-T (odds ratio 2.89, 95% C.I. 1.98-4.19, p < 0.001). Overall, CHRS was able to predict the occurrence of t-MN after CAR-T with good specificity.
    DOI:  https://doi.org/10.1111/bjh.19905
  30. J Hematol Oncol. 2024 Nov 13. 17(1): 111
    Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD-positive AML.
    Jorge Cortes.
      Mutations in FMS-related receptor tyrosine kinase 3 (FLT3) are among the most common alterations in acute myeloid leukemia (AML), present in ≈30% of newly diagnosed AML cases. Internal tandem duplications (ITD) in FLT3 (FLT3-ITD) occur in ≈25% of newly diagnosed AML cases and are associated with unfavorable outcomes. Quizartinib (formerly AC220) is a novel, second-generation, highly potent, and selective type II FLT3 inhibitor. Quizartinib is approved in Japan as monotherapy for the treatment of adult patients with FLT3-ITD-positive relapsed/refractory (R/R) AML. Quizartinib is also approved in the United States, Japan, Europe, and United Kingdom in combination with chemotherapy during induction and consolidation, and as maintenance monotherapy (but, in the United States, not after allogeneic hematopoietic cell transplantation [allo-HCT]), for the treatment of adult patients with newly diagnosed FLT3-ITD-positive AML. In this review, we summarize preclinical studies that established quizartinib as a potent and selective type II FLT3 inhibitor as well as early and pivotal phase 3 clinical studies (QuANTUM-R and QuANTUM-First) that led to the approvals of quizartinib. We also summarize mechanisms of resistance to quizartinib along with its safety profile. Furthermore, we review the ongoing post hoc analyses of the QuANTUM-First data elucidating the impact of allo-HCT, the presence of measurable residual disease, and number and length of ITD on the clinical outcomes of quizartinib. We also describe the impact of quizartinib on patient-reported outcomes. Finally, we highlight some of the ongoing studies that test quizartinib in patients with FLT3-ITD-positive AML, patients with FLT3-ITD-negative AML, in both the first-line and R/R settings, in patients fit or unfit for intensive chemotherapy, including studies for quizartinib-based combination with other compounds such as decitabine and venetoclax. Future research should aim to further optimize the clinical value of quizartinib and explore its use in additional clinical settings, which could be achieved by testing quizartinib with other drugs, better characterization of the mechanisms of resistance, identification of the role of quizartinib as a maintenance therapy after allo-HCT, and investigating quizartinib in patients with FLT3-ITD-negative AML.
    Keywords:   FLT3-ITD; AML; QuANTUM-First; QuANTUM-R; Quizartinib
    DOI:  https://doi.org/10.1186/s13045-024-01617-7
  31. Haematologica. 2024 Nov 14.
    Germline genetics, disease, and exposure to medication influence longitudinal dynamics of clonal hematopoiesis.
    Taralynn Mack, Yash Pershad, Caitlyn Vlasschaert, Cosmin A Bejan, Jonathan Brett Heimlich, Yajing Li, Nicole A Mickels, Joseph C Van Amburg, Jessica Ulloa, Alexander J Silver, Leo Y Luo, Angela Jones, Paul Brent Ferrell, Ashwin Kishtagari, Yaomin Xu, Michael R Savona, Alexander G Bick.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.286513
  32. Blood. 2024 Nov 07. 144(19): 1987-1992
    Perspectives on drug development in chronic myelomonocytic leukemia: changing the paradigm.
    Anthony M Hunter, Mrinal M Patnaik, Raphael Itzykson, Ruben Mesa, Chatchada Karanes, Yanxia Li, R Angelo de Claro, Kelly J Norsworthy, Marc Theoret, Elizabeth Pulte, Eric Padron.
       ABSTRACT: Drug development for chronic myelomonocytic leukemia (CMML) has failed to parallel the recent success observed in related myeloid neoplasms. To address these shortcomings, the US Food and Drug Administration (FDA) held a "Mini-symposium on CMML: Current State of the Art and Trial Design" in September 2023. This symposium brought together a panel of key FDA regulators and academic experts in CMML drug development to discuss challenges and provide perspectives on future drug development for this disease. The panel explored unique challenges that underlie the lack of therapeutic advances in CMML to date and discussed relevant topics such as clinical trial design, study end points, and key regulatory considerations. This article summarizes the key points of discussion from this symposium to facilitate advancements in the field.
    DOI:  https://doi.org/10.1182/blood.2024025648
  33. Nat Commun. 2024 Nov 13. 15(1): 9820
    Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation.
    Yifan Chen, Miao Xian, Wenwen Ying, Jiayi Liu, Shaowei Bing, Xiaomin Wang, Jiayi Yu, Xiaojun Xu, Senfeng Xiang, Xuejing Shao, Ji Cao, Qiaojun He, Bo Yang, Meidan Ying.
      Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct metabolic processes. Here, we identify succinate dehydrogenase (SDH) deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to various anti-cancer therapies. Mechanistically, succinate promotes the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function is mediated by succinate-triggered upregulation of ubiquitin-conjugating enzyme E2M (UBC12) phosphorylation, which impairs its E2 function in cullins neddylation. Notably, decreasing succinate by fludarabine can restore the sensitivity of anti-cancer drugs in SDH-deficient AML. Together, we uncover the function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.
    DOI:  https://doi.org/10.1038/s41467-024-53398-9
  34. Blood Adv. 2024 Nov 13. pii: bloodadvances.2024014984. [Epub ahead of print]
    Clonal hematopoiesis in patients with autoimmune thrombocytopenia: an international multicenter study.
    Bruno Fattizzo, Alfredo Marchetti, Alessandro Bosi, Carmelo Gurnari, Juri Alessandro Giannotta, Giacinto Luca Pedone, Elena Rossi, Valentina Carrai, Andrea Guido, Filippo Brioschi, Monica Carpenedo, Monica Crugnola, Domenica Caramazza, Livia Leuzzi, Monia Marchetti, Gabriele Merati, Simona Malato, Fabrizio Vianello, Andrea Patriarca, Hussein Awada, Marta Bortolotti, Marta Canzi, Niccolò Bolli, Marco Capecchi, Frederick Chen, Andrea Artoni, Jaroslaw P Maciejewski, Wilma Barcellini.
      Diagnostic boundaries between immune thrombocytopenia (ITP) and other thrombocytopenic states such as thrombocytopenic myelodysplastic syndromes, may be difficult to establish, and the detection of somatic mutations by next generation sequencing (NGS) may be of aid. Here we aimed at characterizing the prevalence and clinical significance of clonal hematopoiesis in ITP. In this multicentric retrospective observational study we enrolled 167 adult ITP patients, followed at 13 centers in Italy, UK, and USA. Patients underwent NGS evaluation after a median of 3.6 years from ITP onset and 83% had received at least one therapy line, median 2 (0-9) lines; 51 out of 167 patients had at least one mutation (30%). After exclusion of germline variants and polymorphisms, 18.5% (31/167) were defined as having clonal hemopoiesis. Most commonly mutated genes were TET2, DNMT3A, SRSF2, and ASXL1 (median VAF 29%); 19 of 31 subjects (68%) had high-risk variants, and 8 multiple mutations. Mutated patients were more frequently elderly males and showed a shorter time from first to second line therapy, particularly with TPO-RA. Additionally, clonal hematopoiesis was associated with increased thrombotic risk (26% vs 8% in NGS-negative cases, p=0.01), independently from TPO-RA exposure, though with an age effect. These data demonstrated the prevalence of clonal hematopoiesis in 18% of adult ITP patients, being associated with older age, relapsed/refractory disease, and high risk of thrombotic complications.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014984
  35. Br J Haematol. 2024 Nov 14.
    Dissecting the genomic traits and clinical course of secondary myelodysplastic syndrome following aplastic anaemia: A milestone.
    Carmelo Gurnari, Valeria Visconte.
      Dissecting the genomic traits and clinical course of secondary myelodysplastic syndrome following aplastic anaemia is a milestone. The report by Li and colleagues investigates determinants of evolution to myelodysplastic syndrome and acute myeloid leukaemia in patients with aplastic anaemia and paroxysmal nocturnal haemoglobinuria with a specific focus on post-transplant outcomes. Commentary on: Li et al. Clinical and genetic profiles and outcomes of allogeneic haematopoietic stem cell transplantation in secondary myelodysplastic syndrome following aplastic anaemia. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19855.
    Keywords:  aplastic anemia; genomic traits; secondary myelodysplastic syndrome
    DOI:  https://doi.org/10.1111/bjh.19898
  36. Leuk Res. 2024 Nov 06. pii: S0145-2126(24)00178-4. [Epub ahead of print]147 107612
    Causes of death in patients with myelodysplastic syndrome and spliceosome mutations.
    Panayiotis D Kontoyiannis, Arjun S Peddireddy, Koji Sasaki, Kelly Chien, Jayastu Senapati, Guillermo Montalban-Bravo, Courtney DiNardo, Gautam Borthakur, Rashmi Kanagal-Shamanna, Carlos Bueso-Ramos, Sherry Pierce, Hagop Kantarjian, Guillermo Garcia-Manero, Samuel Urrutia.
      
    Keywords:  Mortality; Myelodysplastic syndrome; Spliceosome mutations
    DOI:  https://doi.org/10.1016/j.leukres.2024.107612
  37. Cell Stem Cell. 2024 Nov 08. pii: S1934-5909(24)00375-8. [Epub ahead of print]
    Post-transplant G-CSF impedes engraftment of gene-edited human hematopoietic stem cells by exacerbating p53-mediated DNA damage response.
    Daisuke Araki, Vicky Chen, Neelam Redekar, Christi Salisbury-Ruf, Yan Luo, Poching Liu, Yuesheng Li, Richard H Smith, Pradeep Dagur, Christian Combs, Andre Larochelle.
      Granulocyte-colony-stimulating factor (G-CSF) is commonly used to accelerate recovery from neutropenia following chemotherapy and autologous transplantation of hematopoietic stem and progenitor cells (HSPCs) for malignant disorders. However, its utility after ex vivo gene therapy in human HSPCs remains unexplored. We show that administering G-CSF from day 1 to 14 post-transplant impedes engraftment of CRISPR-Cas9 gene-edited human HSPCs in murine xenograft models. G-CSF affects gene-edited HSPCs through a cell-intrinsic mechanism, causing proliferative stress and amplifying the early p53-mediated DNA damage response triggered by Cas9-mediated DNA double-strand breaks. This underscores a threshold mechanism where p53 activation must reach a critical level to impair cellular function. Transiently inhibiting p53 or delaying the initiation of G-CSF treatment to day 5 post-transplant attenuates its negative impact on gene-edited HSPCs. The potential for increased HSPC toxicity associated with post-transplant G-CSF administration in CRISPR-Cas9 autologous HSPC gene therapy warrants consideration in clinical trials.
    Keywords:  CRISPR-Cas9; DNA damage response; DNA double-stranded breaks; G-CSF; apoptosis; cell-cycle arrest; gene editing; granulocyte colony stimulating factor; hematopoietic stem and progenitor cells; p53 pathway
    DOI:  https://doi.org/10.1016/j.stem.2024.10.013
  38. Eur J Haematol. 2024 Nov 13.
    Unveiling the Genetic and Clinical Differences of Acute Myeloid Leukemia (AML) in Obese Patients.
    Fevzi F Yalniz, Anna Johnson, Yanal Alnimer, Zena Chahine, Trevor Morris, Rina Yadav, Hiffsa Taj, Chaitanya Iragavarapu, Reinhold Munker, Gregory Monohan, Sainan Wai, Shulin Zhang, Sahar Nozad, Ayman Qasrawi.
       BACKGROUND: The molecular architecture of acute myeloid leukemia (AML) is heterogeneous. Obesity has been identified as a risk factor for the development of AML. There remains a scarcity of data elucidating the specific genetic profile of AML in obese patients.
    METHODS: We conducted a review of adult patients treated at our institution for newly diagnosed AML from January 1, 2017, to January 1, 2023. Obesity is defined as BMI > 30 kg/m2. Demographic, clinical, laboratory, and pathologic data were collected retrospectively. The primary outcome of interest was the molecular features of obese compared to non-obese AML patients. The secondary outcome was overall survival (OS). Inverse probability of treatment weights (IPTW) used to balance both groups on several confounding variables.
    RESULTS: A total of 185 patients were included in the analysis. 90 (49%) were obese. Compared with non-obese patients, obese patients were younger and more likely to be females (55 vs. 63, p = 0.04, 55% vs. 38%, p value, p = 0.02, respectively). After matching on age, gender, and ethnicity, obese patients exhibit lower rates of total number of gene mutations (median 2.7 vs. 3.2, p = 0.05), significantly lower rates of mutations in transcriptional factor genes (15.7% vs. 33.2%, p = 0.01), and near-significant in spliceosome genes (12% vs. 22.3%, p = 0.08), and higher rates of NPM1 mutation (23.3% vs. 12.6%, p = 0.08). Median OS was not significantly different in the matched cohort.
    CONCLUSIONS: The molecular features of obese AML patients significantly differ from non-obese counterparts. These findings suggest distinct underlying mechanisms in leukemogenesis in obese patients.
    Keywords:  acute myeloid leukemia; molecular architecture; obesity
    DOI:  https://doi.org/10.1111/ejh.14338
  39. J Clin Oncol. 2024 Nov 07. JCO2401265
    Revumenib Revises the Treatment Landscape for KMT2A-r Leukemia.
    Emily B Heikamp, Scott A Armstrong.
      
    DOI:  https://doi.org/10.1200/JCO-24-01265
  40. Leuk Lymphoma. 2024 Nov 14. 1-19
    When and how to transplant in myelofibrosis - recent trends.
    Naman Sharma, Giuseppe G Loscocco, Naseema Gangat, Paola Guglielmelli, Animesh Pardanani, Alessandro M Vannucchi, Hassan B Alkhateeb, Ayalew Tefferi, Vincent T Ho.
      Allogeneic hematopoietic stem cell transplantation (AHSCT) is currently the only treatment modality that is capable of curing myelofibrosis (MF). Although outcomes of AHSCT have improved vastly in recent years owing to advancements in HLA typing, conditioning regimens, and supportive care, it remains a procedure with a considerable risk in MF patients due to conditioning regimen related toxicity, higher rates of graft failure, infections, and graft versus host disease (GVHD). Recent progress in the treatment and prevention of GVHD with post-transplant cyclophosphamide has also rendered transplantation from alternative donors feasible and safer, thus improving access to patients without HLA-identical donors. Accordingly, all patients with intermediate or high-risk MF today should be referred for potential transplant evaluation to consider the pros and cons of an early versus a delayed transplant strategy. Individual risk assessment in MF is best facilitated by contemporary prognostic models that incorporate both clinical and genetic risk factors. The current review highlights new information regarding risk stratification in MF, anchored by practical algorithms that facilitate patient selection for specific treatment actions, including AHSCT.
    Keywords:  HCT; HSCT; Myelofibrosis; allogeneic stem cell; transplantation
    DOI:  https://doi.org/10.1080/10428194.2024.2422835
  41. Science. 2024 Nov 15. 386(6723): eadh9215
    A glutamine metabolic switch supports erythropoiesis.
    Junhua Lyu, Zhimin Gu, Yuannyu Zhang, Hieu S Vu, Christophe Lechauve, Feng Cai, Hui Cao, Julia Keith, Valentina Brancaleoni, Francesca Granata, Irene Motta, Maria Domenica Cappellini, Lily Jun-Shen Huang, Ralph J DeBerardinis, Mitchell J Weiss, Min Ni, Jian Xu.
      Metabolic requirements vary during development, and our understanding of how metabolic activity influences cell specialization is incomplete. Here, we describe a switch from glutamine catabolism to synthesis required for erythroid cell maturation. Glutamine synthetase (GS), one of the oldest functioning genes in evolution, is activated during erythroid maturation to detoxify ammonium generated from heme biosynthesis, which is up-regulated to support hemoglobin production. Loss of GS in mouse erythroid precursors caused ammonium accumulation and oxidative stress, impairing erythroid maturation and recovery from anemia. In β-thalassemia, GS activity is inhibited by protein oxidation, leading to glutamate and ammonium accumulation, whereas enhancing GS activity alleviates the metabolic and pathological defects. Our findings identify an evolutionarily conserved metabolic adaptation that could potentially be leveraged to treat common red blood cell disorders.
    DOI:  https://doi.org/10.1126/science.adh9215
  42. Blood. 2024 Nov 14. pii: blood.2024025627. [Epub ahead of print]
    How I approach the treatment of thrombotic complications in patients with myeloproliferative neoplasms.
    Alexandre Guy, Pierre-Emmanuel Morange, Chloé James.
      Arterial and venous thromboses are the most significant complications in patients with myeloproliferative neoplasms (MPN), with the primary treatment goal being thrombotic risk reduction. In MPN with no history of thrombosis, primary prevention mainly involves the use of aspirin and cytoreduction is added in high-risk patients. However, thrombotic complications can unveil an MPN in approximately 20% of cases, necessitating the initiation of both antithrombotic therapy for the thrombosis and cytoreductive treatment for the MPN. The duration of anticoagulant therapy following an initial venous thromboembolic event (VTE) is subject to discussion. Furthermore, the occurrence of a thrombotic complication in patients with a known diagnosis of MPN prompts a reconsideration of both antithrombotic and hematological management. This review employs case-based discussions to explore the management of thrombotic complications in MPN patients. It addresses the nature and duration of antithrombotic treatments, as well as the approach to cytoreduction. Special attention is given to the place of direct oral anticoagulants and to the management of MPN patients with splanchnic vein thrombosis, which is disproportionately common in this group.
    DOI:  https://doi.org/10.1182/blood.2024025627
  43. Blood. 2024 Nov 14. pii: blood.2024025702. [Epub ahead of print]
    Imetelstat: A new addition to the Therapeutic Landscape of Lower-Risk MDS.
    Yasmin Abaza, Amy E DeZern.
      Anemia is the most prevalent cytopenia in lower-risk myelodysplastic neoplasms (LR-MDS). There is a paucity of drugs for red blood cell transfusion dependence (RBC-TD) and erythropoiesis-stimulating agents (ESAs) are the mainstay of therapy in many centers. Imetelstat, an oligonucleotide telomerase inhibitor, was recently approved for RBC-TD LR-MDS adults who are ineligible or failed prior ESA therapy. While not yet approved worldwide, here, we spotlight the current data for imetelstat and where it may fit in the therapeutic landscape of LR-MDS.
    DOI:  https://doi.org/10.1182/blood.2024025702
  44. Nat Commun. 2024 Nov 14. 15(1): 9853
    Longitudinal ultra-sensitive mutation burden sequencing for precise minimal residual disease assessment in AML.
    Yitian Wu, Shuai Zhang, Ru Feng, Kangming Xiao, Ting Wang, Jiefei Bai, Xiaoyu Zhou, Yuji Wang, Peng Dai, Hui Liu, Lucia Ruojia Wu.
      Relapse is one of the major challenges in clinical treatment of acute myeloid leukemia (AML). Though minimal residual disease (MRD) monitoring plays a crucial role in quantitative assessment of the disease, molecular MRD analysis has been mainly limited to patients diagnosed with gene fusions and NPM1 mutations. Here, we report a longitudinal ultra-sensitive mutation burden (UMB) monitoring strategy for accurate MRD analysis in AML patients regardless of genetic abnormality types. Using a Quantitative Blocker Displacement Amplification (QBDA) sequencing panel with limit of detection below 0.01% variant allele frequency (VAF), a hazard ratio of 14.8 (p < 0.001) is observed in cumulative incidence of relapse analysis of 20 patients with ≥ 2 samples during complete remission (CR). The ROC area under curve (AUC) is 0.98 when predicting relapse within 30 weeks of CR timepoint 2 (N = 20). Furthermore, we demonstrate quantitating VAF below 0.01% is essential for accurate relapse prediction.
    DOI:  https://doi.org/10.1038/s41467-024-54254-6
  45. Blood. 2024 Nov 14. 144(20): 2069-2070
    Ruxolitinib REACHes FOR children with GVHD.
    Tomomi Toubai.
      
    DOI:  https://doi.org/10.1182/blood.2024026120
  46. Transplant Cell Ther. 2024 Nov 13. pii: S2666-6367(24)00759-0. [Epub ahead of print]
    Early mixed donor chimerism is a strong negative prognostic indicator in allogeneic stem cell transplant for AML and MDS.
    Michael Radford, Alejandro Garcia-Horton, Rohail Badami, Elaine Jin, Nida Usmani, Daria Grafodatskaya, Elizabeth McCready, Dina Khalaf, Irwin Walker, Brian Leber, Kylie Lepic, Gregory Pond, Tobias Berg.
       BACKGROUND: Allogeneic bone marrow transplantation remains the most potent curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) due to the graft-versus-tumor effect provided by donor cells. Donor chimerism is utilized early after transplantation to evaluate engraftment and to monitor the persistence of donor hematopoiesis.
    OBJECTIVE(S): Literature is conflicting regarding to the prognostic utility of early mixed donor chimerism, chimerism kinetic patterns as well as factors associated with it and we sought to clarify this uncertainty.
    STUDY DESIGN: In this single-centre retrospective analysis, 141 adults aged 18 years of age or older with AML (n=104) and MDS (n=37) who received their first transplant from HLA matched related, matched unrelated or mismatched related (haploidentical) donors between 2016 and 2022 and had at least day 30 chimerism measured were included. Approximately 30% received post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis and 67% of subjects received reduced-intensity conditioning. Chimerism was measured using STR-PCR from unfractionated peripheral blood mononuclear cells (whole blood; WB) and CD3+ (T cell; TC) compartment at each time point. Complete donor chimerism was defined as ≥95% whereas <95% defined as mixed. Competing risk analysis was used to estimate cumulative incidence of relapse with kinetic calculations completed using an increment factor. Kaplan-Meier was used for overall survival (OS) and relapse-free survival (RFS). Cox proportional hazards regression was used to explore prognostic factors for OS and RFS.
    RESULTS: Both day 30 mixed WB and TC donor chimerism were individually associated with an increased risk of relapse and worse overall and relapse-free survival at days 30, 60 and 90 post-transplant. Day 30 mixed WB was more specific for relapse (86%), while mixed TC was more sensitive (67%). Complete day 30 chimerism had a negative predictive value of 63% and 70% and positive predictive value of 57% and 67% for WB and TC, respectively. Day 30 WB and TC donor chimerism of <88.92% and 89.29% had specificities of 79.17% and 82.19% although sensitivities only approximated 50%. Evaluating the kinetics of chimerism over the first 90 days provided additional information for prognosticating relapse than absolute chimerism values at individual time points in both WB day 30 to 90 [HR, 1.75 (95% CI, 1.04-2.94); p<0.035] and TC day 60 to 90 [HR, 1.32 (95% CI, 1.03, 1.69); p<0.29]. Twice as many patients with complete chimerism developed acute GVHD compared to those with mixed chimerism. Factors that were found to be associated with day 30 mixed TC chimerism were donor source, ATG GVHD prophylaxis, myeloablative conditioning and female sex, while only donor source was associated with mixed WB.
    CONCLUSIONS: Both TC and WB day 30 mixed chimerism were associated with an increased risk of relapse. Early mixed WB and TC chimerism is strongly associated with a worse overall and relapse-free survival. The serial measurement of chimerism early post-transplant for monitoring chimerism kinetics provides additional prognostic information beyond the absolute donor chimerism value at a single time point. Haploidentical stem cell transplants were associated with a lower likelihood of mixed chimerism than other donor sources.
    Keywords:  Disease Relapse; Hematopoietic Stem Cell Transplantation; STR-PCR
    DOI:  https://doi.org/10.1016/j.jtct.2024.11.006
  47. N Engl J Med. 2024 Nov 14.
    Inebilizumab for Treatment of IgG4-Related Disease.
    MITIGATE Trial Investigators
       BACKGROUND: IgG4-related disease is a multiorgan, relapsing, fibroinflammatory, immune-mediated disorder with no approved therapy. Inebilizumab targets and depletes CD19+ B cells and may be effective for treating patients with IgG4-related disease.
    METHODS: In this phase 3, multicenter, double-blind, randomized, placebo-controlled trial, adults with active IgG4-related disease underwent randomization in a 1:1 ratio to receive inebilizumab (300-mg intravenous infusions on days 1 and 15 and week 26) or placebo for a 52-week treatment period. Participants in both groups received identical glucocorticoid tapers. Glucocorticoids were allowed to treat disease flares, but background immunosuppressants were not permitted. The primary end point was the first treated, adjudicated disease flare during the treatment period, assessed in a time-to-event analysis. Key secondary end points were the annualized flare rate and treatment-free and glucocorticoid-free complete remission.
    RESULTS: A total of 135 participants with IgG4-related disease underwent randomization: 68 participants were assigned to receive inebilizumab and 67 were assigned to receive placebo. Treatment with inebilizumab reduced flare risk; 7 participants (10%) in the inebilizumab group had at least one flare, as compared with 40 participants (60%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.06 to 0.28; P<0.001). The annualized flare rate was lower with inebilizumab than with placebo (rate ratio, 0.14; 95% CI, 0.06 to 0.31; P<0.001). More participants in the inebilizumab group than in the placebo group had flare-free, treatment-free complete remission (odds ratio, 4.68; 95% CI, 2.21 to 9.91; P<0.001) and flare-free, glucocorticoid-free complete remission (odds ratio, 4.96; 95% CI, 2.34 to 10.52; P<0.001). Serious adverse events occurred during the treatment period in 12 of the participants (18%) who received inebilizumab and 6 of the participants (9%) who received placebo.
    CONCLUSIONS: Inebilizumab reduced the risk of flares of IgG4-related disease and increased the likelihood of flare-free complete remission at 1 year, confirming the role of CD19-targeted B-cell depletion as a potential treatment for IgG4-related disease. (Funded by Amgen; MITIGATE ClinicalTrials.gov number, NCT04540497.).
    DOI:  https://doi.org/10.1056/NEJMoa2409712
  48. Leukemia. 2024 Nov 08.
    Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS.
    Peng Li, F N U Alnoor, Wei Xie, Margaret Williams, Julie Feusier, Yi Ding, Xiangrong Zhao, Gang Zheng, Chen Zhao, Arthur W Zieske, Youli Zu, Philipp W Raess, Srinivas Tantravahi, Afaf Osman, Ami B Patel, Tsewang Tashi, Jay L Patel, Anna P Matynia, Madhu P Menon, Rodney R Miles, Jeffrey R Jacobsen, Tracy I George, Douglas W Sborov, Philippe Szankasi, Paul Rindler, Devin Close, Robert S Ohgami.
      
    DOI:  https://doi.org/10.1038/s41375-024-02397-2
  49. Cell Rep. 2024 Nov 12. pii: S2211-1247(24)01322-6. [Epub ahead of print]43(11): 114971
    PP2A licenses the FANCD2/FANCI complex for chromosome loading.
    Di Yang, Fengxiang Bai, David Lopez Martinez, Hannan Xu, Ai Johjima-Murata, Lily Jiaqi Cao, Martin A Cohn.
      The Fanconi anemia (FA) pathway removes interstrand crosslinks (ICLs) between the Watson-Crick strands of the DNA double helix in humans. Central to the pathway is the FANCD2/FANCI complex, which must be loaded onto chromosomes. Here, we report the identification of a PP2A phosphatase complex, which specifically dephosphorylates an inhibitory cluster in FANCD2, thereby licensing its loading in response to DNA damage. We show that PP2A is required for normal monoubiquitination of the FANCD2/FANCI complex and for its loading onto chromosomes. We have fully reconstituted a coupled dephosphorylation-ubiquitination reaction in vitro using a highly purified PP2A complex. Using super-resolution live-cell single-molecule tracking, we show how PP2A switches on the FA pathway in response to ICLs and that cells are sensitive to ICL-forming drugs in the absence of PP2A. Our work uncovers a mechanism where PP2A facilitates the activation of the FA pathway by licensing chromosome loading of the FANCD2/FANCI complex.
    Keywords:  CP: Molecular biology; DNA interstrand crosslink repair; FANCD2; FANCD2/FANCI complex; Fanconi anemia; ICL repair; PP2A; dephosphorylation; genome stability; phosphorylation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114971
  50. Blood Adv. 2024 Nov 08. pii: bloodadvances.2024013968. [Epub ahead of print]
    Increased exercise tolerance in humanized G6PD deficient mice.
    Francesca I Cendali, Christina Lisk, Monika Dzieciatkowska, Ian S LaCroix, Julie A Reisz, Julie Harral, Daniel Stephenson, Ariel M Hay, Eric Wartchow, Anza Darehshouri, Karolina Dziewulska, Paul W Buehler, Philip J Norris, Xutao Deng, Michael P Busch, Eric J Earley, Grier P Page, Kirk C Hansen, James C Zimring, David Irwin, Travis Nemkov, Angelo D'Alessandro.
      Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects 500 million people globally, impacting red blood cell (RBC) antioxidant pathways and increasing susceptibility to hemolysis under oxidative stress. Despite the systemic generation of reactive oxygen species during exercise, the effects of exercise on individuals with G6PD deficiency remain poorly understood This study utilized humanized mouse models expressing the G6PD Mediterranean variant (S188F, with 10% enzymatic activity) to investigate exercise performance and molecular outcomes. Surprisingly, despite decreased enzyme activity, G6PD-deficient mice have faster critical speed (CS) compared to mice expressing human canonical G6PD. Post-exercise, deficient mice did not exhibit differences in RBC morphology or hemolysis, but had improved cardiac function, including cardiac output, stroke volume, sarcomere length and mitochondrial content. Proteomics analyses of cardiac and skeletal muscles (gastrocnemius, soleus) from G6PD deficient compared to sufficient mice revealed improvements in mitochondrial function and increased protein turnover via ubiquitination, especially for mitochondrial and structural myofibrillar proteins. Mass spectrometry-based metabolomics revealed alterations in energy metabolism and fatty acid oxidation. These findings challenge the traditional assumptions regarding hemolytic risk during exercise in G6PD deficiency, suggesting a potential metabolic advantage in exercise performance for individuals carrying non-canonical G6PD variants.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013968
  51. Nature. 2024 Nov 13.
    Adult skull bone marrow is an expanding and resilient haematopoietic reservoir.
    Bong Ihn Koh, Vishal Mohanakrishnan, Hyun-Woo Jeong, Hongryeol Park, Kai Kruse, Young Jun Choi, Melina Nieminen-Kelhä, Rahul Kumar, Raquel S Pereira, Susanne Adams, Hyuek Jong Lee, M Gabriele Bixel, Peter Vajkoczy, Daniela S Krause, Ralf H Adams.
      The bone marrow microenvironment is a critical regulator of haematopoietic stem cell self-renewal and fate1. Although it is appreciated that ageing, chronic inflammation and other insults compromise bone marrow function and thereby negatively affect haematopoiesis2, it is not known whether different bone compartments exhibit distinct microenvironmental properties and functional resilience. Here we use imaging, pharmacological approaches and mouse genetics to uncover specialized properties of bone marrow in adult and ageing skull. Specifically, we show that the skull bone marrow undergoes lifelong expansion involving vascular growth, which results in an increasing contribution to total haematopoietic output. Furthermore, skull is largely protected against major hallmarks of ageing, including upregulation of pro-inflammatory cytokines, adipogenesis and loss of vascular integrity. Conspicuous rapid and dynamic changes to the skull vasculature and bone marrow are induced by physiological alterations, namely pregnancy, but also pathological challenges, such as stroke and experimental chronic myeloid leukaemia. These responses are highly distinct from femur, the most extensively studied bone marrow compartment. We propose that skull harbours a protected and dynamically expanding bone marrow microenvironment, which is relevant for experimental studies and, potentially, for clinical treatments in humans.
    DOI:  https://doi.org/10.1038/s41586-024-08163-9
  52. Cell Metab. 2024 Nov 13. pii: S1550-4131(24)00412-1. [Epub ahead of print]
    Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis.
    Jivani M Gengatharan, Michal K Handzlik, Zoya Y Chih, Maureen L Ruchhoeft, Patrick Secrest, Ethan L Ashley, Courtney R Green, Martina Wallace, Philip L S M Gordts, Christian M Metallo.
      Dietary fat drives the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), particularly through circulating cholesterol and triglyceride-rich lipoprotein remnants. Industrially produced trans-unsaturated fatty acids (TFAs) incorporated into food supplies significantly promote ASCVD. However, the molecular trafficking of TFAs responsible for this association is not well understood. Here, we demonstrate that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT) and secreted from cells in vitro. Administering high-fat diets (HFDs) enriched in TFAs to Ldlr-/- mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a cis-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of SPTLC2 versus SPTLC3 subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.
    Keywords:  SPTLC3; TRL remnant; VLDL; atherosclerosis; lipoprotein; monounsaturated fatty acid; myriocin; sphingolipid; sphingomyelin; trans fatty acid
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.016
  53. Leukemia. 2024 Nov 11.
    Endothelial heterogeneity in bone marrow: insights across development, adult life and leukemia.
    I L Boueya, L Sandhow, J R P Albuquerque, R Znaidi, D Passaro.
      The central role of the endothelial microenvironment in orchestrating bone marrow (BM) homeostasis and hematopoietic support has been confirmed at various developmental stages and in adult life. The BM vasculature is crucial in mediating communication between BM parenchyma and circulating blood, displaying remarkable heterogeneity in structure and function. While vascular cell diversity in other tissues has long been recognized, the molecular basis of this phenomenon in BM is just now emerging. Over the past decade, single-cell approaches and microscopic observations have expanded our understanding of BM vasculature. While solely characterized for their paracrine properties in the past, recent advances have revolutionized our perception of endothelial function, revealing distinct anatomical locations associated with diverse endothelial cell states. The identification of phenotypic differences between normal and pathological conditions has therefore deepened our understanding of vascular dynamics and their impact on hematopoiesis in health and disease. In this review, we highlight key milestones and recent advances in understanding vascular heterogeneity within BM microenvironment during development, adulthood and aging. We also explore how leukemia affects this heterogeneity and how we can take this knowledge forward to improve clinical practices. By synthesizing existing literature, we aim to address unresolved questions and outline future research directions.
    DOI:  https://doi.org/10.1038/s41375-024-02453-x
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