bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–01–12
33 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML.
  2. Dual ASXL1 and CSF3R mutations drive myeloid biased stem cell expansion and enhance neutrophil differentiation.
  3. A novel prognostic risk model for patients with refractory/relapsed acute myeloid leukemia receiving venetoclax plus hypomethylating agents.
  4. We still need to hit hard in acute myeloid leukemia, but only in the right patients.
  5. Recipient sex and donor leukemic cell characteristics determine leukemogenesis in patient-derived models.
  6. α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
  7. Modeling GATA2 deficiency in mice: the R396Q mutation disrupts normal hematopoiesis.
  8. Pediatric Myeloid Neoplasms With UBTF Tandem Duplications: Morphologic, Immunophenotypic, and Clinical Characterization.
  9. Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1-familial platelet disorder.
  10. IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs.
  11. Selenoprotein-Mediated Redox Regulation Shapes the Cell Fate of HSCs and Mature Lineages.
  12. FLT3 inhibitors induce p53 instability, driven by STAT5/MDM2/p53 competitive interactions in acute myeloid leukemia.
  13. Advancing Drug Development in Myelodysplastic Syndromes.
  14. How age affects human hematopoietic stem and progenitor cells and strategies to mitigate HSPC aging.
  15. Clearance of Driver Mutations after Transplantation for Myelofibrosis.
  16. Advances and Challenges in Quizartinib-Based FLT3 Inhibition for Acute Myeloid Leukemia: Mechanisms of Resistance and Prospective Combination Therapies.
  17. HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism.
  18. Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases.
  19. High-throughput drug screening identifies SMAC mimetics as enhancers of NK cell cytotoxicity in chronic myeloid leukemia.
  20. Non canonical c-CBL mutations define a specific phenotype of myeloid neoplasia.
  21. DNTT-mediated DNA Damage Response Drives Inotuzumab Ozogamicin Resistance in B-cell Acute Lymphoblastic Leukemia.
  22. Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells.
  23. Non-selective b adrenergic receptor inhibitors impair hematopoietic regeneration in mice and humans after hematopoietic cell transplants.
  24. Radioimmunotherapy of acute myeloid leukemia: a critical assessment of its prospects and limitations.
  25. Spatiotemporal dynamics of fetal liver hematopoietic niches.
  26. EZH2 modulates mRNA splicing and exerts part of its oncogenic function through repression of splicing factors in CML.
  27. FDA-approved therapies for chronic GVHD.
  28. Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity.
  29. Overcoming CD226-related immune evasion in acute myeloid leukemia with CD38 CAR-engineered NK cells.
  30. Chronic viral mimicry induction following p53 loss promotes immune evasion.
  31. How I Manage Patients with Unexplained Cytopenia.
  32. Donor Regulatory T-Cell Therapy to Prevent Graft-Versus-Host Disease.
  33. Triacylglycerol mobilization underpins mitochondrial stress recovery.
  1. Blood. 2025 Jan 07. pii: blood.2024025154. [Epub ahead of print]
    Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML.
    Mark J Levis, Mehdi Hamadani, Brent R Logan, Richard J Jones, Anurag K Singh, Mark R Litzow, John R Wingard, Esperanza B Papadopoulos, Alexander E Perl, Robert J Soiffer, Celalettin Ustun, Masumi Ueda Oshima, Geoffrey L Uy, Edmund K Waller, Sumithira Vasu, Melhem M Solh, Asmita Mishra, Lori Muffly, Hee-Je Kim, Matthias Stelljes, Yuho Najima, Masahiro Onozawa, Kirsty J Thomson, Arnon Nagler, Andrew H Wei, Guido Marcucci, Caroline Chen, Nahla Hasabou, Matt Rosales, Jason E Hill, Stanley C Gill, Rishita Nuthethi, Denise King, Adam M Mendizabal, Steven M Devine, Mary M Horowitz, Yi-Bin Chen.
      BMT CTN 1506 ("MORPHO"; NCT02997202) was a randomized phase 3 study of gilteritinib compared to placebo as maintenance therapy after hematopoietic stem cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary endpoint was to determine the impact on survival of pre- and/or post-HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post-hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively impacted RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared to 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild type clones (as assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multi-clonal disease. These data demonstrate the potential of using FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML.
    DOI:  https://doi.org/10.1182/blood.2024025154
  2. Blood Adv. 2025 Jan 07. pii: bloodadvances.2024014362. [Epub ahead of print]
    Dual ASXL1 and CSF3R mutations drive myeloid biased stem cell expansion and enhance neutrophil differentiation.
    Lucie Darmusey, Anna J Bagley, Thai T Nguyen, Hanqian L Carlson, Hunter Blaylock, Shawn B Shrestha, Amara Pang, Samantha Tauchmann, Sarah C Taylor, Amy C Foley, Katia E Niño, Eric M Pietras, Theodore P Braun, Julia E Maxson.
      Mutations in the epigenetic regulator Additional Sex Combs-Like 1 (ASXL1) are frequently observed in chronic neutrophilic leukemia (CNL). CNL is a myeloproliferative neoplasm (MPN) driven by activating mutations in the Colony Stimulating Factor 3 Receptor (CSF3R), which cause excessive neutrophil production. Despite the high rates of co-occurrence, the interplay between ASXL1 and CSF3R mutations in hematopoiesis and leukemia remains poorly understood. Here, we present a new mouse model with both Asxl1Y588X and Csf3rT621I mutations, which recapitulates features of human MPNs. Csf3r-mutant mice exhibit an age-associated depletion of hematopoietic stem cells, which is tempered by adding of Asxl1Y588X. This combination of mutations causes an expansion of myeloid-biased long-term hematopoietic stem cells. As the mice age, they develop neutrophilia, but leukemia is rare, suggesting additional mutations may be required for transformation. Using models of myeloid differentiation, we find that Asxl1 truncation enhances CSF3RT618I-driven neutrophil differentiation, activating inflammatory pathways associated with mature myeloid cell production. Moreover, cells with both mutations have increased H3K4me1 at neutrophil-associated enhancers. Mutant ASXL1 is known to decrease the genome-wide abundance of the repressive histone mark H2AK119ub. While we see the expected decrease in H2AK119ub in Asxl1-mutant cells, this effect is reversed when CSF3R is also mutated, suggesting a complex interplay between these mutations in regulating chromatin dynamics during hematopoiesis. Our findings highlight context-dependent effects of ASXL1 mutation in myeloid disorders and provide insights into the mechanisms underlying neutrophil differentiation in ASXL1 and CSF3R dual mutant MPN.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014362
  3. Leukemia. 2025 Jan 08.
    A novel prognostic risk model for patients with refractory/relapsed acute myeloid leukemia receiving venetoclax plus hypomethylating agents.
    Rabia Shahswar, Razif Gabdoulline, Katja Krueger, Martin Wichmann, Katharina S Götze, Krischan Braitsch, Manja Meggendorfer, Laura Schmalbrock, Lars Bullinger, Franziska Modemann, Walter Fiedler, Juergen Krauter, Stephan Kaun, Susanne Rotermund, Andreas Voß, Yvonne Lisa Behrens, Anke Katharina Bergmann, Elisabeth Koller, Gernot Beutel, Felicitas Thol, Florian Heidel, Michael Heuser.
      Off-label hypomethylating agents and venetoclax (HMA/VEN) are often used for relapsed and refractory (R/R) AML patients. However, predictors of outcome are elusive. The objective of the current retrospective observational multicenter study of 240 adult patients (median age 68.6 years) with R/R AML was to establish a prognostic risk score. Overall response was documented in 106 (44%) patients. With a median follow-up of 31.5 months, 179 deaths were recorded. Median overall survival (mOS) was 7.9 months. In multivariate analysis of the subgroup with molecular information (n = 174), risk factors for inferior survival included the presence of extramedullary disease, HMA pretreatment and mutations in NF1, PTPN11, FLT3, and TP53, whereas mutated SF3B1 was identified as favorable risk factor. These risk factors were subsequently applied to construct an HR-weighted risk model that allocated patients to one of three risk groups with significantly different survival outcomes: favorable (n = 46; mOS 21.4 months), intermediate (n = 75; mOS 7.5 months), and adverse (n = 53; mOS 4.6 months; p < 0.001). The model was validated in 189 AML patients treated with HMA/VEN in first line. This clinical-molecular, 3-tiered venetoclax prognostic risk score (VEN-PRS) for HMA/VEN treatment outcomes in R/R AML patients will support the selection of appropriate treatment options in this high-risk population.
    DOI:  https://doi.org/10.1038/s41375-024-02501-6
  4. Haematologica. 2025 Jan 09.
    We still need to hit hard in acute myeloid leukemia, but only in the right patients.
    Arnold Ganser.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.286822
  5. Haematologica. 2025 01 09.
    Recipient sex and donor leukemic cell characteristics determine leukemogenesis in patient-derived models.
    Anna MP Stanger, Marlon Arnone, Pauline Hanns, Lucca M Kimmich, Jessica Kübler, Sarah Gekeler, Elsa S Görsch, Lea Kramer, Marcelle Baer, Jan C Schroeder, Taylor S Mills, Martina Konantz, Saskia S Rudat, Claudia Lengerke.
      In acute myeloid leukemia (AML), leukemogenesis depends on cell-intrinsic genetic aberrations and thus, studies on AML require investigations in an in vivo setting as provided by patient derived xenografts (PDX) models. Here we report that, next to leukemic cell characteristics, recipient sex highly influences the outgrowth of AML cells in PDX models, with females being much better repopulated than males in primary as well as secondary transplantation assays. Testosterone may be the more important player since, strikingly, better engraftment was seen in castrated versus control male recipients, while ovariectomy did not significantly impair engraftment in females. Shorter time-to-engraftment and mouse survival were observed with adverse molecular risk, and respectively with high FLT3-ITD ratio mutated AML cells. Adverse risk AML furthermore showed higher percentages of phenotypic leukemic stem cells (LSCs), suggesting impaired differentiation capacity in these AML subtypes. Overall, we achieved successful repopulation with 14/23 (61%) favorable, 18/30 (60%) intermediate and 4/8 (50%) adverse risk AML cases in female recipient PDX models. Our data identify recipient sex as an important experimental confounder in leukemia PDX models, and the contribution of the sex hormones to leukemogenesis as an intriguing, underexplored research area.
    DOI:  https://doi.org/10.3324/haematol.2023.284647
  6. Blood. 2024 Dec 27. pii: blood.2024025245. [Epub ahead of print]
    α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
    Scott Evan Millman, Almudena Chaves-Perez, Sudha Janaki-Raman, Yu-Jui Ho, John P Morris Iv, Varun Narendra, Chi-Chao Chen, Benjamin T Jackson, Jossie J Yashinskie, Riccardo Mezzadra, Tessa I Devine, Valentin J A Barthet, Michelle Saoi, Timour Baslan, Sha Tian, Zohar Sachs, Lydia Ws Finley, Justin R Cross, Scott W Lowe.
      Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.
    DOI:  https://doi.org/10.1182/blood.2024025245
  7. Leukemia. 2025 Jan 07.
    Modeling GATA2 deficiency in mice: the R396Q mutation disrupts normal hematopoiesis.
    Trent Hall, Rashid Mehmood, Diana Sá da Bandeira, Anitria Cotton, Jonathon Klein, Shondra M Pruett-Miller, Shai Izraeli, Wilson K Clements, John D Crispino.
      GATA2 deficiency is an autosomal dominant germline disorder of immune dysfunction and bone marrow failure with a high propensity for leukemic transformation. While sequencing studies have identified several secondary mutations thought to contribute to malignancy, the mechanisms of disease progression have been difficult to identify due to a lack of disease-specific experimental models. Here, we describe a murine model of one of the most common GATA2 mutations associated with leukemic progression in GATA2 deficiency, Gata2R396Q/+. While mutant mice exhibit mild defects in peripheral blood, they display significant hematopoietic abnormalities in the bone marrow, including a reduction in hematopoietic stem cell (HSC) function and intrinsic biases toward specific stem cell subsets that differ from previous models of GATA2 loss. Supporting this observation, single-cell RNA sequencing of hematopoietic progenitors revealed a loss of stemness, myeloid-bias, and indications of accelerated aging. Importantly, we show that Gata2R396Q/+ exerts effects early in hematopoietic development, as mutant mice generate fewer HSCs in the aorta gonad mesonephros, and fetal liver HSCs have reduced function. This reduced and altered pool of HSCs could be potential contributors to leukemic transformation in patients, and our model provides a useful tool to study the mechanisms of malignant transformation in GATA2 deficiency.
    DOI:  https://doi.org/10.1038/s41375-024-02508-z
  8. Am J Surg Pathol. 2025 Jan 06.
    Pediatric Myeloid Neoplasms With UBTF Tandem Duplications: Morphologic, Immunophenotypic, and Clinical Characterization.
    Mahsa Khanlari, Wei Wang, Yonghui Ni, Paul E Mead, Masayuki Umeda, Tami Westover, Jing Ma, Jeffrey E Rubnitz, Juan M Barajas, Stanley Pounds, Jeffery M Klco.
      Tandem duplications (TDs) in exons of upstream binding transcription factor (UBTF-TD) are a rare recurrent alteration in pediatric and adult acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)/neoplasm. Although recently identified, AML with UBTF-TD is now considered a distinct subtype of AML. To further our understanding of myeloid neoplasms with UBTF-TD, we analyzed clinical, morphologic, and immunophenotypic characteristics of 27 pediatric patients with UBTF-TD-positive myeloid neoplasm, including 21 diagnosed as AML and 6 as MDS. Our data demonstrated that UBTF-TD is frequently associated with cytopenia, hypercellular marrow with erythroid hyperplasia, and trilineage dysplasia. Blasts and maturing myeloid cells show a characteristic dysplastic feature with condensed eosinophilic cytoplasm. Blasts have a myeloid or myelomonocytic immunophenotype with a variably dim expression of CD34 and/or CD117, and except for CD7 expression lack a consistent pattern of aberrant lineage-specific antigen expression. Patients with MDS had a lower blast count in the peripheral blood (P = 0.03) and bone marrow (P <0.001) but otherwise had no significant differences in other hematological parameters. Three patients with MDS rapidly progressed to AML in 33, 39, and 210 days from the initial diagnosis and there was no difference in overall survival between patients with MDS and AML (P = 0.18). Our data suggest that MDS with UBTF-TD is prognostically equivalent to AML with UBTF-TD and thus should be considered as a continuum of the same molecularly defined myeloid neoplasm. These collective data also provide morphologic and immunophenotypic clues that can prompt screening for UBTF-TD in patients with MDS or AML.
    DOI:  https://doi.org/10.1097/PAS.0000000000002350
  9. Sci Transl Med. 2025 Jan 08. 17(780): eadn9832
    Targeting the CD74 signaling axis suppresses inflammation and rescues defective hematopoiesis in RUNX1-familial platelet disorder.
    Mona Mohammadhosseini, Trevor Enright, Adam Duvall, Alex Chitsazan, Hsin-Yun Lin, Aysegul Ors, Brett A Davis, Olga Nikolova, Erica Bresciani, Jamie Diemer, Kathleen Craft, Ana Catarina Menezes, Matthew Merguerian, Shawn Chong, Katherine R Calvo, Natalie T Deuitch, Shira Glushakow-Smith, Kira Gritsman, Lucy A Godley, Marshall S Horwitz, Sioban Keel, Lucio H Castilla, Emek Demir, Hisham Mohammed, Paul Liu, Anupriya Agarwal.
      Familial platelet disorder (FPD) is associated with germline RUNX1 mutations, establishing a preleukemic state and increasing the risk of developing leukemia. Currently, there are no intervention strategies to prevent leukemia progression. Single-cell RNA sequencing (n = 10) combined with functional analysis of samples from patients with RUNX1-FPD (n > 75) revealed that FPD hematopoietic stem and progenitor cells (HSPCs) displayed increased myeloid differentiation and suppressed megakaryopoiesis because of increased activation of prosurvival and inflammatory pathways. Bone marrow from patients with RUNX1-FPD contained an elevated cytokine milieu, exerting chronic inflammatory stress on HSPCs. RUNX1-FPD HSPCs were myeloid biased, had increased self-renewal, and were resistant to inflammation-mediated exhaustion. The bone marrow from patients with RUNX1-FPD showed high transcript and protein expression of CD74 at the preleukemic stage compared with that of healthy controls, which remained high upon patient transformation into leukemia. Further, CD74-mediated signaling was exaggerated in RUNX1-FPD HSPCs compared with healthy controls, leading to the activation of mTOR and JAK/STAT pathways with increased cytokine production. Genetic and pharmacological targeting of CD74 with ISO-1 and its downstream targets JAK1/2 and mTOR reversed RUNX1-FPD differentiation defects in vitro and in vivo and reduced inflammation. Our results highlight that inflammation is an early event in RUNX1-FPD pathogenesis, and CD74 signaling is one of the drivers of this inflammation. The repurposing of JAK1/2i (ruxolitinib) and mTORi (sirolimus) and promoting the advancement of CD74 inhibitors in clinical settings as an early intervention strategy would be beneficial to improve the phenotype of patients with RUNX1-FPD and prevent myeloid progression.
    DOI:  https://doi.org/10.1126/scitranslmed.adn9832
  10. Nat Immunol. 2025 Jan 09.
    IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs.
    Brendan M Barton, Francheska Son, Akanksha Verma, Saswat Kumar Bal, Qianzi Tang, Rui Wang, Katharine Umphred-Wilson, Rehan Khan, Josephine Trichka, Han Dong, Claudia Lentucci, Xi Chen, Yinghua Chen, Yuning Hong, Cihangir Duy, Olivier Elemento, Ari M Melnick, Jin Cao, Xi Chen, Laurie H Glimcher, Stanley Adoro.
      Hematopoietic stem cells must mitigate myriad stressors throughout their lifetime to ensure normal blood cell generation. Here, we uncover unfolded protein response stress sensor inositol-requiring enzyme-1α (IRE1α) signaling in hematopoietic stem and progenitor cells (HSPCs) as a safeguard against myeloid leukemogenesis. Activated in part by an NADPH oxidase-2 mechanism, IRE1α-induced X-box binding protein-1 (XBP1) mediated repression of pro-leukemogenic programs exemplified by the Wnt-β-catenin pathway. Transcriptome analysis and genome-wide mapping of XBP1 targets in HSPCs identified an '18-gene signature' of XBP1-repressed β-catenin targets that were highly expressed in acute myeloid leukemia (AML) cases with worse prognosis. Accordingly, IRE1α deficiency cooperated with a myeloproliferative oncogene in HSPCs to cause a lethal AML in mice, while genetic induction of XBP1 suppressed the leukemia stem cell program and activity of patient-derived AML cells. Thus, IRE1α-XBP1 signaling safeguards the integrity of the blood system by restricting pro-leukemogenic programs in HSPCs.
    DOI:  https://doi.org/10.1038/s41590-024-02063-w
  11. Blood. 2025 Jan 07. pii: blood.2024025402. [Epub ahead of print]
    Selenoprotein-Mediated Redox Regulation Shapes the Cell Fate of HSCs and Mature Lineages.
    Yumi Aoyama, Hiromi Yamazaki, Koutarou Nishimua, Masaki Nomura, Tsukasa Shigehiro, Takafumi Suzuki, Weijia Zang, Yota Tatara, Hiromi Ito, Yasutaka Hayashi, Yui Koike, Miki Fukumoto, Atsushi Tanaka, Yifan Zhang, Wataru Saika, Chihiro Hasegawa, Shuya Kasai, Yingyi Kong, Yohei Minakuchi, Ken Itoh, Masayuki Yamamoto, Shinya Toyokuni, Atsushi Toyoda, Tomokatsu Ikawa, Akifumi Takaori-Kondo, Daichi Inoue.
      The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of mRNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we employed tRNASec gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs' self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. While Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.
    DOI:  https://doi.org/10.1182/blood.2024025402
  12. Cancer Lett. 2025 Jan 03. pii: S0304-3835(25)00010-2. [Epub ahead of print]611 217446
    FLT3 inhibitors induce p53 instability, driven by STAT5/MDM2/p53 competitive interactions in acute myeloid leukemia.
    Han Zhong Pei, Yao Guo, Yuming Zhao, Dengyang Zhang, Zhiguang Chang, Jingfeng Zhou, Suk-Hwan Baek, Zhizhuang Joe Zhao, Chun Chen, Yun Chen.
      FLT3 mutations are present in one third of patients with Acute myeloid leukemia (AML) and stand as an attractive therapeutic target. Although FLT3 inhibitors demonstrate clinical efficacy, the drug resistance remains challenging attributed to multiple mechanisms. In this study, we found that tyrosine kinase inhibitors (TKIs) targeting FLT3 prompt p53 degradation in AML cells with FLT3-ITD through ubiquitination. STAT5 phosphorylation facilitates its nuclear localization, leading to competitive interactions among STAT5, MDM2, and p53. TKIs blocked STAT5 nuclear entry, amplifying MDM2/p53 binding and subsequent p53 degradation. Additionally, STAT5 overexpression inhibited MDM2-mediated p53 ubiquitination, whereas knock-down of STAT5 destabilizes p53. Co-administration of MDM2 inhibitors stabilizes p53 ubiquitination induced by TKIs, enhancing pro-apoptotic effects on AML cells. Moreover, in mice engrafted with AML cells, gilteritinib treatment results in decreased p53 protein levels and the transcriptional repression of downstream genes in leukemia cells, which are mitigated by the co-administration of MDM2 inhibitors. In conclusion, our study shows that FLT3 TKIs impede STAT5 nuclear translocation, strengthening p53/MDM2 interaction and consequent p53 degradation. This finding reveals a novel mechanism of TKIs resistance and indicates a combination of MDM2 inhibitors with TKIs for AML therapy, offering new insights into effective treatment strategies.
    Keywords:  AML; FLT3 inhibitor; MDM2 inhibitor; STAT5; p53 ubiquitination
    DOI:  https://doi.org/10.1016/j.canlet.2025.217446
  13. Blood Adv. 2024 Dec 30. pii: bloodadvances.2024014865. [Epub ahead of print]
    Advancing Drug Development in Myelodysplastic Syndromes.
    Alain Mina, Kathy L McGraw, Lea Cunningham, Nina Kim, Emily Y Jen, Katherine R Calvo, Lori A Ehrlich, Peter D Aplan, Guillermo Garcia-Manero, James M Foran, Jacqueline S Garcia, Amer M Zeidan, Amy E DeZern, Rami S Komrokji, Mikkael A Sekeres, Bart L Scott, Rena J Buckstein, Sara Tinsley-Vance, Amit Verma, Tanya Wroblewski, Steven Z Pavletic, Kelly J Norsworthy.
      Myelodysplastic syndromes/neoplasms (MDS) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the United States Food and Drug Administration (FDA), (e.g., luspatercept, ivosidenib, decitabine/cedazuridine and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories including criteria for risk stratification and eligibility, response definitions, time-to-event endpoints, transfusion endpoints, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014865
  14. Exp Hematol. 2025 Jan 07. pii: S0301-472X(25)00002-5. [Epub ahead of print] 104711
    How age affects human hematopoietic stem and progenitor cells and strategies to mitigate HSPC aging.
    Xueling Li, Jianwei Wang, Linping Hu, Tao Cheng.
      Hematopoietic stem cells (HSCs) are central to blood formation and play a pivotal role in hematopoietic and systemic aging. With aging, HSCs undergo significant functional changes, such as an increased stem cell pool, declined homing and reconstitution capacity, and skewed differentiation towards myeloid and megakaryocyte/platelet progenitors. These phenotypic alterations are likely due to the expansion of certain clones, known as clonal hematopoiesis (CH), which leads to disrupted hematopoietic homeostasis, including anemia, impaired immunity, higher risks of hematological malignancies, and even associations with cardiovascular disease, highlighting the broader impact of HSC aging on overall health. HSC aging is driven by a range of mechanisms involving both intrinsic and extrinsic factors, such as DNA damage accumulation, epigenetic remodeling, inflammaging and metabolic regulation. In this review, we summarize the update understanding of age-related changes in HSPCs and the mechanisms underlie the aging process in mammalian models, especially in human study. Additionally, we provide insights into potential therapeutic strategies to counteract aging process and enhance HSC regenerative capacity, which will support therapeutic interventions and promote healthy aging.
    DOI:  https://doi.org/10.1016/j.exphem.2025.104711
  15. N Engl J Med. 2025 Jan 09. 392(2): 150-160
    Clearance of Driver Mutations after Transplantation for Myelofibrosis.
    Nico Gagelmann, Marie Quarder, Anita Badbaran, Kristin Rathje, Dietlinde Janson, Catherina Lück, Johanna Richter, Franziska Marquard, Sofia Oechsler, Radwan Massoud, Evgeny Klyuchnikov, Ina Rudolph, Mathias Schäfersküpper, Christian Niederwieser, Silke Heidenreich, Carolina Berger, Boris Fehse, Christine Wolschke, Francis Ayuk, Nicolaus Kröger.
       BACKGROUND: Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for myelofibrosis. Driver mutations are the pathophysiological hallmark of the disease, but the role of mutation clearance after transplantation is unclear.
    METHODS: We used highly sensitive polymerase-chain-reaction technology to analyze the dynamics of driver mutations in peripheral-blood samples from 324 patients with myelofibrosis (73% with JAK2 mutations, 23% with CALR mutations, and 4% with MPL mutations) who were undergoing transplantation after reduced-intensity conditioning. Mutations were detected before transplantation and at 30, 100, and 180 days after transplantation to measure clearance and its effect on relapse and cure. The two primary end points were relapse and disease-free survival.
    RESULTS: At day 30 after transplantation, mutation clearance was found in 42% of the patients who had JAK2 mutations, 73% of those who had CALR mutations, and 54% of those who had MPL mutations; the corresponding percentages at day 100 were 63%, 82%, and 100%. The cumulative incidence of relapse at 1 year was 6% (95% confidence interval [CI], 2 to 10) among patients with mutation clearance at day 30 after transplantation and 21% (95% CI, 15 to 27) among those without mutation clearance at day 30. Disease-free and overall survival at 6 years were 61% and 74%, respectively, among patients with mutation clearance at day 30 after transplantation and 41% and 60%, respectively, among those without mutation clearance at day 30. Mutation clearance at day 30 appeared to outperform traditional donor chimerism as a measure of response; it was independently associated with a reduced risk of relapse or progression (hazard ratio, 0.36; 95% CI, 0.21 to 0.61) and appeared to overcome differences in prognosis based on the type of driver mutation (JAK2 vs. MPL or CALR).
    CONCLUSIONS: In patients with myelofibrosis, clearance of driver mutations at day 30 after transplantation appeared to influence relapse and survival, irrespective of the underlying driver mutation.
    DOI:  https://doi.org/10.1056/NEJMoa2408941
  16. Eur J Haematol. 2025 Jan 06.
    Advances and Challenges in Quizartinib-Based FLT3 Inhibition for Acute Myeloid Leukemia: Mechanisms of Resistance and Prospective Combination Therapies.
    Antonella Bruzzese, Enrica Antonia Martino, Caterina Labanca, Francesco Mendicino, Eugenio Lucia, Virginia Olivito, Teresa Rossi, Antonino Neri, Fortunato Morabito, Ernesto Vigna, Massimo Gentile.
      FLT3 mutations are among the most common genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Significant advancements have been made in developing FLT3 inhibitors (FLT3Is), such as quizartinib, which have improved treatment outcomes in both newly diagnosed and relapsed/refractory AML. Resistance to FLT3Is remains a major clinical challenge, driven by diverse mechanisms including FLT3 point mutations, cellular escape pathways, and the influence of the bone marrow microenvironment. Sustained STAT5 phosphorylation, AXL upregulation, and CXCR4 signaling have been identified as key factors in FLT3I resistance. Additionally, metabolic adaptations have been shown to support the survival of FLT3I-resistant cells. Ongoing clinical trials are investigating various combination regimens, including quizartinib with chemotherapy, Bcl-2 inhibitors, hypomethylating agents, and immune-modulatory drugs, with promising preliminary results. The European LeukemiaNet 2022 guidelines recommend incorporating FLT3Is into treatment regimens; however, questions remain regarding the best timing for the administration of each FLT3I. Additional studies are required to determine the optimal FLT3I-based combinations, reduce resistance emergence, and improve outcomes. This review highlights the current state of FLT3I therapy, ongoing challenges with resistance, and future directions in optimizing treatment for FLT3-mutated AML, focusing on quizartinib.
    Keywords:  FLT3 inhibitors; FLT3 inhibitors resistance; FLT3‐ITD; acute myeloid leukemia; quizartinib
    DOI:  https://doi.org/10.1111/ejh.14383
  17. Cell Signal. 2025 Jan 03. pii: S0898-6568(24)00559-X. [Epub ahead of print]127 111583
    HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism.
    Ruipeng Bian, Yingying Shang, Nahua Xu, Baiping Liu, Yanni Ma, Hui Li, Jieping Chen, Qi Yao.
      Acute Myeloid Leukemia (AML) are challenging blood cancers with limited long-term survival rates, necessitating novel therapeutic strategies. This study explored the role of Histone deacetylase (HDAC) inhibitors in enhancing ferroptosis in AML cells by modulating iron metabolism. We demonstrated that HDAC inhibitors (Entinostat and Vorinostat) sensitize AML cells to ferroptosis both in vitro and in vivo. Mechanistically, we show that HDAC inhibitor treatment upregulated the expression of iron metabolism genes that lead to increased labile iron pool. Notably, NCOA4, a ferritin degradation mediator, and HMOX1/2 proteins, involved in heme breakdown, were identified as critical contributors to this process. The functional role of these genes was confirmed through CRISPR-Cas9 mediated knockouts, which significantly rescued cells from HDAC-induced ferroptosis sensitivity. Our results suggest a novel therapeutic approach for AML, where combining HDAC inhibitors with ferroptosis inducers could exploit the disrupted iron metabolism in AML cells. This study highlights the potential of HDAC inhibitors to modulate iron metabolism pathways, offering new insights into the treatment of these malignancies.
    Keywords:  AML; Ferroptosis; HDAC inhibitors; Iron metabolism
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111583
  18. Blood. 2024 Dec 27. pii: blood.2024025598. [Epub ahead of print]
    Population dynamics modeling reveals that myeloid bias involves both HSC differentiation and progenitor proliferation biases.
    Apeksha Singh, Jennifer J Chia, Dinesh S Rao, Alexander Hoffmann.
      Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) amongst hematopoietic stem and progenitor cells (HSPCs). While HSC differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated. Here, we analyzed bone marrow data from the IκB- (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model of inflammation with elevated NFκB activity, which shows increased myeloid-biased MPPs. We interpreted these data with differential equations models of population dynamics to identify alterations of HSPC proliferation and differentiation rates. This analysis revealed that short-term (ST) HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs. To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of IκB- and wild-type HSPCs to track the continuous differentiation-trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors. Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification amongst HSCs, but also increased expansion of early myeloid-primed progenitors. Differentially expressed genes along the differentiation-trajectories supported increased proliferation amongst these progenitors. These findings were conserved when wild-type HSPCs were transplanted into IκB- recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver. We then applied our analysis pipeline to scRNA-seq measurements of HSPCs isolated from aged mice, as well as human myeloid neoplasm patients. These analyses identified the same myeloid-primed progenitor expansion as in the IκB- models, suggesting that it is a common feature across different settings of myeloid bias.
    DOI:  https://doi.org/10.1182/blood.2024025598
  19. Blood. 2025 Jan 10. pii: blood.2024025286. [Epub ahead of print]
    High-throughput drug screening identifies SMAC mimetics as enhancers of NK cell cytotoxicity in chronic myeloid leukemia.
    Petra Johanna Nygren, Jonas Otto Vilhelm Bouhlal, Emmi Jokinen, Sofia Forstén, Essi Laajala, Diogo Artur Alves Dias, Shady Adnan Awad, Aleksandr Ianevski, Jay Klievink, Hanna Lähteenmäki, Heikki Kuusanmäki, Mikko Myllymäki, Tiina Kasanen, Khalid Saeed, Dean A Lee, iCAN Flagship, Henrik Hjorth-Hansen, Tero Aittokallio, Olli Dufva, Satu Mustjoki.
      Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK cell function with oncological drugs could improve NK cell-based immunotherapies. Here, we used a high-throughput drug screen consisting of over 500 small-molecule compounds to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells. We identified SMAC mimetics as potent enhancers of NK cell cytotoxicity in both cell lines and primary patient samples. In contrast, several drug classes, including glucocorticoids and tyrosine kinase inhibitors such as dasatinib, inhibited NK cell cytotoxicity. Single-cell RNA sequencing revealed drug-induced transcriptomic changes in both NK and target CML cells. SMAC mimetics upregulated NF-κB target genes in NK cells, potentially contributing to their enhanced cytotoxicity. Inhibitory drugs dexamethasone, dasatinib, and sotrastaurin prevented NK cell transition to an activated state and suppressed the expression of IFN-γ by NK cells, thus preventing IFN-γ mediated target cell transcriptomic response. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK cell mediated killing, with potential clinical applications especially in patients with advanced phase CML.
    DOI:  https://doi.org/10.1182/blood.2024025286
  20. Leukemia. 2025 Jan 05.
    Non canonical c-CBL mutations define a specific phenotype of myeloid neoplasia.
    Luca Guarnera, Carmelo Gurnari, Carlos Bravo-Perez, Arda Durmaz, Nakisha D Williams, Hussein Awada, Naomi Kawashima, Arooj Ahmed, Serhan Unlu, Olisaemeka D Ogbue, Christopher Haddad, Aashray Mandala, Yasuo Kubota, Juraj Bodo, Genevieve M Crane, Heesun J Rogers, Jaroslaw P Maciejewski, Valeria Visconte.
      
    DOI:  https://doi.org/10.1038/s41375-024-02429-x
  21. Blood. 2024 Dec 27. pii: blood.2024026085. [Epub ahead of print]
    DNTT-mediated DNA Damage Response Drives Inotuzumab Ozogamicin Resistance in B-cell Acute Lymphoblastic Leukemia.
    Carolin S Escherich, Takaya Moriyama, Zhenhua Li, YuChih Hsiao, Wenjian Yang, Yizhen Li, Noemi Reyes, Megan Walker, Amit Budhraja, Sheetal Bhatara, Ernesto Diaz-Flores, Wendy Stock, Elisabeth Paietta, Marina Y Konopleva, Steven M Kornblau, Mark R Litzow, Hiroto Inaba, Ching-Hon Pui, Joseph T Opferman, Mignon L Loh, Jiyang Yu, Maureen O'Brien, William E Evans, Jun J Yang.
      Inotuzumab Ozogamicin (InO) is an antibody-calicheamicin conjugate with striking efficacy in B-cell acute lymphoblastic leukemia (B-ALL). However, there is wide inter-patient variability in treatment response, and the genetic basis of this variation remains largely unknown. Using a genome-wide CRISPR screen, we discovered the loss of DNTT as a primary driver of InO resistance. Mechanistically, DNTT downregulation attenuated InO-induced DNA damage response, cell cycle arrest, and mitochondrial apoptotic priming, ultimately leading to leukemia resistance to InO. Ex vivo leukemia InO sensitivity was highly associated with DNTT expression in ALL blasts, with substantial intra-leukemia heterogeneity as revealed by scRNA sequencing. In B-ALL patients enrolled in the COG trial AALL1621, we observed consistent DNTT downregulation in residual blasts post-InO treatment. The selection of DNTT-low blasts by InO therapy was also recapitulated in vivo using patient-derived xenograft models. Collectively, our data indicate that DNTT is a key regulator of calicheamicin response in leukemia and thus a potential biomarker for individualizing InO therapy in B-ALL.
    DOI:  https://doi.org/10.1182/blood.2024026085
  22. J Clin Invest. 2025 Jan 09. pii: e184069. [Epub ahead of print]
    Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells.
    Jue Li, Jie Bai, Vincent T Pham, Michihiro Hashimoto, Maiko Sezaki, Qili Shi, Qiushi Jin, Chenhui He, Amy Armstrong, Tian Li, Mingzhe Pan, Shujun Liu, Yu Luan, Hui Zeng, Paul R Andreassen, Gang Huang.
      Hematopoietic stem cells (HSCs) rely on self-renewal to sustain stem cell potential and undergo differentiation to generate mature blood cells. Mitochondrial fatty acid β-oxidation (FAO) is essential for HSC maintenance. However, the role of Carnitine palmitoyl transferase 1a (CPT1A), a key enzyme in FAO, remains unclear in HSCs. Using a Cpt1a hematopoietic specific conditional knock-out (Cpt1aΔ/Δ) mouse model, we found that loss of Cpt1a leads to HSC defects, including loss of HSC quiescence and self-renewal, and increased differentiation. Mechanistically, we find that loss of Cpt1a results in elevated levels of mitochondrial respiratory chain complex components and their activities, as well as increased ATP production, and accumulation of mitochondrial reactive oxygen species (mitoROS) in HSCs. Taken together, this suggests hyperactivation of mitochondria and metabolic rewiring via upregulated glucose-fueled oxidative phosphorylation (OXPHOS). In summary, our findings demonstrate a novel role for Cpt1a in HSC maintenance and provide insight into the regulation of mitochondrial metabolism via control of the balance between FAO and glucose-fueled OXPHOS.
    Keywords:  Hematology; Hematopoietic stem cells; Metabolism
    DOI:  https://doi.org/10.1172/JCI184069
  23. Cancer Discov. 2024 Dec 30.
    Non-selective b adrenergic receptor inhibitors impair hematopoietic regeneration in mice and humans after hematopoietic cell transplants.
    Jinsuke Nishino, Wenhuo Hu, Ashwin Kishtagari, Bo Shen, Xiang Gao, Caroline M Blackman, Adetola Kassim, Naimisha Marneni, Abhisar V Cherukuri, Russell Vittrup, Fatma N Kalkan, Rahul Shah, Chul Ahn, Ang Gao, Abeer Ahmedrabie, Robert H Collins, Amer M Zeidan, Aram Bidikian, Lohith Gowda, Brian C Shaffer, Yazan F Madanat, Zhiyu Zhao, Stephen S Chung, Sean J Morrison.
      Peripheral nerves promote mouse bone marrow regeneration by activating b2 and b3 adrenergic receptor signaling, raising the possibility that non-selective b blockers could inhibit engraftment after hematopoietic cell transplants (HCTs). We observed no effect of b blockers on steady-state mouse hematopoiesis. However, mice treated with a non-selective b blocker (carvedilol), but not a b1-selective inhibitor (metoprolol), exhibited impaired hematopoietic regeneration after syngeneic or allogeneic HCTs. At two institutions, patients who received non-selective, but not b1-selective, b blockers after allogeneic HCT exhibited delayed platelet engraftment and reduced survival. This was particularly observed in patients who received post-transplant chemotherapy for graft-versus-host disease prophylaxis, which also accentuated the inhibitory effect of carvedilol on engraftment in mice. In patients who received autologous HCTs, non-selective b blockers were associated with little or no delay in engraftment. The inhibitory effect of non-selective b blockers after allogeneic HCT was overcome by transplanting larger doses of hematopoietic cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0719
  24. Expert Rev Hematol. 2025 Jan 10. 1-9
    Radioimmunotherapy of acute myeloid leukemia: a critical assessment of its prospects and limitations.
    Donald Bunjes.
       INTRODUCTION: Leukemic stem cells (LSC) are the source of relapse in acute myeloid leukemia (AML). Thus, eliminating LSC is one of the overarching goals of AML research. Radioimmunotherapy is an immunotherapeutic approach which utilizes radioactive isotopes as effector molecules based on the proven ability of ionizing radiation (IR) to kill LSC.It has the potential to eliminate target-antigen negative LSC.
    AREAS COVERED: LSC biology, radiobiological principles of RIT, an overview of published and unpublished clinical results of RIT in AML. Issues of practical implementation of RIT in clinical trials.
    EXPERT OPINION: RIT for AML isat a critical juncture. Its ability to target antigen negative LSC gives it an advantage compared with other forms of immunotherapy. In order to compete with other forms of targeted therapy the procedure has to be simplified.
    Keywords:  211At; 225 Ac; CD123; apamistamab; besilesomab; crossfire; leukemic stem cell; sierra trial
    DOI:  https://doi.org/10.1080/17474086.2025.2449863
  25. J Exp Med. 2025 Feb 03. pii: e20240592. [Epub ahead of print]222(2):
    Spatiotemporal dynamics of fetal liver hematopoietic niches.
    Márcia Mesquita Peixoto, Francisca Soares-da-Silva, Valentin Bonnet, Yanping Zhou, Gustave Ronteix, Rita Faria Santos, Marie-Pierre Mailhe, Gonçalo Nogueira, Xing Feng, João Pedro Pereira, Emanuele Azzoni, Giorgio Anselmi, Marella F T R de Bruijn, Archibald Perkins, Charles N Baroud, Perpétua Pinto-do-Ó, Ana Cumano.
      Embryonic hematopoietic cells develop in the fetal liver (FL), surrounded by diverse non-hematopoietic stromal cells. However, the spatial organization and cytokine production patterns of the stroma during FL development remain poorly understood. Here, we characterized and mapped the hematopoietic and stromal cell populations at early (E12.5-14.5) FL stages, revealing that while hepatoblasts were the primary source of hematopoietic growth factors, other stromal cells-including mesenchymal, mesothelial, and endothelial cells-also contributed to this signaling network. Using a dedicated image analysis pipeline, we quantified cell distances to tissue structures and defined neighbor relationships, uncovering that different hematopoietic progenitors exhibit distinct preferences for neighboring stromal cells and show developmental changes in spatial distribution. Notably, our data suggest that the sub-mesothelium region plays a prominent role in early fetal hematopoiesis. This approach offers a valuable tool for studying complex cellular interactions in biological systems, providing new insights into hematopoietic niche organization during development.
    DOI:  https://doi.org/10.1084/jem.20240592
  26. Leukemia. 2025 Jan 07.
    EZH2 modulates mRNA splicing and exerts part of its oncogenic function through repression of splicing factors in CML.
    Reinhard Brunmeir, Li Ying, Junli Yan, Yan Ting Hee, Baohong Lin, Harvinder Kaur, Qiao Zheng Leong, Wei Wen Teo, Gerald Choong, Wei-Ying Jen, Liang Piu Koh, Lip Kun Tan, Esther Chan, Melissa Ooi, Henry Yang, Wee Joo Chng.
      The polycomb protein EZH2 is up-regulated in Chronic Myeloid Leukaemia (CML) and associated with transcriptional reprogramming. Here we tested whether EZH2 might also act as a modulator of the mRNA splicing landscape to elicit its oncogenic function in CML. We treated CML cell lines with EZH2 inhibitors and detected differential splicing of several hundreds of events, potentially caused by the transcriptional regulation of splicing factors. Amongst those genes, CELF2 was identified as a candidate to mediate part of the EZH2 inhibitor induced phenotype. Upon over-expression, we observed (1) reduced cell growth, viability, and colony formation of CML cell lines, (2) a change in the splicing landscape, partially overlapping with EZH2 mediated changes, (3) the down-regulation of MYC signalling. Importantly, these findings were successfully validated in a cohort of CML patient samples, confirming the role of CELF2 as EZH2-regulated tumour-suppressor, contributing to the severe splicing de-regulation present in CML. Based on this we propose that EZH2 exerts part of its oncogenic function in CML through the transcriptional repression of splicing factors. Finally, analysis of publicly available datasets suggests that splicing modulation by EZH2 might not be restricted to CML.
    DOI:  https://doi.org/10.1038/s41375-024-02509-y
  27. Blood. 2024 Dec 30. pii: blood.2024026633. [Epub ahead of print]
    FDA-approved therapies for chronic GVHD.
    Stephanie J Lee, Robert Zeiser.
      Despite novel prophylactic regimens, chronic graft-versus-host disease (cGVHD) remains a challenging complication after allogeneic hematopoietic cell transplantation. Chronic GVHD can affect multiple organs and reduces quality of life, and treatment can cause serious side effects. In the last ten years, the drugs ibrutinib, ruxolitinib, belumosudil and axatilimab were FDA-approved for cGVHD. Here we discuss which signaling pathways and cell types are targeted, the clinical studies that were the basis for FDA-approval, and future directions for clinical research.
    DOI:  https://doi.org/10.1182/blood.2024026633
  28. Proc Natl Acad Sci U S A. 2025 Jan 07. 122(1): e2403862122
    Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity.
    Noa Furth, Niv Cohen, Avishay Spitzer, Tomer-Meir Salame, Bareket Dassa, Tevie Mehlman, Alexander Brandis, Arieh Moussaieff, Dinorah Friedmann-Morvinski, Maria G Castro, Jerome Fortin, Mario L Suvà, Itay Tirosh, Ayelet Erez, Guy Ron, Efrat Shema.
      Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2mut) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDHmut cells has not been thoroughly explored. Here, we applied an unbiased approach, leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, to systematically profile the effect of mutant-IDH1 expression on a broad panel of histone modifications at single-cell resolution. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH1, with the most prominent being deregulation of histone acetylation marks. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Notably, the changes in acetylation are not predominantly driven by 2-HG, can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations. Furthermore, cells expressing mutant-IDH1 show higher epigenetic and transcriptional heterogeneity and upregulation of oncogenes such as KRAS and MYC, highlighting its tumorigenic potential. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma and highlights epigenetic and oncogenic pathways affected by mutant-IDH1-driven metabolic rewiring.
    Keywords:  CyTOF; chromatin; epigenetics; mutant-IDH1; oncometabolite
    DOI:  https://doi.org/10.1073/pnas.2403862122
  29. Cell Rep. 2025 Jan 03. pii: S2211-1247(24)01473-6. [Epub ahead of print]44(1): 115122
    Overcoming CD226-related immune evasion in acute myeloid leukemia with CD38 CAR-engineered NK cells.
    Luciana Melo Garcia, Achintyan Gangadharan, Pinaki Banerjee, Ye Li, Andy G X Zeng, Hind Rafei, Paul Lin, Bijender Kumar, Sunil Acharya, May Daher, Luis Muniz-Feliciano, Gary M Deyter, Gabriel Dominguez, Jeong Min Park, Francia Reyes Silva, Ana Karen Nunez Cortes, Rafet Basar, Nadima Uprety, Mayra Shanley, Mecit Kaplan, Enli Liu, Elizabeth J Shpall, Katayoun Rezvani.
      CD226 plays a vital role in natural killer (NK) cell cytotoxicity, interacting with its ligands CD112 and CD155 to initiate immune synapse formation, primarily through leukocyte function-associated-1 (LFA-1). Our study examined the role of CD226 in NK cell surveillance of acute myeloid leukemia (AML). NK cells in patients with AML had lower expression of CD226. CRISPR-Cas9 deletion of CD226 led to reduced LFA-1 recruitment, poor synapse formation, and decreased NK cell anti-leukemic activity. Engineering NK cells to express a chimeric antigen receptor targeting the AML antigen CD38 (CAR38) could overcome the need for CD226 to establish strong immune synapses. LFA-1 blockade reduced CAR38 NK cell activity, and this depended on the CD38 expression levels of AML cells. This suggests parallel but potentially cooperative roles for LFA-1 and CAR38 in synapse formation. Our findings suggest that CAR38 NK cells could be an effective therapeutic strategy to overcome CD226-mediated immune evasion in AML.
    Keywords:  CAR-NK cell; CD226; CP: Cancer; CP: Immunology; LFA-1; acute myeloid leukemia; immune synapse
    DOI:  https://doi.org/10.1016/j.celrep.2024.115122
  30. Cancer Discov. 2025 Jan 07.
    Chronic viral mimicry induction following p53 loss promotes immune evasion.
    Charles A Ishak, Sajid A Marhon, Nairi Tchrakian, Anjelica Hodgson, Helen Loo Yau, Isabela M Gonzaga, Melanie Peralta, Ilinca M Lungu, Stephanie Gomez, Sheng-Ben Liang, Shu Yi Shen, Raymond Chen, Jocelyn Chen, Biji Chatterjee, Kevin N Wanniarachchi, Junwoo Lee, Nicholas Zehrbach, Amir Hosseini, Parinaz Mehdipour, Siyu Sun, Alexander Solovyov, Ilias Ettayebi, Kyle E Francis, Aobo He, Taiyi Wu, Shengrui Feng, Tiago da Silva Medina, Felipe Campos de Almeida, Jane Bayani, Jason Li, Spencer MacDonald, Yadong Wang, Sarah S Garcia, Elisa Arthofer, Noor Diab, Aneil Srivastava, Paul Tran Austin, Peter J B Sabatini, Benjamin D Greenbaum, Catherine A O'Brien, Trevor G Shepherd, Ming Sound Tsao, Katherine B Chiappinelli, Amit M Oza, Blaise A Clarke, Robert Rottapel, Stephanie Lheureux, Daniel D De Carvalho.
      Epigenetic therapies facilitate transcription of immunogenic repetitive elements that cull cancer cells through 'viral mimicry' responses. Paradoxically, cancer-initiating events also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss permits transcription of immunogenic repetitive elements and chronic viral mimicry activation that increases cellular tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity. This selection process can be partially attenuated pharmacologically. Altogether, these results reveal that viral mimicry conditioning following p53 loss promotes immune evasion and may represent a pharmacological target for early cancer interception.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0094
  31. Blood. 2024 Dec 30. pii: blood.2024025771. [Epub ahead of print]
    How I Manage Patients with Unexplained Cytopenia.
    Luca Malcovati, Mario Cazzola.
      The term "unexplained cytopenia" is used to describe a condition characterized by peripheral blood (PB) cytopenia that cannot be attributed to identifiable causes using conventional tests or to any concomitant diseases. Unexplained cytopenia requires clinical attention and further investigation to identify individuals at risk of developing a hematologic neoplasm. The available evidence suggests that somatic mutation analysis may effectively complement the diagnostic work-up and clinical management of unexplained cytopenia. Indeed, the presence or absence of somatic mutation(s) in myeloid genes shows high positive and negative predictive values for myeloid neoplasms (MN). Mutation analysis is also crucial for identifying patients with clonal cytopenia of undetermined significance (CCUS), a condition at increased risk of developing a MN. Recently, clinical/molecular prognostic models have been developed, providing valuable tools for the personalization of clinical and molecular surveillance. Most patients with CCUS show mild cytopenia and do not require therapeutic intervention. Currently, there is no treatment approved for CCUS, and transfusion therapy is the sole therapeutic option for patients with severe symptomatic cytopenia. However, this field has been emerging as a domain of active clinical investigation. This article presents four case studies of patients with unexplained cytopenia, which hematologists may encounter in their clinical practice.
    DOI:  https://doi.org/10.1182/blood.2024025771
  32. Blood. 2025 Jan 10. pii: blood.2024026446. [Epub ahead of print]
    Donor Regulatory T-Cell Therapy to Prevent Graft-Versus-Host Disease.
    Everett Meyer, Anna Pavlova, Alejandro Villar-Prados, Cameron S Bader, Bryan Xie, Lori Muffly, Paige Kim, Katherine C Sutherland, Sushma Bharadwaj, Saurabh Dahiya, Matthew J Frank, Sally Arai, Laura Johnston, David B Miklos, Andrew R Rezvani, Parveen Shiraz, Surbhi Sidana, Judith A Shizuru, Wen-Kai Weng, Vaibhav Agrawal, Amy Putnam, Nathanial B Fernhoff, John Tamaresis, Ying Lu, Rahul D Pawar, J Scott McClellan, Robert Lowsky, Robert S Negrin.
      Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy limited by graft-versus-host disease (GVHD). In preclinical studies and early-phase clinical studies enrichment of donor regulatory T cells (Tregs) appears to prevent GVHD and promote healthy immunity.We enrolled 44 patients on an open-label, single-center, phase 2 efficacy study investigating if a precision selected and highly purified Treg cell therapy manufactured from donor mobilized peripheral blood improves one-year GVHD-free relapse free survival (GRFS) after myeloablative conditioning (trial NCT01660607). We compared this study arm to a concomitant standard of care (SOC) cohort. All donor Treg cell products were successfully manufactured and administered without cryopreservation within 72 hours. Participants had a one-year incidence of acute grade III-IV GVHD of 7%, moderate to severe chronic GVHD of 11% and non-relapse mortality rate of 4.5%. The primary endpoint of significantly improved one-year GRFS was achieved at 64% evaluated against a predicted incidence of 40% (p = 0.002) with a realized incidence of 36% in the SOC comparitor. For those trial patients whow developed grade II-IV acute GVHD, 91% responded to front-line steroid therapy wheras 50% responded in the SOC comparator group. Trial participants had a reduced incidence and burden of GVHD and improved GRFS, as compared to rates common to highly variable unmanipulated donor grafts and multi-agent immune suppression.
    DOI:  https://doi.org/10.1182/blood.2024026446
  33. Nat Cell Biol. 2025 Jan 08.
    Triacylglycerol mobilization underpins mitochondrial stress recovery.
    Zakery N Baker, Yunyun Zhu, Rachel M Guerra, Andrew J Smith, Aline Arra, Lia R Serrano, Katherine A Overmyer, Shankar Mukherji, Elizabeth A Craig, Joshua J Coon, David J Pagliarini.
      Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01586-6
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