bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023‒02‒19
28 papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London
  1. Control of focal adhesion kinase activation by RUNX1-regulated miRNAs in high-risk AML.
  2. Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancy.
  3. Immunophenotypic aberrant hematopoietic stem cells in myelodysplastic syndromes: a biomarker for leukemic progression.
  4. FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia.
  5. Selective homing of CAR-CIK cells to the bone marrow niche enhances control of the Acute Myeloid Leukemia burden.
  6. CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis.
  7. Favorable pharmacokinetics and pharmacodynamics properties of Gilteritinib in cerebrospinal fluid: a potential effective treatment in relapsing meningeal acute myeloid leukaemia FLT3-ITD patients.
  8. Invasive Fungal Infections After CLAG-M/CLAG Chemotherapy for Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms.
  9. Updating the American Society of Hematology Guidelines for Treating Older Adults with Acute Myeloid Leukemia.
  10. Black African-American patients with primary myelofibrosis: a comparative analysis of phenotype and survival.
  11. A global study for acute myeloid leukemia with RARG rearrangement.
  12. Targeting Unc51-like Autophagy Activating Kinase 1 (ULK1) overcomes adaptive drug resistance in acute myelogenous leukemia.
  13. Hematopoietic Stem Cell Aging and Leukemia Transformation.
  14. GVHD occurrence does not reduce AML relapse following PTCy-based haploidentical transplantation: a study from the ALWP of the EBMT.
  15. Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Evolves from TP53-Mutated Clonal Hematopoiesis.
  16. Results from a phase I/II trial of cusatuzumab combined with azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy.
  17. Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke.
  18. KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress.
  19. Midostaurin in addition to intensive chemotherapy in acute myeloid leukemia with t(8;21) and KIT and/or FLT3-ITD mutations: results of the SAL MIDOKIT trial.
  20. CPX-351 (Vyxeos™) treatment in blast-phase myeloproliferative neoplasm (MPN-BP): real-world experience in 12 consecutive cases.
  21. Core binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.
  22. European standard clinical practice - Key issues for the medical care of individuals with familial leukemia.
  23. Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia.
  24. Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Clinical Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT).
  25. Sanders MA, Chew E, Flensburg C, et al. MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Blood. 2018;132(14):1526-1534.
  26. Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.
  27. Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS.
  28. How I manage anemia related to myelofibrosis and its treatment regimens.
  1. Leukemia. 2023 Feb 14.
    Control of focal adhesion kinase activation by RUNX1-regulated miRNAs in high-risk AML.
    Vijay Suresh Akhade, Tian Liu, T Roderick Docking, Jihong Jiang, Aparna Gopal, Aly Karsan.
      We recently described a 16-gene expression signature for improved risk stratification of acute myeloid leukemia (AML) patients called the AML Prognostic Score (APS). A subset of APS-high-risk AML patients showed increased levels of focal adhesion kinase (FAK), encoded by the Protein Tyrosine Kinase 2 (PTK2) gene, which was correlated with RUNX1 mutations. RUNX1 mutant cells are more sensitive to PTK2 inhibitors. As we were not able to detect RUNX1-binding sites in the PTK2 promoter, we hypothesized that RUNX1 might regulate micro(mi)RNAs that repress PTK2, such that loss-of-function RUNX1 mutations would result in reduced miRNA expression and derepression of PTK2. Examination of paired RNA-seq and miRNA-seq data from 301 AML cases revealed two miRNAs that positively correlated with RUNX1 expression, contained RUNX1-binding sites in their promoters and were predicted to target PTK2. We show that the hsa-let7a-2-3p and hsa-miR-135a-5p promoters are regulated by RUNX1, and that PTK2 is a direct target of both miRNAs. Even in the absence of RUNX1 mutations, hsa-let7a-2-3p and hsa-miR-135a-5p regulate PTK2 expression, and reduced expression of these two miRNAs sensitizes AML cells to PTK2 inhibition. These data explain how RUNX1 regulates PTK2, and identify potential miRNA biomarkers for targeting AML with PTK2 inhibitors.
    DOI:  https://doi.org/10.1038/s41375-023-01841-z
  2. bioRxiv. 2023 Jan 17. pii: 2023.01.17.524290. [Epub ahead of print]
    Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancy.
    Kai Yu, Natalie Deuitch, Matthew Merguerian, Lea Cunningham, Joie Davis, Erica Bresciani, Jamie Diemer, Elizabeth Andrews, Alice Young, Frank Donovan, Raman Sood, Kathleen Craft, Shawn Chong, Settara Chandrasekharappa, Jim Mullikin, Paul P Liu.
      Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancies (FPDMM), which is characterized by thrombocytopenia and a life-long risk (35-45%) of hematological malignancies. We recently launched a longitudinal natural history study for patients with FPDMM at the NIH Clinical Center. Among 29 families with research genomic data, 28 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 24 of 54 (44.4%) non-malignant patients, somatic mutations were detected in at least one of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 7 other CHIP or AML driver genes ( DNMT3A, TET2, NRAS, SETBP1, SF3B1, KMT2C , and LRP1B ) were also found in more than one non-malignant patient. Moreover, three unrelated patients (one with myeloid malignancy) carried somatic mutations in NFE2 , which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in elderly patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring dynamic changes of somatic mutations prospectively will benefit patients’ clinical management and reveal mechanisms for progression to myeloid malignancies.Key Points: Comprehensive genomic profile of patients with FPDMM with germline RUNX1 mutations. Rising clonal hematopoiesis related secondary mutations that may lead to myeloid malignancies.
    DOI:  https://doi.org/10.1101/2023.01.17.524290
  3. Leukemia. 2023 Feb 15.
    Immunophenotypic aberrant hematopoietic stem cells in myelodysplastic syndromes: a biomarker for leukemic progression.
    Margot F van Spronsen, Diana Hanekamp, Theresia M Westers, Noortje van Gils, Eline Vermue, Arjo Rutten, Joop H Jansen, Birgit I Lissenberg-Witte, Linda Smit, Gerrit J Schuurhuis, Arjan A van de Loosdrecht.
      Myelodysplastic syndromes (MDS) comprise hematological disorders that originate from the neoplastic transformation of hematopoietic stem cells (HSCs). However, discrimination between HSCs and their neoplastic counterparts in MDS-derived bone marrows (MDS-BMs) remains challenging. We hypothesized that in MDS patients immature CD34+CD38- cells with aberrant expression of immunophenotypic markers reflect neoplastic stem cells and that their frequency predicts leukemic progression. We analyzed samples from 68 MDS patients and 53 controls and discriminated HSCs from immunophenotypic aberrant HSCs (IA-HSCs) expressing membrane aberrancies (CD7, CD11b, CD22, CD33, CD44, CD45RA, CD56, CD123, CD366 or CD371). One-third of the MDS-BMs (23/68) contained IA-HSCs. The presence of IA-HSCs correlated with perturbed hematopoiesis (disproportionally expanded CD34+ subsets beside cytopenias) and an increased hazard of leukemic progression (HR = 25, 95% CI: 2.9-218) that was independent of conventional risk factors. At 2 years follow-up, the sensitivity and specificity of presence of IA-HSCs for predicting leukemic progression was 83% (95% CI: 36-99%) and 71% (95% CI: 58-81%), respectively. In a selected cohort (n = 10), most MDS-BMs with IA-HSCs showed genomic complexity and high human blast counts following xenotransplantation into immunodeficient mice, contrasting MDS-BMs without IA-HSCs. This study demonstrates that the presence of IA-HSCs within MDS-BMs predicts leukemic progression, indicating the clinical potential of IA-HSCs as a prognostic biomarker.
    DOI:  https://doi.org/10.1038/s41375-023-01811-5
  4. J Hematol Oncol. 2023 Feb 11. 16(1): 9
    FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia.
    Xiao-Na Zhu, Yu-Sheng Wei, Qian Yang, Hao-Ran Liu, Zhe Zhi, Di Zhu, Li Xia, Deng-Li Hong, Yun Yu, Guo-Qiang Chen.
      BACKGROUND: Selectively targeting leukemia stem cells (LSCs) is a promising approach in treating acute myeloid leukemia (AML), for which identification of such therapeutic targets is critical. Increasing lines of evidence indicate that FBXO22 plays a critical role in solid tumor development and therapy response. However, its potential roles in leukemogenesis remain largely unknown.METHODS: We established a mixed lineage leukemia (MLL)-AF9-induced AML model with hematopoietic cell-specific FBXO22 knockout mice to elucidate the role of FBXO22 in AML progression and LSCs regulation, including self-renewal, cell cycle, apoptosis and survival analysis. Immunoprecipitation combined with liquid chromatography-tandem mass spectrometry analysis, Western blotting and rescue experiments were performed to study the mechanisms underlying the oncogenic role of FBXO22.
    RESULTS: FBXO22 was highly expressed in AML, especially in MLL-rearranged (MLLr) AML. Upon FBXO22 knockdown, human MLLr leukemia cells presented markedly increased apoptosis. Although conditional deletion of Fbxo22 in hematopoietic cells did not significantly affect the function of hematopoietic stem cells, MLL-AF9-induced leukemogenesis was dramatically abrogated upon Fbxo22 deletion, together with remarkably reduced LSCs after serial transplantations. Mechanistically, FBXO22 promoted degradation of BACH1 in MLLr AML cells, and overexpression of BACH1 suppressed MLLr AML progression. In line with this, heterozygous deletion of BACH1 significantly reversed delayed leukemogenesis in Fbxo22-deficient mice.
    CONCLUSIONS: FBXO22 promotes MLLr AML progression by targeting BACH1 and targeting FBXO22 might be an ideal strategy to eradicate LSCs without influencing normal hematopoiesis.
    Keywords:  Acute myeloid leukemia (AML); BTB and CNC homology 1 (BACH1); FBXO22; Leukemia stem cells (LSCs)
    DOI:  https://doi.org/10.1186/s13045-023-01400-0
  5. Blood. 2023 Feb 14. pii: blood.2022018330. [Epub ahead of print]
    Selective homing of CAR-CIK cells to the bone marrow niche enhances control of the Acute Myeloid Leukemia burden.
    Marta Biondi, Sarah Tettamanti, Stefania Galimberti, Beatrice Cerina, Chiara Tomasoni, Rocco Piazza, Samantha Donsante, Simone Bido, Vincenzo Maria Perriello, Vania Broccoli, Andrea Andrea Doni, Francesco Dazzi, Alberto Mantovani, Gianpietro Dotti, Andrea Biondi, Alice Pievani, Marta Serafini.
      Acute myeloid leukemia (AML) is a hematological malignancy derived from neoplastic myeloid progenitor cells characterized by abnormal clonal proliferation and differentiation. Although novel therapeutic strategies have recently been introduced, the prognosis of AML remains unsatisfactory. So far, the efficacy of chimeric antigen receptor (CAR)-T therapy in AML has been hampered by several factors including the poor accumulation of the blood-injected cells in the leukemia bone marrow (BM) niche, where chemotherapy-resistant leukemic stem cells reside. Thus, we hypothesized that overexpression of CXCR4, whose ligand CXCL12 is highly expressed by BM stromal cells within the niche, could improve T cell homing to the BM and consequently enhance their intimate contact with BM-resident AML cells facilitating disease eradication. Specifically, we engineered conventional CD33.CAR-cytokine induced killer cells (CIKs) with the wild-type CXCR4 and the variant CXCR4R334X, responsible for leukocyte sequestration in the BM of WHIM syndrome patients. Overexpression of both CXCR4wt and CXCR4mut in CD33.CAR-CIKs resulted in significant improvement of chemotaxis toward recombinant CXCL12 or BM stromal cell conditioned medium with no observed impairment of cytotoxic potential in vitro. Moreover, CXCR4-overexpressing CD33.CAR-CIKs showed enhanced in vivo BM homing, associated with a prolonged retention for the CXCR4R334X variant. However, only CD33.CAR-CIKs co-expressing CXCR4wt but not CXCR4mut exerted a more sustained in vivo antileukemic activity and extended animal survival, suggesting a non-canonical role for CXCR4 in modulating CAR-CIK functions independent of BM homing. Taken together, these data suggest that arming CAR-CIKs with CXCR4 may represent a promising strategy for increasing their therapeutic potential for AML.
    DOI:  https://doi.org/10.1182/blood.2022018330
  6. Blood. 2023 Feb 17. pii: blood.2022015418. [Epub ahead of print]
    CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis.
    Andrew Dunbar, Dongjoo Kim, Min Lu, Mirko Farina, Robert L Bowman, Julie L Yang, Young C Park, Abdul Karzai, Wenbin Xiao, Zach Zaroogian, Kavi O'Connor, Shoron Mowla, Francesca Gobbo, Paola Verachi, Fabrizio Martelli, Giuseppe Sarli, Lijuan Xia, Nada Elmansy, Maria Kleppe, Zhuo Chen, Yang Xiao, Erin M McGovern, Jenna Snyder, Aishwarya Krishnan, Corinne E Hill, Keith Bryan Cordner, Anouar Zouak, Mohamed E Salama, Jayden Yohai, Eric Tucker, Jonathan J Chen, Jing Zhou, Timothy S McConnell, Anna Rita Migliaccio, Richard Patrick Koche, Raajit K Rampal, Rong Fan, Ross L Levine, Ronald Hoffman.
      Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-kB pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and the hMPLW515L murine model of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched for a CXCL8/CXCR2 gene signature and display enhanced proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients.
    DOI:  https://doi.org/10.1182/blood.2022015418
  7. Haematologica. 2023 Feb 16.
    Favorable pharmacokinetics and pharmacodynamics properties of Gilteritinib in cerebrospinal fluid: a potential effective treatment in relapsing meningeal acute myeloid leukaemia FLT3-ITD patients.
    Nicolas Vignal, Loïs Kelly, Etienne Lengline, Aurélie Cabannes-Hamy, Justine Siavellis, David Ghez, Hélène Sauvageon, Thorsten Braun, Evelyne Jacqz-Aigrain, Milena Kohn, Philippe Rousselot, Alexandre Puissant, Emmanuel Raffoux, Samia Mourah, Lauriane Goldwirt.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2022.282596
  8. Blood Adv. 2023 Feb 15. pii: bloodadvances.2022009562. [Epub ahead of print]
    Invasive Fungal Infections After CLAG-M/CLAG Chemotherapy for Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms.
    Julian Lindsay, Carla S Walti, Anna B Halpern, Hu Xie, E Lisa Chung, Kelda G Schonhoff, Emily M Huebner, Guang-Shing Cheng, Louise Kimball, Wendy M Leisenring, Matthew Greenwood, Sharon C-A Chen, David Cm Kong, Monica A Slavin, Michael Boeckh, David Fredricks, Catherine Liu, Steven A Pergam, Roland B Walter, Joshua A Hill.
      CLAG-M (cladribine, high-dose cytarabine [HiDAC], G-CSF, mitoxantrone)/CLAG are contemporary intensive chemotherapy regimens associated with higher and deeper complete remission rates than 7+3 (cytarabine, anthracycline)/HiDAC, but with greater myelosuppression and potential infection risks. Here, we compared the cumulative incidence (CI) and patterns of invasive fungal disease (IFD) between these regimens by identifying proven/probable and possible cases of IFD following CLAG-M (n=332) and 7+3 (n=115) chemotherapy and subsequent treatment cycles in adults ≥18 years old with newly diagnosed (ND) or relapsed/refractory (R/R) AML or other high-grade myeloid neoplasms between 2006 and 2018. By 90 days (D90) after initiating treatment, the CI of proven/probable IFD was 20% with CLAG-M and 12% with 7+3 (p=0.17). There was no significant difference in the CI of IFD between ND CLAG-M and R/R CLAG-M. Without mold-active prophylaxis, the D90 CI of proven/probable IFD was significantly higher in the CLAG-M than the 7+3 cohort (28% versus 11%; p=0.007), but this difference was mitigated with mold-active prophylaxis (CLAG-M, 7.5%; 7+3, 0%; p=0.65). After each chemotherapy treatment cycle, the CI of newly diagnosed IFD was similar, ranging from 15-20%. Use of mold-active prophylaxis was the only factor associated with reduced IFD risk in adjusted models (HR, 0.32; 95% confidence interval, 0.18-0.56). Together, these data indicate that the IFD risk with CLAG-M is higher than with 7+3 in the absence of mold-active prophylaxis; use of mold-active prophylaxis mitigates this risk.
    DOI:  https://doi.org/10.1182/bloodadvances.2022009562
  9. Blood Adv. 2023 Feb 13. pii: bloodadvances.2023009696. [Epub ahead of print]
    Updating the American Society of Hematology Guidelines for Treating Older Adults with Acute Myeloid Leukemia.
    Richard M Stone, Jessica K Altman, Mikkael A Sekeres.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2023009696
  10. Blood Adv. 2023 Feb 13. pii: bloodadvances.2022009611. [Epub ahead of print]
    Black African-American patients with primary myelofibrosis: a comparative analysis of phenotype and survival.
    Naseema Gangat, Andrew T Kuykendall, Najla H Al Ali, Swati Goel, Maymona Abdelmagid, Aref Al-Kali, Hassan B Alkhateeb, Kebede Begna, Abhishek A Mangaonkar, Mark R Litzow, William J Hogan, Mithun Vinod Shah, Mrinal M Patnaik, Animesh D Pardanani, Rami S Komrokji, Ayalew Tefferi.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2022009611
  11. Blood Adv. 2023 Feb 17. pii: bloodadvances.2022008364. [Epub ahead of print]
    A global study for acute myeloid leukemia with RARG rearrangement.
    Honghu Zhu, Yazhen Qin, Zhang-Lin Zhang, Yong-Jing Liu, Lijun Wen, M James You, Cheng Zhang, Esperanza Such, Hong Luo, Hongjian Yuan, Hong-Sheng Zhou, Hongxing Liu, Ren Xu, Ji Li, Jian-Hu Li, Jian-Ping Hao, Jie Jin, Liang Yu, Jing-Ying Zhang, Li-Ping- Liu, Le-Ping Zhang, Rui-Bin Huang, Shuhong Shen, Sujun Jun Gao, Wei Wang, Xiaojing Yan, Xinyou Zhang, Xin Du, Xiaoxia Chu, Yanfang Yu, Yi Wang, Ying-Chang Mi, Ying Lu, Zhen Cai, Zhan Su, David Christopher C Taussig, Suzanne MacMahon, Edward D Ball, Huan-You Wang, John S Welch, C Cameron Yin, Gautam Borthakur, Miguel A A Sanz, Hagop M Kantarjian, Jinyan Huang, Jiong Hu, Suning Chen.
      Acute myeloid leukemia (AML) with RARG rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four AML with RARG rearrangements were identified. Bleeding or ecchymosis was present at 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of cases, respectively. Immunophenotyping showed following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6 (n=14), NUP98 (n=11), HNRNPc (n=6), HNRNPm (n=1), PML (n=1), and NPM1 (n=1). WT1- and NRAS/KRAS-mutations were common co-mutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (~29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA-seq data from 201 AML patients showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008364
  12. Mol Cancer Res. 2023 Feb 14. pii: MCR-22-0343. [Epub ahead of print]
    Targeting Unc51-like Autophagy Activating Kinase 1 (ULK1) overcomes adaptive drug resistance in acute myelogenous leukemia.
    Seemana Bhattacharya, Sujan Piya, Huaxian Ma, Priyanka Sharma, Qi Zhang, Natalia Baran, Vivian R Ruvolo, Teresa McQueen, R Eric Davis, Rasoul Pourebrahim, Marina Konopleva, Hagop Kantarjian, Nicholas D P Cosford, Michael Andreeff, Gautam Borthakur.
      Despite effective new therapies, adaptive resistance remains the main obstacle in AML therapy. Autophagy induction is a key mechanism for adaptive resistance. Leukemic blasts at diagnosis express higher levels of the apical autophagy kinase ULK1 compared to normal hematopoietic cells. Exposure to chemotherapy and targeted agents upregulate ULK1, hence we hypothesize that developing ULK1 inhibitors may present the unique opportunity for clinical translation of autophagy inhibition. Accordingly, we demonstrate that ULK1 inhibition, by genetic and pharmacological means, suppresses treatment-induced autophagy, overcomes adaptive drug-resistance, and synergizes with chemotherapy and emerging anti-leukemia agents like venetoclax (ABT-199). The study next aims at exploring the underlying mechanisms. Mechanistically, ULK1 inhibition downregulates MCL1 anti-apoptotic gene, impairs mitochondrial function and downregulates components of the CD44-xCT system, resulting in impaired reactive oxygen species (ROS) mitigation, DNA damage and apoptosis. For further validation, several mouse models of AML were generated. In these mouse models, ULK1 deficiency impaired leukemic cell homing and engraftment, delayed disease progression and improved survival. Therefore, in the study we validated our hypothesis and identified ULK1 as an important mediator of adaptive resistance to therapy and an ideal candidate for combination therapy in AML. Therefore, we propose ULK1 inhibition as a therapeutically relevant treatment option to overcome adaptive drug-resistance in AML. Implications: ULK1 drives a cell-intrinsic adaptive resistance in AML and targeting ULK1 mediated autophagy can synergize with existing and emerging AML therapies to overcome drug-resistance and induce apoptosis.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-0343
  13. Blood. 2023 Feb 17. pii: blood.2022017933. [Epub ahead of print]
    Hematopoietic Stem Cell Aging and Leukemia Transformation.
    Patricia A Colom Díaz, Jayna J Mistry, Jennifer J Trowbridge.
      With aging, hematopoietic stem cells (HSCs) have an impaired ability to regenerate, differentiate, and produce the entire repertoire of mature blood and immune cells. Due to dysfunctional hematopoiesis, the incidence of hematologic malignancies increases in elderly individuals. Here, we provide an update on HSC-intrinsic and HSC-extrinsic factors and processes recently discovered to contribute to functional decline of HSCs during aging. In addition, we discuss targets and timing of intervention approaches to maintain HSC function during aging and the extent to which these same targets may prevent or delay transformation to hematologic malignancies.
    DOI:  https://doi.org/10.1182/blood.2022017933
  14. J Hematol Oncol. 2023 Feb 13. 16(1): 10
    GVHD occurrence does not reduce AML relapse following PTCy-based haploidentical transplantation: a study from the ALWP of the EBMT.
    Frédéric Baron, Myriam Labopin, Johanna Tischer, Anna Maria Raiola, Jan Vydra, Didier Blaise, Patrizia Chiusolo, Friedrich Stölzel, Renato Fanin, Patrice Chevallier, Arnon Nagler, Fabio Ciceri, Mohamad Mohty.
      The association between graft-versus-host disease (GVHD) occurrence and acute myeloid leukemia (AML) relapse in patients treated with HLA-haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) with post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis has remained debated. Here, we addressed this issue in patients with active AML at transplantation. 2-year cumulative incidences of relapse and leukemia-free survival (LFS) were 49% and 32.3%, respectively. There were no associations between acute nor chronic GVHD of any grade and lower relapse incidence. However, grade I acute GVHD was associated with better LFS (HR = 0.71, 95% CI 0.51-0.99, P = 0.04). In contrast, grade III-IV acute (HR = 3.09, 95% CI 1.87-5.12, P < 0.0001) as well as extensive chronic (HR = 3.3, 95% CI 1.81-6.04, P = 0.0001) GVHD correlated with higher nonrelapse mortality leading to lower LFS (HR = 1.36, 95% CI 0.99-1.86, P = 0.056 and HR = 1.97, 95% CI 1.35-2.89, P = 0.0004, respectively). In conclusion, these data suggest a dissociation of graft-versus-leukemia effects from GVHD in patients with active AML treated with PTCy-based Haplo-HCT.
    Keywords:  AML; Acute myeloid leukemia; HLA-haploidentical; Mismatched unrelated donor; PTCy; Post-transplant cyclophosphamide
    DOI:  https://doi.org/10.1186/s13045-023-01403-x
  15. Blood Cancer Discov. 2023 Feb 13. OF1-OF4
    Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Evolves from TP53-Mutated Clonal Hematopoiesis.
    Ryunosuke Saiki, Seishi Ogawa.
      SUMMARY: Low-hypodiploid acute lymphoblastic leukemia (LH-ALL) in both children and adults is characterized by biallelic TP53 alterations in virtually all cases. However, in contrast to a common germline origin of the TP53 mutations in pediatric cases, those in adult cases are mostly somatic and are derived from age-related clonal hematopoiesis (ARCH), highlighting the role of TP53-mutant ARCH in the development not only of myeloid leukemogenesis but also of LH-ALL in aged populations. See related article by Kim et al., (4).
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0006
  16. Haematologica. 2023 Feb 09. 0
    Results from a phase I/II trial of cusatuzumab combined with azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy.
    Thomas Pabst, Norbert Vey, Lionel Adès, Ulrike Bacher, Mario Bargetzi, Samson Fung, Gianluca Gaidano, Domenica Gandini, Anna Hultberg, Amy Johnson, Xuewen Ma, Rouven Müller, Kerri Nottage, Cristina Papayannidis, Christian Recher, Carsten Riether, Priya Shah, Jeffrey Tryon, Liang Xiu, Adrian F Ochsenbein.
      Cusatuzumab is a high-affinity, anti-CD70 monoclonal antibody under investigation in AML. This two-part, open-label, multicenter, phase I/II trial evaluated cusatuzumab plus azacitidine in patients with newly diagnosed AML ineligible for intensive chemotherapy. Patients received a single dose of cusatuzumab at one of four dose levels (1, 3, 10, or 20 mg/kg), 14 days before starting combination therapy. In phase I dose-escalation, cusatuzumab was then administered on days 3 and 17, in combination with azacitidine (75 mg/m2) on days 1-7, every 28 days. Primary objective in phase I was to determine the recommended phase II dose (RP2D) of cusatuzumab plus azacitidine. Phase II primary objective was efficacy at the RP2D (selected as 10 mg/kg). Thirty-eight patients enrolled: 12 in phase I (three per dose level; four with ELN adverse risk) and 26 in phase II (21 with adverse risk). Objective response (≥ partial remission) was achieved by 19/38 patients (including 8/26 in phase II); 14/38 achieved complete remission. Eleven patients (37.9%) achieved objective response among the 29 patients in phase I and phase II treated at the RP2D. At median follow-up of 10.9 months, median duration of first response was 4.5 months and median overall survival was 11.5 months. Most common treatment-emergent adverse events were infections (84.2%) and hematologic toxicities (78.9%). Seven patients (18.4%) reported infusion-related reactions, including two with grade 3 events. Thus, cusatuzumab/azacitidine appears generally well tolerated and shows preliminary efficacy in this setting. Investigation of cusatuzumab combined with current standard-of-care therapy, comprising venetoclax and azacitidine, is ongoing.
    DOI:  https://doi.org/10.3324/haematol.2022.281563
  17. Stroke. 2023 Feb 15.
    Prevalence and Therapeutic Implications of Clonal Hematopoiesis of Indeterminate Potential in Young Patients With Stroke.
    Ernst Mayerhofer, Christoph Strecker, Heiko Becker, Marios K Georgakis, Md Mesbah Uddin, Michael M Hoffmann, Niroshan Nadarajah, Manja Meggendorfer, Torsten Haferlach, Jonathan Rosand, Pradeep Natarajan, Christopher D Anderson, Andreas Harloff, Gregor Hoermann.
      BACKGROUND: Undetermined stroke etiology hampers optimal secondary prevention in a large proportion of young patients. We explored whether genetic screening for clonal hematopoiesis of indetermined potential (CHIP), a novel risk factor for stroke, could identify patients with myeloid precursor lesions or covert myeloid neoplasm requiring specific treatment.METHODS: We performed targeted sequencing on 56 genes recurrently mutated in hematologic neoplasms in a prospective cohort of patients with acute brain ischemia between 18 and 60 years. CHIP prevalence was compared with age-matched healthy controls from the Nijmegen Biomedical Study (n=1604) and the UK Biobank (n=101 678). Patients with suspicion of high-risk CHIP or myeloid neoplasm were invited for further hematologic evaluation.
    RESULTS: We included 248 consecutive patients (39% women) of whom 176 (71%) had cryptogenic stroke etiology. Fifty-one (21%) patients had CHIP, 3-fold more than in the general population (7.7% versus 2.6% for the Nijmegen Biomedical Study and 11.9% versus 4.1% for UK Biobank; P<0.001 for both). Patients with CHIP were older (median [interquartile range], 53 [50-59] versus 51 [41-56] years; P<0.001), had higher carotid intima-media thickness (0.68 [0.58-0.80] versus 0.59 [0.51-0.73] mm; P=0.009), and had higher burden of atherosclerosis (29.4% versus 16.7%; P=0.04). We invited 11 patients (4.4%) for further hematologic assessment, which in 7 led to the diagnosis of high-risk CHIP and in 2 to the new diagnosis of a myeloproliferative neoplasm with indication for cytoreductive therapy.
    CONCLUSIONS: Using genetic screening for myeloid disorders in patients with stroke of predominantly undetermined etiology, we found a 3-fold higher CHIP prevalence than in the general population. We identified high-risk CHIP and previously covert myeloproliferative neoplasms as potential stroke etiologies in 4.4% and 1% of patients, respectively. Our findings demonstrate the diagnostic and therapeutic yield of genetic screening in young patients with stroke. Future studies should investigate the role of CHIP for stroke recurrence and optimal secondary prevention.
    Keywords:  clonal hematopoiesis; humans; ischemic stroke; myeloproliferative disorders; stroke
    DOI:  https://doi.org/10.1161/STROKEAHA.122.041416
  18. Leukemia. 2023 Feb 17.
    KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress.
    Nancy Issa, Hassan Bjeije, Elisabeth R Wilson, Aishwarya Krishnan, Wangisa M B Dunuwille, Tyler M Parsons, Christine R Zhang, Wentao Han, Andrew L Young, Zhizhong Ren, Kai Ge, Eunice S Wang, Andrew P Weng, Amanda Cashen, David H Spencer, Grant A Challen.
      T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1 mutations are the dominant genetic drivers of T-ALL, epigenetic dysfunction plays a central role in the pathology of T-ALL and can provide alternative mechanisms to oncogenesis in lieu of or in combination with genetic mutations. The histone demethylase enzyme KDM6A (UTX) is also recurrently mutated in T-ALL patients and functions as a tumor suppressor. However, its gene paralog, KDM6B (JMJD3), is never mutated and can be significantly overexpressed, suggesting it may be necessary for sustaining the disease. Here, we used mouse and human T-ALL models to show that KDM6B is required for T-ALL development and maintenance. Using NOTCH1 gain-of-function retroviral models, mouse cells genetically deficient for Kdm6b were unable to propagate T-ALL. Inactivating KDM6B in human T-ALL patient cells by CRISPR/Cas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6B was proportional to the oncogenic strength of NOTCH1 mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6B in sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.
    DOI:  https://doi.org/10.1038/s41375-023-01853-9
  19. Haematologica. 2023 Feb 09.
    Midostaurin in addition to intensive chemotherapy in acute myeloid leukemia with t(8;21) and KIT and/or FLT3-ITD mutations: results of the SAL MIDOKIT trial.
    Leo Ruhnke, Christoph Röllig, Sylvia Herold, Tim Sauer, Christian H Brandts, Björn Steffen, Kerstin Schäfer-Eckart, Stefan W Krause, Mathias Hänel, Albrecht Reichle, Sebastian Scholl, Andreas Neubauer, Jan-Henrik Mikesch, Johannes Schetelig, Friedrich Stölzel, Michael Kramer, Annett Haake, Julia Frimmel, Alwin Krämer, Richard Schlenk, Uwe Platzbecker, Hubert Serve, Claudia D Baldus, Carsten Müller-Tidow, Daniela Aust, Martin Bornhäuser, Gerhard Ehninger, Christian Thiede.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2022.281636
  20. Blood Cancer J. 2023 Feb 17. 13(1): 26
    CPX-351 (Vyxeos™) treatment in blast-phase myeloproliferative neoplasm (MPN-BP): real-world experience in 12 consecutive cases.
    Rimal Ilyas, Kristen McCullough, Talha Badar, Mrinal M Patnaik, Hassan Alkhateeb, Abhishek Mangaonkar, Animesh Pardanani, Ayalew Tefferi, Naseema Gangat.
      
    DOI:  https://doi.org/10.1038/s41408-023-00800-2
  21. Blood. 2023 Feb 16. pii: blood.2022015830. [Epub ahead of print]
    Core binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.
    Mingrui Guo, Hon Man Tim Chan, Qi-Ling Zhou, Omer An, Ying Li, Yangyang Song, Zi Hui Tan, Hui En Vanessa Ng, Philomina Sona Peramangalam, Zhi Qing Tan, Xinang Cao, Eisaku Iwanaga, Masao Matsuoka, Melissa G Ooi, Wei Ying Jen, Liang Piu Koh, Esther Chan, Lip Kun Tan, Yufen Goh, Wilson Wang, Bryan T H Koh, Ming Chun Chan, Melissa J Fullwood, Wee Joo Chng, Motomi Osato, John Anto Pulikkan, Henry Yang, Leilei Chen, Daniel G Tenen.
      Adenosine to inosine (A-to-I) RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than chronic myeloid leukemia (CML) blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core binding factor (CBF) AML with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO AE9a fusion protein in a dominant negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of two exemplary ADAR2-regulated RNA editing targets COPA and COG3 inhibited clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.
    DOI:  https://doi.org/10.1182/blood.2022015830
  22. Eur J Med Genet. 2023 Feb 10. pii: S1769-7212(23)00033-2. [Epub ahead of print] 104727
    European standard clinical practice - Key issues for the medical care of individuals with familial leukemia.
    Alisa Förster, Claudia Davenport, Nicolas Duployez, Miriam Erlacher, Alina Ferster, Jude Fitzgibbon, Gudrun Göhring, Henrik Hasle, Marjolijn C Jongmans, Alexandra Kolenova, Geertruijte Kronnie, Tim Lammens, Cristina Mecucci, Wojciech Mlynarski, Charlotte M Niemeyer, Francesc Sole, Tomasz Szczepanski, Esmé Waanders, Andrea Biondi, Marcin Wlodarski, Brigitte Schlegelberger, Tim Ripperger.
      Although hematologic malignancies (HM) are no longer considered exclusively sporadic, additional awareness of familial cases has yet to be created. Individuals carrying a (likely) pathogenic germline variant (e.g., in ETV6, GATA2, SAMD9, SAMD9L, or RUNX1) are at an increased risk for developing HM. Given the clinical and psychological impact associated with the diagnosis of a genetic predisposition to HM, it is of utmost importance to provide high-quality, standardized patient care. To address these issues and harmonize care across Europe, the Familial Leukemia Subnetwork within the ERN PaedCan has been assigned to draft an European Standard Clinical Practice (ESCP) document reflecting current best practices for pediatric patients and (healthy) relatives with (suspected) familial leukemia. The group was supported by members of the German network for rare diseases MyPred, of the Host Genome Working Group of SIOPE, and of the COST action LEGEND. The ESCP on familial leukemia is proposed by an interdisciplinary team of experts including hematologists, oncologists, and human geneticists. It is intended to provide general recommendations in areas where disease-specific recommendations do not yet exist. Here, we describe key issues for the medical care of familial leukemia that shall pave the way for a future consensus guideline: (i) identification of individuals with or suggestive of familial leukemia, (ii) genetic analysis and variant interpretation, (iii) genetic counseling and patient education, and (iv) surveillance and (psychological) support. To address the question on how to proceed with individuals suggestive of or at risk of familial leukemia, we developed an algorithm covering four different, partially linked clinical scenarios, and additionally a decision tree to guide clinicians in their considerations regarding familial leukemia in minors with HM. Our recommendations cover, not only patients but also relatives that both should have access to adequate medical care. We illustrate the importance of natural history studies and the need for respective registries for future evidence-based recommendations that shall be updated as new evidence-based standards are established.
    Keywords:  Cancer predisposition; Familial leukemia; Genetic analyses; Genetic counseling; Germline variants; Patient care
    DOI:  https://doi.org/10.1016/j.ejmg.2023.104727
  23. Nat Commun. 2023 Feb 13. 14(1): 809
    Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia.
    Jennifer L Kamens, Stephanie Nance, Cary Koss, Beisi Xu, Anitria Cotton, Jeannie W Lam, Elizabeth A R Garfinkle, Pratima Nallagatla, Amelia M R Smith, Sharnise Mitchell, Jing Ma, Duane Currier, Charlie Wright, Kanisha Kavdia, Vishwajeeth R Pagala, Wonil Kim, LaShanale M Wallace, Ji-Hoon Cho, Yiping Fan, Aman Seth, Nathaniel Twarog, John K Choi, Esther A Obeng, Mark E Hatley, Monika L Metzger, Hiroto Inaba, Sima Jeha, Jeffrey E Rubnitz, Junmin Peng, Taosheng Chen, Anang A Shelat, R Kiplin Guy, Tanja A Gruber.
      Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.
    DOI:  https://doi.org/10.1038/s41467-023-36370-x
  24. Br J Haematol. 2023 Feb 14.
    Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Clinical Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT).
    Andrew Clark, Sally Thomas, Angela Hamblin, Polly Talley, Austin Kulasekararaj, Jacob Grinfeld, Beverley Speight, Katie Snape, Terri P McVeigh, John A Snowden.
      Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high-throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD-box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non-malignant syndromic features. Allogeneic blood and marrow transplantation (BMT) is central to management in many haematological cancers. Identification of germline variants may have implications for the patient and potential family donors. Beyond selection of an appropriate haematopoietic stem cell donor there may be sensitive issues surrounding identification and counselling of hitherto asymptomatic relatives. If BMT is needed, there is frequently a clinical urgency that demands a rapid integrated multidisciplinary approach to testing and decision making involving haematologists in collaboration with Clinical and Laboratory Geneticists. Here, we present best practice consensus guidelines arrived at following a meeting convened by the UK Cancer Genetics Group (UKCGG), the Cancer Research UK (CRUK) funded CanGene-CanVar research programme (CGCV), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT).
    Keywords:  BMT; Leukaemia; germline cancer predisposition; transplant donor selection
    DOI:  https://doi.org/10.1111/bjh.18682
  25. Blood. 2023 Feb 16. 141(7): 808-809
    Sanders MA, Chew E, Flensburg C, et al. MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Blood. 2018;132(14):1526-1534.
      
    DOI:  https://doi.org/10.1182/blood.2022018609
  26. bioRxiv. 2023 Feb 12. pii: 2023.02.12.527706. [Epub ahead of print]
    Efficient megakaryopoiesis and platelet production require phospholipid remodeling and PUFA uptake through CD36.
    Maria N Barrachina, Gerard Pernes, Isabelle C Becker, Isabelle Allaeys, Thomas I Hirsch, Dafna J Groeneveld, Abdullah O Khan, Daniela Freire, Karen Guo, Estelle Carminita, Pooranee K Morgan, Thomas J Collins, Natalie A Mellett, Zimu Wei, Ibrahim Almazni, Joseph E Italiano, James Luyendyk, Peter J Meikle, Mark Puder, Neil V Morgan, Eric Boilard, Andrew J Murphy, Kellie R Machlus.
      Lipids contribute to hematopoiesis and membrane properties and dynamics, however, little is known about the role of lipids in megakaryopoiesis. Here, a lipidomic analysis of megakaryocyte progenitors, megakaryocytes, and platelets revealed a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake and de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in thrombocytopenia. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production, and that changes in dietary fatty acids may be a novel and viable target to modulate platelet counts.
    DOI:  https://doi.org/10.1101/2023.02.12.527706
  27. Bone Marrow Transplant. 2023 Feb 11.
    Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS.
    Claire Michel, Marie Robin, Stephane Morisset, Didier Blaise, Johan Maertens, Patrice Chevalier, Cristina Castilla-Llorente, Edouard Forcade, Patrice Ceballos, Ibrahim Yakoug-Agha, Xavier Poire, Martin Carre, Jacques-Olivier Bay, Yves Beguin, Michael Loschi, Anne Huynh, Gaëlle Guillerm, Sylvie François, Jean-Baptiste Mear, Rémy Duléry, Felipe Suarez, Karin Bilger, Jérôme Cornillon, Yves Chalandon, Natacha Maillard, Hélène Labussière-Wallet, Amandine Charbonnier, Pascal Turlure, Ana Berceanu, Sylvain Chantepie, Sébastien Maury, Ali Bazarbachi, Anne-Lise Menard, Stephanie Nguyen-Quoc, Marie-Thérèse Rubio, Maud D'Aveni.
      Allogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome.
    DOI:  https://doi.org/10.1038/s41409-023-01931-7
  28. Ann Hematol. 2023 Feb 14.
    How I manage anemia related to myelofibrosis and its treatment regimens.
    Srdan Verstovsek.
      Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by mutations (most frequently in JAK2, CALR, or MPL), burdensome symptoms, splenomegaly, cytopenia, and shortened life expectancy. In addition to other clinical manifestations, patients with MF often develop anemia, which can either be directly related to MF pathogenesis or a result of MF treatment with Janus kinase (JAK) inhibitors, such as ruxolitinib and fedratinib. Although symptoms and clinical manifestations can be similar between the 2 anemia types, only MF-related anemia is prognostic of reduced survival. In this review, I detail treatment and patient management approaches for both types of anemia presentations and provide recommendations for the treatment of MF in the presence of anemia.
    Keywords:  Anemia; Janus kinase; Myelofibrosis; Myeloproliferative neoplasm; Ruxolitinib
    DOI:  https://doi.org/10.1007/s00277-023-05126-4
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