bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024–05–12
35 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease.
  2. Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.
  3. Mapping genotypes to chromatin accessibility profiles in single cells.
  4. AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML.
  5. A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
  6. The Menin story in acute myeloid leukaemia-The road to success.
  7. PIKing the right target in AML.
  8. A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
  9. A chemically adjustable BMP6-IL6 axis in mesenchymal stem cells drives acute myeloid leukemia cell differentiation.
  10. Safety and tolerability of AMG 330 in adults with relapsed/refractory AML: a phase 1a dose-escalation study.
  11. Targetable leukaemia dependency on noncanonical PI3Kγ signalling.
  12. Cre recombinase promotes leukemogenesis in the presence of both homozygous and heterozygous FLT3-ITD.
  13. Complete Remission with Partial Hematological Recovery as a Palliative Endpoint for Treatment of Acute Myeloid Leukemia.
  14. Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes.
  15. Advances in the management of higher-risk myelodysplastic syndromes: future prospects.
  16. Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.
  17. Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.
  18. Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9-dependent AML.
  19. Decitabine in Older Patients with AML: Quality of Life Results of the EORTC-GIMEMA-GMDS-SG Randomized Phase III Trial.
  20. Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging.
  21. Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia: a multicenter, randomized, open-label, phase 3 trial.
  22. Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis.
  23. Building bones for blood and beyond: the growing field of bone marrow niche model development.
  24. Enigmatic missense mutations can cause disease via creation of de novo nuclear export signals.
  25. Favorable outcomes in MDS and oligoblastic AML-MR after reduced-intensity conditioning allogeneic bone marrow transplantation with post-transplantation cyclophosphamide.
  26. Inducible CXCL12/CXCR4-dependent extramedullary hematopoietic niches in the adrenal gland.
  27. Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.
  28. Management of hyperleukocytosis in pediatric acute myeloid leukemia using immediate chemotherapy without leukapheresis: results from the NOPHO-DBH AML 2012 Protocol.
  29. Does IPSS-R down staging before transplantation improve the prognosis of patients with Myelodysplastic neoplasms?
  30. A case of familial donor-derived acute myeloid leukemia with underlying pre-leukemic mutations.
  31. Determinants of mosaic chromosomal alteration fitness.
  32. Transplant in AML: just follow the NPM1 guide!
  33. The intrinsic substrate specificity of the human tyrosine kinome.
  34. The insertion/deletion polymorphism rs201494641 at ITGA9 influences blood CD34+ cell levels by altering ZNF384 binding.
  35. Clinical characteristics of acute myeloid leukaemia patients with a large number of azurophilic granules: A single-centre retrospective study.
  1. Br J Haematol. 2024 May 09.
    Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease.
    Wei-Ying Jen, Hagop Kantarjian, Tapan M Kadia, Courtney D DiNardo, Ghayas C Issa, Nicholas J Short, Musa Yilmaz, Gautam Borthakur, Farhad Ravandi, Naval G Daver.
      The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation-targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A-rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision-making in both intensive and low-intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on-label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.
    Keywords:  acute myeloid leukaemia; novel agents; novel combinations; targeted treatment
    DOI:  https://doi.org/10.1111/bjh.19519
  2. Cancer Discov. 2024 May 09.
    Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.
    Santiago Demajo, Joan Enric Ramis-Zaldivar, Ferran Muinos, Miguel L Grau, Maria Andrianova, Nuria Lopez-Bigas, Abel Gonzalez-Perez.
      Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking. Here, we trained machine-learning models for 12 of the most recurrent CH genes to identify their driver mutations. These models outperform expert-curated rules based on prior knowledge of the function of these genes. Moreover, their application to identify CH driver mutations across almost half a million donors of the UK Biobank reproduces known associations between CH driver mutations and age, and the prevalence of several diseases and conditions. We thus propose that these models support the accurate identification of CH across healthy individuals.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1416
  3. Nature. 2024 May 08.
    Mapping genotypes to chromatin accessibility profiles in single cells.
    Franco Izzo, Robert M Myers, Saravanan Ganesan, Levan Mekerishvili, Sanjay Kottapalli, Tamara Prieto, Elliot O Eton, Theo Botella, Andrew J Dunbar, Robert L Bowman, Jesus Sotelo, Catherine Potenski, Eleni P Mimitou, Maximilian Stahl, Sebastian El Ghaity-Beckley, JoAnn Arandela, Ramya Raviram, Daniel C Choi, Ronald Hoffman, Ronan Chaligné, Omar Abdel-Wahab, Peter Smibert, Irene M Ghobrial, Joseph M Scandura, Bridget Marcellino, Ross L Levine, Dan A Landau.
      In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from patients with myeloproliferative neoplasms with JAK2V617F-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2V617F-mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts.
    DOI:  https://doi.org/10.1038/s41586-024-07388-y
  4. Leukemia. 2024 May 09.
    AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML.
    Ece Canan Sayitoglu, Bogdan A Luca, Allison Paige Boss, Benjamin Craig Thomas, Robert Arthur Freeborn, Molly Javier Uyeda, Pauline Ping Chen, Yusuke Nakauchi, Colin Waichler, Norman Lacayo, Rosa Bacchetta, Ravindra Majeti, Andrew J Gentles, Alma-Martina Cepika, Maria Grazia Roncarolo.
      T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human-engineered cytotoxic CD4+ T cells. Single-cell RNA-seq of primary AML samples and CD4+ T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4+ T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing by primary ex vivo-isolated CD8+ T cells in vitro, and engineered CD4+ T cells in vitro and in vivo. While AML heterogeneity implies that multiple factors may determine their sensitivity to T cell killing, these data show that ICAM1 acts as an immune trigger, allowing T cell killing, and could play a role in AML patient survival in vivo.
    DOI:  https://doi.org/10.1038/s41375-024-02255-1
  5. bioRxiv. 2024 Apr 23. pii: 2023.06.25.546449. [Epub ahead of print]
    A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
    Xiaolei Liu, Sudhish A Devadiga, Robert F Stanley, Ryan Morrow, Kevin Janssen, Mathieu Quesnel-Vallières, Oz Pomp, Adam A Moverley, Chenchen Li, Nicolas Skuli, Martin P Carroll, Jian Huang, Douglas C Wallace, Kristen W Lynch, Omar Abdel-Wahab, Peter S Klein.
      Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2 P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2 P95H -induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2 P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2 P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2 P95H mutant MDS and AML.
    DOI:  https://doi.org/10.1101/2023.06.25.546449
  6. Br J Haematol. 2024 May 06.
    The Menin story in acute myeloid leukaemia-The road to success.
    Michael W M Kühn, Arnold Ganser.
      The treatment of acute myeloid leukaemia (AML) has changed fundamentally in the last decade with many new targeted therapies entering clinics. Some of the most interesting agents under development are Menin inhibitors which interfere with the interaction of Menin with wild-type (wt) KMT2A or a KMT2A-fusion protein and thereby downregulate the leukaemic gene expression (MEIS1, PBX3, HOX) in NPM1 mutant or KMT2A-rearranged leukaemia. Other HOX and MEIS1 expressing leukaemias may also be sensitive to Menin inhibition. Following the encouraging results as monotherapy in refractory and relapsed AML, the combination of Menin inhibitors with chemotherapeutic agents and other targeted drugs is being investigated clinically.
    Keywords:  KMT2A rearrangement; Menin; Menin inhibitors; NPM1 mutation; acute myeloid leukaemia
    DOI:  https://doi.org/10.1111/bjh.19508
  7. Blood. 2024 May 09. 143(19): 1884-1885
    PIKing the right target in AML.
    Pamela J Sung.
      
    DOI:  https://doi.org/10.1182/blood.2024024035
  8. J Clin Invest. 2024 May 07. pii: e175619. [Epub ahead of print]
    A mitochondrial surveillance mechanism activated by SRSF2 mutations in hematologic malignancies.
    Xiaolei Liu, Sudhish A Devadiga, Robert F Stanley, Ryan M Morrow, Kevin A Janssen, Mathieu Quesnel-Vallières, Oz Pomp, Adam A Moverley, Chenchen Li, Nicolas Skuli, Martin P Carroll, Jian Huang, Douglas C Wallace, Kristen W Lynch, Omar Abdel-Wahab, Peter S Klein.
      Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic SRSF2P95H/+ mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. SRSF2P95H-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of SRSF2P95H/+ cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in SRSF2P95H/+ cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in SRSF2P95H mutant MDS and AML.
    Keywords:  Autophagy; Hematology; Leukemias; Mitochondria; Oncology
    DOI:  https://doi.org/10.1172/JCI175619
  9. Biochem Pharmacol. 2024 May 03. pii: S0006-2952(24)00245-4. [Epub ahead of print]225 116262
    A chemically adjustable BMP6-IL6 axis in mesenchymal stem cells drives acute myeloid leukemia cell differentiation.
    Luchen Sun, Shangrui Rao, Kamran Kerim, Jianhua Lu, Hongzheng Li, Shengsheng Zhao, Pingping Shen, Weijian Sun.
      Chemotherapy alone or in combination with allogeneic stem cell transplantation has been the standard of care for acute myeloid leukemia (AML) for decades. Leukemia relapse with limited treatment options remains the main cause of treatment failure. Therefore, an effective and safe approach to improve treatment outcomes is urgently needed for most AML patients. Mesenchymal stem cells (MSCs) have been reported to efficiently induce apoptosis and shape the fate of acute myeloid leukemia cells. Here, we identified LG190155 as a potent compound that enhances the antileukemia efficiency of MSCs. Pretreatment of MSCs with LG190155 significantly provoked differentiation in both AML patient-derived primary leukemia cells and AML cell lines and reduced the tumor burden in the AML mouse model. Using the quantitative proteomic technique, we discovered a pivotal mechanism that mediates AML cell differentiation, in which autocrine bone morphogenetic protein 6 (BMP6) in MSCs boosted IL-6 secretion and further acted on leukemic cells to trigger differentiation. Furthermore, the activity of the BMP6-IL6 axis was dramatically enhanced by activating vitamin D receptor (VDR) in MSCs. Our data illustrated an effective preactivated approach to reinforcing the antileukemia effect of MSCs, which could serve as an effective therapeutic strategy for AML.
    Keywords:  AML; BMP6-IL-6 axis; MSC; Pretreatment; VDR
    DOI:  https://doi.org/10.1016/j.bcp.2024.116262
  10. Leuk Lymphoma. 2024 May 07. 1-11
    Safety and tolerability of AMG 330 in adults with relapsed/refractory AML: a phase 1a dose-escalation study.
    Farhad Ravandi, Marion Subklewe, Roland B Walter, Pankit Vachhani, Gert Ossenkoppele, Veit Buecklein, Hartmut Döhner, Mojca Jongen-Lavrencic, Claudia D Baldus, Lars Fransecky, Timothy S Pardee, Hagop Kantarjian, Priscilla K Yen, Lata Mukundan, Bharat Panwar, Marc R Yago, Suresh Agarwal, Sophia K Khaldoyanidi, Anthony Stein.
      AMG 330, a bispecific T-cell engager (BiTE®) that binds CD33 and CD3 on T cells facilitates T-cell-mediated cytotoxicity against CD33+ cells. This first-in-human, open-label, dose-escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AMG 330 in adults with relapsed/refractory acute myeloid leukemia (R/R AML). Amongst 77 patients treated with AMG 330 (0.5 µg/day-1.6 mg/day) on 14-day or 28-day cycles, maximum tolerated dose was not reached; median duration of treatment was 29 days. The most frequent treatment-related adverse events were cytokine release syndrome (CRS; 78%) and rash (30%); 10% of patients experienced grade 3/4 CRS. CRS was mitigated with stepwise dosing of AMG 330, prophylactic dexamethasone, and early treatment with tocilizumab. Among 60 evaluable patients, eight achieved complete remission or morphologic leukemia-free state; of the 52 non-responders, 37% had ≥50% reduction in AML bone marrow blasts. AMG 330 is a promising CD33-targeted therapeutic strategy for R/R AML.
    Keywords:  AML; BiTE®; CD33; CRS; T-cell; dose-escalation; interleukin
    DOI:  https://doi.org/10.1080/10428194.2024.2346755
  11. Nature. 2024 May 08.
    Targetable leukaemia dependency on noncanonical PI3Kγ signalling.
    Qingyu Luo, Evangeline G Raulston, Miguel A Prado, Xiaowei Wu, Kira Gritsman, Karley S Whalen, Kezhi Yan, Christopher A G Booth, Ran Xu, Peter van Galen, John G Doench, Shai Shimony, Henry W Long, Donna S Neuberg, Joao A Paulo, Andrew A Lane.
      Phosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1-4. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid and dendritic lineages. This dependency is characterized by innate inflammatory signalling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3Kγ5 and stabilizes the active enzymatic complex. We identify p21 (RAC1)-activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency and find that dephosphorylation of PAK1 by PI3Kγ inhibition impairs mitochondrial oxidative phosphorylation. Treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukaemias with activated PIK3R5. In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3Kγ-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia.
    DOI:  https://doi.org/10.1038/s41586-024-07410-3
  12. Leukemia. 2024 May 08.
    Cre recombinase promotes leukemogenesis in the presence of both homozygous and heterozygous FLT3-ITD.
    Min Yang, Zhiyuan Ma, Chonggang Wang, Muammer Cihan Agca, Hongyun Liu, Kezhi Huang, Silke Glage, Regina Rumpel, Alexander Gerbaulet, Axel Roers, Xuemei Liu, Fatih Noyan, Nils von Neuhoff, Arnold Ganser, Ligen Liu, Haiyang Yun, Zhixiong Li.
      
    DOI:  https://doi.org/10.1038/s41375-024-02259-x
  13. Blood. 2024 May 10. pii: blood.2023023313. [Epub ahead of print]
    Complete Remission with Partial Hematological Recovery as a Palliative Endpoint for Treatment of Acute Myeloid Leukemia.
    Robert Q Le, Donna Przepiorka, Haiyan Chen, Yuan Li Shen, E Dianne Pulte, Kelly J Norsworthy, Marc R Theoret, R Angelo De Claro.
      Complete remission with partial hematological recovery (CRh) has been used as an efficacy endpoint in clinical trials of nonmyelosuppressive drugs for acute myeloid leukemia (AML). We conducted a pooled analysis to characterize the clinical outcomes for patients with AML who achieved CRh after treatment with ivosidenib, olutasidenib, enasidenib, or gilteritinib monotherapy in clinical trials used to support marketing applications. The study cohort included 841 adult patients treated at the recommended drug dosage; 64.6% were red blood cell or platelet transfusion dependent at study baseline. Correlations between disease response and outcomes were assessed by logistic regression modeling for categorical variables and by Cox proportional hazards modeling for time-to-event variables. In comparison to patients with no response (NR), those with CRh had a higher proportion with transfusion independence (TI) for at least 56 days (92.3% vs 22.3%, p < 0.0001) or TI for at least 112 days (63.5% vs 8.7%, p < 0.0001), a reduced risk over time for severe infection (HR 0.43, p = 0.0007) or severe bleeding (HR 0.17, p = 0.01), and a longer overall survival (OS) (HR 0.31, p < 0.0001). The effects were consistent across drugs. In comparison to patients with CR, the effect sizes for CRh were similar for TI-56 and for risk over time of infection or bleeding but less for TI-112 and OS. CRh is associated with clinical benefits consistent with clinically meaningful palliative effects for treatment of AML with nonmyelosuppressive drugs, although less robustly than for CR.
    DOI:  https://doi.org/10.1182/blood.2023023313
  14. J Clin Oncol. 2024 May 09. JCO2302175
    Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes.
    GenoMed4All, Synthema, GESMD, FISIM, and EuroBloodNET
       PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M).
    PATIENTS AND METHODS: We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies.
    RESULTS: Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R-based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M-based policy (P = .001).
    CONCLUSION: These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.
    DOI:  https://doi.org/10.1200/JCO.23.02175
  15. Leuk Lymphoma. 2024 May 07. 1-12
    Advances in the management of higher-risk myelodysplastic syndromes: future prospects.
    Georgina Gener-Ricos, Juan Jose Rodriguez-Sevilla, Samuel Urrutia, Alex Bataller, Alexandre Bazinet, Guillermo Garcia-Manero.
      Higher-risk myelodysplastic syndromes (HR-MDS) are defined using a number of prognostic scoring systems that include the degree of cytopenias, percentage of blasts, cytogenetic alterations, and more recently genomic data. HR-MDS encompasses characteristics such as progressive cytopenias, increased bone marrow blasts, unfavorable cytogenetics, and an adverse mutational profile. Survival is generally poor, and patients require therapy to improve outcomes. Hypomethylating agents (HMAs), such as azacitidine, decitabine, and more recently, oral decitabine/cedazuridine, are the only approved therapies for HR-MDS. These are often continued until loss of response, progression, or unacceptable toxicity. Combinations including an HMA plus other drugs have been investigated but have not demonstrated better outcomes compared to single-agent HMA. Moreover, in a disease of high genomic complexity such as HR-MDS, therapy targeting specific genomic abnormalities is of interest. This review will examine the biological underpinnings of HR-MDS, its therapeutic landscape in the frontline and relapsed settings, as well as the impact of hematopoietic stem cell transplantation, the only known curative intervention for this disease.
    Keywords:  Higher-risk myelodysplastic syndromes; allogeneic stem cell transplant; hypomethylating agents; targeted therapies
    DOI:  https://doi.org/10.1080/10428194.2024.2344061
  16. Nat Commun. 2024 May 06. 15(1): 3785
    Active site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms.
    Matthew Mealka, Nicole A Sierra, Diego Avellaneda Matteo, Elene Albekioni, Rachel Khoury, Timothy Mai, Brittany M Conley, Nalani J Coleman, Kaitlyn A Sabo, Elizabeth A Komives, Andrey A Bobkov, Andrew L Cooksy, Steve Silletti, Jamie M Schiffer, Tom Huxford, Christal D Sohl.
      Mutations in human isocitrate dehydrogenase 1 (IDH1) drive tumor formation in a variety of cancers by replacing its conventional activity with a neomorphic activity that generates an oncometabolite. Little is understood of the mechanistic differences among tumor-driving IDH1 mutants. We previously reported that the R132Q mutant unusually preserves conventional activity while catalyzing robust oncometabolite production, allowing an opportunity to compare these reaction mechanisms within a single active site. Here, we employ static and dynamic structural methods and observe that, compared to R132H, the R132Q active site adopts a conformation primed for catalysis with optimized substrate binding and hydride transfer to drive improved conventional and neomorphic activity over R132H. This active site remodeling reveals a possible mechanism of resistance to selective mutant IDH1 therapeutic inhibitors. This work enhances our understanding of fundamental IDH1 mechanisms while pinpointing regions for improving inhibitor selectivity.
    DOI:  https://doi.org/10.1038/s41467-024-48277-2
  17. JAMA. 2024 May 09.
    Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.
    Elias Jabbour, Hagop M Kantarjian, Ibrahim Aldoss, Pau Montesinos, Jessica T Leonard, David Gómez-Almaguer, Maria R Baer, Carlo Gambacorti-Passerini, James McCloskey, Yosuke Minami, Cristina Papayannidis, Vanderson Rocha, Philippe Rousselot, Pankit Vachhani, Eunice S Wang, Bingxia Wang, Meliessa Hennessy, Alexander Vorog, Niti Patel, Tammie Yeh, Jose-Maria Ribera.
       Importance: In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I.
    Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL.
    Design, Setting, and Participants: Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022.
    Intervention: Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission.
    Main Outcomes and Measures: The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival.
    Results: Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%).
    Conclusions and Relevance: Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib.
    Trial Registration: ClinicalTrials.gov Identifier: NCT03589326.
    DOI:  https://doi.org/10.1001/jama.2024.4783
  18. Hemasphere. 2024 May;8(5): e77
    Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9-dependent AML.
    Mélanie Lambert, Samy Jambon, Mohamed A Bouhlel, Sabine Depauw, Julie Vrevin, Samuel Blanck, Guillemette Marot, Martin Figeac, Claude Preudhomme, Bruno Quesnel, David W Boykin, Marie-Hélène David-Cordonnier.
      The mainstay of acute myeloid leukemia (AML) treatment still relies on traditional chemotherapy, with a survival rate of approximately 30% for patients under 65 years of age and as low as 5% for those beyond. This unfavorable prognosis primarily stems from frequent relapses, resistance to chemotherapy, and limited approved targeted therapies for specific AML subtypes. Around 70% of all AML cases show overexpression of the transcription factor HOXA9, which is associated with a poor prognosis, increased chemoresistance, and higher relapse rates. However, direct targeting of HOXA9 in a clinical setting has not been achieved yet. The dysregulation caused by the leukemic HOXA9 transcription factor primarily results from its binding activity to DNA, leading to differentiation blockade. Our previous investigations have identified two HOXA9/DNA binding competitors, namely DB1055 and DB818. We assessed their antileukemic effects in comparison to HOXA9 knockdown or cytarabine treatment. Using human AML cell models, DB1055 and DB818 induced in vitro cell growth reduction, death, differentiation, and common transcriptomic deregulation but did not impact human CD34+ bone marrow cells. Furthermore, DB1055 and DB818 exhibited potent antileukemic activities in a human THP-1 AML in vivo model, leading to the differentiation of monocytes into macrophages. In vitro assays also demonstrated the efficacy of DB1055 and DB818 against AML blasts from patients, with DB1055 successfully reducing leukemia burden in patient-derived xenografts in NSG immunodeficient mice. Our findings indicate that inhibiting HOXA9/DNA interaction using DNA ligands may offer a novel differentiation therapy for the future treatment of AML patients dependent on HOXA9.
    DOI:  https://doi.org/10.1002/hem3.77
  19. Blood. 2024 May 08. pii: blood.2023023625. [Epub ahead of print]
    Decitabine in Older Patients with AML: Quality of Life Results of the EORTC-GIMEMA-GMDS-SG Randomized Phase III Trial.
    Fabio Efficace, Michal Kicinski, Corneel Coens, Stefan Suciu, Walter J F M van der Velden, Richard Noppeney, Sylvain P Chantepie, Laimonas Griskevicius, Andreas Neubauer, Ernesta Audisio, Mario Luppi, Stephan Fuhrmann, Robin Foà, Martina Crysandt, Gianluca Gaidano, Radovan Vrhovac, Adriano Venditti, Eduardus F M Posthuma, Anna Candoni, Frédéric Baron, Olivier Legrand, Andrea Mengarelli, Paola Fazi, Marco Vignetti, Anne Giraut, Pierre W Wijermans, Gerwin A Huls, Michael Lübbert.
      We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes compared to those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) to IC (3+7) in older fit AML patients. HRQoL was a secondary endpoint, and it was assessed with the EORTC QLQ-C30 and the QLQ-ELD14. The following scales were a priori selected for defining the primary endpoint: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also prior to allo-HSCT and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm (76% [95% CI, 69 to 82] v 88% [95% CI, 82 to 93]; odds ratio, 0.43 [95% CI, 0.24 to 0.76], P=.003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and post-allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, while this was the case for those in the 3+7 arm, in four out of the five primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC, may be preferable to current standard IC (3+7), in fit older AML patients. ClinicalTrials.gov (NCT02172872).
    DOI:  https://doi.org/10.1182/blood.2023023625
  20. Cell. 2024 May 02. pii: S0092-8674(24)00408-2. [Epub ahead of print]
    Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging.
    Shovik Bandyopadhyay, Michael P Duffy, Kyung Jin Ahn, Jonathan H Sussman, Minxing Pang, David Smith, Gwendolyn Duncan, Iris Zhang, Jeffrey Huang, Yulieh Lin, Barbara Xiong, Tamjid Imtiaz, Chia-Hui Chen, Anusha Thadi, Changya Chen, Jason Xu, Melissa Reichart, Zachary Martinez, Caroline Diorio, Chider Chen, Vinodh Pillai, Oraine Snaith, Derek Oldridge, Siddharth Bhattacharyya, Ivan Maillard, Martin Carroll, Charles Nelson, Ling Qin, Kai Tan.
      Non-hematopoietic cells are essential contributors to hematopoiesis. However, heterogeneity and spatial organization of these cells in human bone marrow remain largely uncharacterized. We used single-cell RNA sequencing (scRNA-seq) to profile 29,325 non-hematopoietic cells and discovered nine transcriptionally distinct subtypes. We simultaneously profiled 53,417 hematopoietic cells and predicted their interactions with non-hematopoietic subsets. We employed co-detection by indexing (CODEX) to spatially profile over 1.2 million cells. We integrated scRNA-seq and CODEX data to link predicted cellular signaling with spatial proximity. Our analysis revealed a hyperoxygenated arterio-endosteal neighborhood for early myelopoiesis, and an adipocytic localization for early hematopoietic stem and progenitor cells (HSPCs). We used our CODEX atlas to annotate new images and uncovered mesenchymal stromal cell (MSC) expansion and spatial neighborhoods co-enriched for leukemic blasts and MSCs in acute myeloid leukemia (AML) patient samples. This spatially resolved, multiomic atlas of human bone marrow provides a reference for investigation of cellular interactions that drive hematopoiesis.
    Keywords:  CODEX; bone marrow; hematopoiesis; leukemia; mesenchymal; microenvironment; neighborhood; signaling; single-cell; spatial omics
    DOI:  https://doi.org/10.1016/j.cell.2024.04.013
  21. Signal Transduct Target Ther. 2024 May 06. 9(1): 108
    Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia: a multicenter, randomized, open-label, phase 3 trial.
    Biqi Zhou, Jia Chen, Tianhui Liu, Yishan Ye, Yanming Zhang, Yiyang Ding, Hong Liu, MingQing Zhu, Xiao Ma, Xiaoli Li, Longfei Zhao, Zhihong Lin, He Huang, Yang Xu, Depei Wu.
      Coinfusion of unrelated cord blood (UCB) units in haploidentical hematopoietic cell transplantation (haplo-HCT) (haplo-cord HCT) for hematopoietic malignancies showed promising results in previous reports, but the efficiency of haplo-cord HCT in acute myeloid leukemia (AML) still lacks sufficient evidence. This multicenter, randomized, phase 3 trial (ClinicalTrials.gov NCT03719534) aimed to assess the efficacy and safety of haplo-cord HCT in AML patients. A total of 268 eligible patients aged 18-60 years, diagnosed with measurable residual disease in AML (excluding acute promyelocytic leukemia), with available haploidentical donors and suitable for allotransplantation, were randomly allocated (1:1) to receive haplo-cord HCT (n = 134) or haplo-HCT (n = 134). The 3-year overall survival (OS) was the primary endpoint in this study. Overall median follow-up was 36.50 months (IQR 24.75-46.50). The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group (80.5%, 95% confidence interval [CI]: 73.7-87.9 vs. 67.8% 95% CI 60.0-76.5, p = 0.013). Favorable progression-free survival (70.3%, 95% CI 62.6-78.8 vs. 57.6%, 95% CI 49.6-67.0, p = 0.012) and cumulative incidence of relapse (12.1%, 95% CI 12.0-12.2 vs. 30.3%, 95% CI 30.1-30.4, p = 0.024) were observed in haplo-cord HCT group. Grade 3-4 adverse events (AEs) within two years posttransplantation in the two groups were similar. Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery (p = 0.026) and increased T-cell reconstitution in the early period posttransplantation. Haplo-cord HCT can improve OS in AML patients without excessive AEs, which may exert additional benefits for recipients of haplo-HCT.
    DOI:  https://doi.org/10.1038/s41392-024-01820-5
  22. Leukemia. 2024 May 07.
    Predicting survival in patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis.
    Fuhui Li, Tiejun Qin, Bing Li, Shiqiang Qu, Lijuan Pan, Peihong Zhang, Qi Sun, Wenyu Cai, Qingyan Gao, Meng Jiao, Junjie Li, Xiaofei Ai, Jiao Ma, Robert Peter Gale, Zefeng Xu, Zhijian Xiao.
      We investigated data from 180 consecutive patients with myelodysplastic/myeloproliferative neoplasms with SF3B1 mutation and thrombocytosis (MDS/MPN-SF3B1-T) who were diagnosed according to the 2022 World Health Organization (WHO) classification of myeloid neoplasms to identify covariates associated with survival. At a median follow-up of 48 months (95% confidence interval [CI] 35-61 months), the median survival was 69 months (95% CI 59-79 months). Patients with bone marrow ring sideroblasts (RS) < 15% had shorter median overall survival (OS) than did those with bone marrow RS ≥ 15% (41 months [95% CI 32-50 months] versus 76 months [95% CI 59-93 months]; P < 0.001). According to the univariable analyses of OS, age ≥ 65 years (P < 0.001), hemoglobin concentration (Hb) < 80 g/L (P = 0.090), platelet count (PLT) ≥ 800 × 10E + 9/L (P = 0.087), bone marrow RS < 15% (P < 0.001), the Revised International Prognostic Scoring System (IPSS-R) cytogenetic category intermediate/poor/very poor (P = 0.005), SETBP1 mutation (P = 0.061) and SRSF2 mutation (P < 0.001) were associated with poor survival. Based on variables selected from univariable analyses, two separate survival prediction models, a clinical survival model, and a clinical-molecular survival model, were developed using multivariable analyses with the minimum value of the Akaike information criterion (AIC) to specifically predict outcomes in patients with MDS/MPN-SF3B1-T according to the 2022 WHO classification.
    DOI:  https://doi.org/10.1038/s41375-024-02262-2
  23. Exp Hematol. 2024 May 08. pii: S0301-472X(24)00091-2. [Epub ahead of print] 104232
    Building bones for blood and beyond: the growing field of bone marrow niche model development.
    W Sebastian Doherty-Boyd, Monica P Tsimbouri, Hannah Donnelly, Matthew J Dalby.
      The bone marrow (BM) niche is a complex microenvironment that provides the signals required for regulation of hematopoietic stem cells (HSCs) and the process of haematopoiesis they are responsible for. Bioengineered models of the BM niche incorporate various elements of the in vivo BM microenvironment, including cellular components, soluble factors, a 3D environment, mechanical stimulation of included cells, and perfusion. Recent advances in the bioengineering field have resulted in a spate of new models that shed light on BM function and are approaching precise imitation of the BM niche. These models promise to improve our understanding of the in vivo microenvironment in health and disease. They also aim to serve as platforms for HSC manipulation, or as preclinical models for screening novel therapies for BM-associated disorders and diseases.
    DOI:  https://doi.org/10.1016/j.exphem.2024.104232
  24. bioRxiv. 2024 Apr 24. pii: 2024.04.24.590854. [Epub ahead of print]
    Enigmatic missense mutations can cause disease via creation of de novo nuclear export signals.
    By Michael McConville, Toby Thomas, Ryan Beckner, Catherine Valadez, YuhMin Chook, Stephen Chung, Glen Liszczak.
      Disease-causing missense mutations that occur within structurally and functionally unannotated protein regions can guide researchers to new mechanisms of protein regulation and dysfunction. Here, we report that the thrombocytopenia-, myelodysplastic syndromes-, and leukemia-associated P214L mutation in the transcriptional regulator ETV6 creates an XPO1-dependent nuclear export signal to cause protein mislocalization. Strategies to disrupt XPO1 activity fully restore ETV6 P214L protein nuclear localization and transcription regulation activity. Mechanistic insight inspired the design of a 'humanized' ETV6 mice, which we employ to demonstrate that the germline P214L mutation is sufficient to elicit severe defects in thrombopoiesis and hematopoietic stem cell maintenance. Beyond ETV6, we employed computational methods to uncover rare disease-associated missense mutations in unrelated proteins that create a nuclear export signal to disrupt protein function. Thus, missense mutations that operate through this mechanism should be predictable and may suggest rational therapeutic strategies for associated diseases.
    DOI:  https://doi.org/10.1101/2024.04.24.590854
  25. Bone Marrow Transplant. 2024 May 07.
    Favorable outcomes in MDS and oligoblastic AML-MR after reduced-intensity conditioning allogeneic bone marrow transplantation with post-transplantation cyclophosphamide.
    Ilias Sinanidis, Michael J Hochman, Hua-Ling Tsai, Michael P Randall, Brandon Bonilla, Ravi Varadhan, Alexander J Ambinder, Richard J Jones, Amy E DeZern, Theodoros Karantanos.
      
    DOI:  https://doi.org/10.1038/s41409-024-02299-y
  26. Blood. 2024 May 10. pii: blood.2023020875. [Epub ahead of print]
    Inducible CXCL12/CXCR4-dependent extramedullary hematopoietic niches in the adrenal gland.
    Frederica Schyrr, Alejandro Alonso Calleja, Anjali Vijaykumar, Jessica Sordet-Dessimoz, Sandra Gebhard, Rita Sarkis, Charles Bataclan, Silvia Ferreira Lopes, Aurélien Laurent Jean-Charles Oggier, Laurence L de Leval, Cesar Nombela-Arrieta, Olaia M Naveiras.
      Adult hematopoietic Stem and Progenitor Cells (HSPCs) reside in the bone marrow hematopoietic niche, which regulates HSPC quiescence, self-renewal, and commitment in a demand-adapted manner. While the complex bone marrow niche is responsible for adult hematopoiesis, evidence exists for simpler, albeit functional and more accessible, extramedullary hematopoietic niches. Inspired by the anecdotal description of retroperitoneal hematopoietic masses occurring at higher frequency upon hormonal dysregulation within the adrenal gland, we hypothesized that the adult adrenal gland could be induced into a hematopoietic supportive environment in a systematic manner, thus revealing mechanisms underlying de novo niche formation in the adult. Here we show that upon splenectomy and hormonal stimulation, the adult adrenal gland of mice can be induced to recruit and host functional HSPCs, capable of serial transplantation, and that this phenomenon is associated with de novo formation of platelet-derived growth factor receptor α (PDGFRα) expressing stromal nodules. We further show in CXCL12-GFP reporter mice that adrenal glands contain a stromal population reminiscent of the CXCL12-Abundant Reticular (CAR) cells which compose the bone marrow HSPC niche. Mechanistically, HSPC homing to hormonally-induced adrenal glands was found dependent on the CXCR4/CXCL12 axis. Mirroring our findings in mice, we found reticular CXCL12+ cells co-expressing master niche-regulator FOXC1 in primary samples from human adrenal myelolipomas, a benign tumor composed of adipose and hematopoietic tissue. Our findings reignite long-standing questions regarding hormonal regulation of hematopoiesis and provide a novel model to facilitate the study of adult-specific inducible hematopoietic niches which may pave the way to therapeutic applications.
    DOI:  https://doi.org/10.1182/blood.2023020875
  27. Blood Cancer Discov. 2024 May 07.
    Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.
    Nicole D Vincelette, Xiaoqing Yu, Andrew T Kuykendall, Jungwon Moon, Siyuan Su, Chia-Ho Cheng, Rinzine Sammut, Tiffany N Razabdouski, Hai Vu Nguyen, Erika A Eksioglu, Onyee Chan, Najla Al Ali, Parth C Patel, Dae Hyun Lee, Shima Nakanishi, Renan B Ferreira, Elizabeth Hyjek, Qianxing Mo, Suzanne Cory, Harshani R Lawrence, Ling Zhang, Daniel J Murphy, Rami S Komrokji, Daesung Lee, Scott H Kaufmann, John L Cleveland, Seongseok Yun.
      Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPNs) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (MF) patients who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in triple negative MF, and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0210
  28. Haematologica. 2024 May 09.
    Management of hyperleukocytosis in pediatric acute myeloid leukemia using immediate chemotherapy without leukapheresis: results from the NOPHO-DBH AML 2012 Protocol.
    Bernward Zeller, Nira Arad-Cohen, Daniel Cheuk, Barbara De Moerloose, Jose M Fernandez Navarro, Henrik Hasle, Kirsi Jahnukainen, Kristian Lovvik Juul-Dam, Gertjan Kaspers, Zanna Kovalova, Olafur G Jonsson, Birgitte Lausen, Monica Munthe-Kaas, Ulrika Noren Nystrom, Josefine Palle, Ramune Pasauliene, Cornelis J Pronk, Kadri Saks, Anne Tierens, Jonas Abrahamsson.
      Hyperleukocytosis (HL) in pediatric acute myeloid leukemia (AML) is associated with severe complications and inferior outcome. We report results on HL patients included in the NOPHO-DBH AML 2012 study. We recommended immediate start of full dose chemotherapy (etoposide [ETO] monotherapy for 5 days as part of the first course), avoiding leukapheresis (LA) and prephase chemotherapy (PCT). Of 714 included patients, 122 (17.1%) had HL, and 111 were treated according to the recommendations with ETO upfront without preceding LA or PCT. The first dose was applied the same day as the AML diagnosis or the day after in 94%. ETO was administered via peripheral veins in 37% of patients without major complications. After initiation of ETO the remaining WBC on days 2-5 was 69%, 36%, 17% and 8% of the pre-treatment level. On day 3, 81% had a WBC.
    DOI:  https://doi.org/10.3324/haematol.2024.285285
  29. Blood. 2024 May 10. pii: blood.2023022273. [Epub ahead of print]
    Does IPSS-R down staging before transplantation improve the prognosis of patients with Myelodysplastic neoplasms?
    Christof Scheid, Diderik-Jan Eikema, Michel Van Gelder, Urpu Salmenniemi, Johan Maertens, Jakob R Passweg, Didier Blaise, Jennifer L Byrne, Nicolaus Kroeger, Katja Sockel, Patrice Chevallier, Jean Henri Bourhis, Jan J Cornelissen, Henrik Sengeloev, Jürgen Finke, John A Snowden, Tobias Gedde-Dahl, Jerôme Cornillon, Urs Schanz, Amit Patel, Linda Koster, Liesbeth C de Wreede, Patrick J Hayden, Kavita Raj, Joanna Drozd-Sokolowska, Carmelo Gurnari, Francesco Onida, Donal P McLornan, Marie Robin, Ibrahim Yakoub-Agha.
      In MDS patients higher IPSS-R at transplant is associated with worse transplant outcome. Thus, it may seem beneficial to improve IPSS-R by therapeutic intervention prior to transplantation in order to "down-stage" the disease risk. However, there is no evidence to date to support this approach. A retrospective analysis of the EBMT transplant registry was performed to investigate the role of therapeutic interventions prior to transplantation with regard to changes in IPSS-R and transplant outcomes. A total of 1482 MDS patients with sufficient data to calculate IPSS-R at diagnosis and at time of transplantation were selected and analysed for transplant outcome in a multivariable Cox model including IPSS-R at diagnosis, treatment intervention, change in IPSS-R before transplant and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R change in untreated patients and moderately superior in chemotherapy-treated patients with improved IPSS-R at transplant. Improved IPSS-R after hypomethylating agents (HMA) or other therapies showed no beneficial effect. However, when IPSS-R progressed after chemotherapy, (HMA) or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit of IPSS-R down staging or reduction of BM blasts after chemotherapy and no benefit for HMA or other treatments and thus question the role of prior therapy in MDS patients scheduled for transplantation. The model-based survival estimates should help inform decision making for both doctors and patients.
    DOI:  https://doi.org/10.1182/blood.2023022273
  30. Haematologica. 2024 May 09.
    A case of familial donor-derived acute myeloid leukemia with underlying pre-leukemic mutations.
    Luca Vincenzo Cappelli, Clara Minotti, Manja Meggendorfer, Marietta Truger, Torsten Haferlach, Cristina Mecucci, Caterina Matteucci, Caterina Alati, Anna Paola Iori, Maurizio Martelli, Robin Foà.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.285156
  31. Nat Commun. 2024 May 07. 15(1): 3800
    Determinants of mosaic chromosomal alteration fitness.
    Yash Pershad, Taralynn Mack, Hannah Poisner, Yasminka A Jakubek, Adrienne M Stilp, Braxton D Mitchell, Joshua P Lewis, Eric Boerwinkle, Ruth J F Loos, Nathalie Chami, Zhe Wang, Kathleen Barnes, Nathan Pankratz, Myriam Fornage, Susan Redline, Bruce M Psaty, Joshua C Bis, Ali Shojaie, Edwin K Silverman, Michael H Cho, Jeong H Yun, Dawn DeMeo, Daniel Levy, Andrew D Johnson, Rasika A Mathias, Margaret A Taub, Donna Arnett, Kari E North, Laura M Raffield, April P Carson, Margaret F Doyle, Stephen S Rich, Jerome I Rotter, Xiuqing Guo, Nancy J Cox, Dan M Roden, Nora Franceschini, Pinkal Desai, Alex P Reiner, Paul L Auer, Paul A Scheet, Siddhartha Jaiswal, Joshua S Weinstock, Alexander G Bick.
      Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.
    DOI:  https://doi.org/10.1038/s41467-024-48190-8
  32. Blood. 2024 May 09. 143(19): 1881-1882
    Transplant in AML: just follow the NPM1 guide!
    Christian Récher.
      
    DOI:  https://doi.org/10.1182/blood.2024024074
  33. Nature. 2024 May 08.
    The intrinsic substrate specificity of the human tyrosine kinome.
    Tomer M Yaron-Barir, Brian A Joughin, Emily M Huntsman, Alexander Kerelsky, Daniel M Cizin, Benjamin M Cohen, Amit Regev, Junho Song, Neil Vasan, Ting-Yu Lin, Jose M Orozco, Christina Schoenherr, Cari Sagum, Mark T Bedford, R Max Wynn, Shih-Chia Tso, David T Chuang, Lei Li, Shawn S-C Li, Pau Creixell, Konstantin Krismer, Mina Takegami, Harin Lee, Bin Zhang, Jingyi Lu, Ian Cossentino, Sean D Landry, Mohamed Uduman, John Blenis, Olivier Elemento, Margaret C Frame, Peter V Hornbeck, Lewis C Cantley, Benjamin E Turk, Michael B Yaffe, Jared L Johnson.
      Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.
    DOI:  https://doi.org/10.1038/s41586-024-07407-y
  34. Haematologica. 2024 May 09.
    The insertion/deletion polymorphism rs201494641 at ITGA9 influences blood CD34+ cell levels by altering ZNF384 binding.
    Caterina Cafaro, Zain Ali, Antton Lamarca, Daniela Torres Di Bello, Laura Duran Lozano, Ludvig Ekdahl, Malte Thodberg, Maroulio Pertesi, Aitzkoa Lopez De Lapuente Portilla, Björn Nilsson.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.285363
  35. Br J Haematol. 2024 May 06.
    Clinical characteristics of acute myeloid leukaemia patients with a large number of azurophilic granules: A single-centre retrospective study.
    Shuqi Zhao, Jinghan Wang, Yinjun Lou, Xin Huang, Wanzhuo Xie, Wenjuan Yu, Lin Liu, Yijing Zhu, Xiangli Gao, Guanghua Ma, Ziyang Zhou, Ehsan Ghoushi, Mohammadyousof Ghafouri, Jie Jin, Hongyan Tong, De Zhou.
      Large amounts of azurophilic granules are considered to be a morphological feature of acute promyelocytic leukaemia (APL). However, a small percentage of acute myeloid leukaemia (AML) patients also have a large number of azurophilic granules. A large cohort of 3210 AML patients in our hospital was screened to identify AML patients who had a large number of azurophilic granules. The clinical parameters of these patients were collected and compared with typical AML patients (control Group 1) and APL patients (control Group 2). The incidence of AML with a large number of azurophilic granules was 1.26%. The fibrinogen and D-dimer levels of patients in the study group were more similar to those of patients in control Group 2, as was the incidence of bleeding events. Additionally, patients in the study group had higher FLT3-ITD and NPM1 mutation rates than patients in control Group 1. Finally, patients in the study group had a higher 30-day mortality rate than those in control Group 2 (24.2% vs. 9.09%) and showed a higher 30-day mortality trend than those in control Group 1. Therefore, we should pay more attention to the prevention of coagulation dysfunction and bleeding events for these patients.
    Keywords:   NPM1 ; D‐dimer; acute myeloid leukaemia; acute promyelocytic leukaemia; azurophilic granules
    DOI:  https://doi.org/10.1111/bjh.19494
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