bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–10–26
twenty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London



  1. Am J Hematol. 2025 Oct 18.
      The World Health Organization (WHO) 5th Edition and International Consensus Classification (ICC) have continued to delineate more genetically defined acute leukemias. Both recognize genetic aberrations associated with myelodysplastic syndromes/neoplasms (MDS) as defining MDS-related AML (AML-MR). Mutations in RUNX1 are included in this category in the ICC, but not WHO. The current classifications are unclear on how acute leukemias with ambiguous lineage (ALAL), including those of mixed lineage (MPAL) and those without a defined lineage (AUL), should be categorized in the presence of such mutations. Our multi-institutional study aims to determine the significance of RUNX1 mutation in ALAL compared to de novo AML. Newly diagnosed MPAL, AUL, and AML with RUNX1 mutations were collected. ALAL with MDS-related cytogenetics, BCR::ABL1, KMT2A rearrangements, or ZNF384 or BCL11b abnormalities were excluded. We analyzed 17 cases of ALAL and 71 cases of AML that met inclusion criteria. ALAL-RUNX1 and AML-RUNX1 showed overlapping mutational landscapes with frequent comutations in MDS-associated genes. No ALAL-RUNX1 or AML-RUNX1 cases showed concomitant TP53 mutation. ALAL-RUNX1 had more bone marrow blasts and more karyotypic abnormalities; however, neither impacted survival, nor did RUNX1 variant allele frequency (VAF). Survival analysis revealed similarly poor outcomes between them. AML-directed therapies and allogeneic hematopoietic stem cell transplant trended toward improved survival in ALAL-RUNX1; however, it did not reach significance. Our results suggest ALAL-RUNX1 is associated with younger age, higher blasts, and more karyotypic abnormalities, but has similar clinical and genetic features and outcomes to AML-RUNX1. Our findings suggest, like other MR mutations, RUNX1-mutated ALALs should be included within AML-MR.
    Keywords:  AML; immunophenotype; molecular genetics; myelodysplastic syndrome; outcomes research
    DOI:  https://doi.org/10.1002/ajh.70116
  2. Blood. 2025 Oct 20. pii: blood.2024026749. [Epub ahead of print]
      Oncogenic growth places great strain and dependence on protein homeostasis (proteostasis). This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers at tolerable doses, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and increased autophagic flux to preserve proteostasis. Genetic inactivation of HSF1 sensitized AML cells to proteasome inhibition, marked by accumulation of unfolded protein, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival and significant slowing of disease progression and extension of survival in vivo. Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed human AML cells, and significantly reduced AML burden and extended survival in vivo. Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and colony formation, and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, compared to normal hematopoietic stem/progenitor cells. Combined autophagy/proteasome inhibition activated a terminal integrated stress response, which was surprisingly driven by Protein kinase R (PKR). These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.
    DOI:  https://doi.org/10.1182/blood.2024026749
  3. Sci Rep. 2025 Oct 23. 15(1): 37099
      EVI1-rearranged acute myeloid leukemia (AML) with inv(3)(q21q26) or t(3;3)(q21q26) represents a distinct and aggressive subtype characterized by poor prognosis and limited treatment options. However, the optimal strategy to overcome resistance to conventional therapy remains elusive. Building upon observations correlating EVI1 overexpression with reduced sensitivity to venetoclax, a BH3-mimetic BCL-2 inhibitor, we investigated the mechanisms of resistance to venetoclax in combination with hypomethylating agents in inv(3)/t(3;3) AML cells. Utilizing novel murine models recapitulating inv(3) AML with concomitant SF3B1 mutations, we conducted comprehensive phenotypic and transcriptomic analyses in the presence or absence of venetoclax-containing therapy. Despite initial therapeutic responses, manifested as partially prolonged survival and myeloid differentiation, resistant leukemic cells demonstrated enhanced dependency on BRD4 and MYB pathways with a dormant phenotype. Notably, inhibition of either BRD4 or MYB significantly augmented the efficacy of venetoclax and hypomethylating agents in both murine and patient-derived AML models harboring inv(3) and SF3B1 mutations. These findings elucidate the transcriptional dynamics underlying venetoclax resistance and propose alternative therapeutic strategies targeting BRD4 and MYB as promising avenues for improving outcomes in patients with EVI1-rearranged AML. Our work highlights the necessity for innovative combination therapies to address the multifaceted mechanisms of resistance in this high-risk leukemia subtype.
    Keywords:  Acute myeloid leukemia; BRD4; EVI1; Hypomethylating agent; MYB; Venetoclax
    DOI:  https://doi.org/10.1038/s41598-025-21034-1
  4. Hemasphere. 2025 Oct;9(10): e70214
      Venetoclax has been combined with intensive chemotherapy regimens in the treatment of acute myeloid leukemia (AML). We aimed to investigate the safety and efficacy of venetoclax combined with full-dose CPX-351 (CPX + VEN) in newly diagnosed (ND) AML. Seventeen patients with a median age of 59 years (range, 43-69) were treated; 71% had secondary AML, 47% had prior hypomethylating agent (HMA) exposure, 59% had myelodysplastic syndrome (MDS)-related (MR) mutations, 47% had complex karyotype, and 29% were TP53 mutated. The overall response rate (ORR) was 82% (95% CI, 57-96) with a composite complete remission rate (CRc) of 71% (95% CI, 50-93). Patients with MR mutations had an ORR of 100% (95% CI, 69-100), including a CRc of 90% (95% CI, 55-100). Patients with prior HMA exposure had a CRc of 63% (95% CI, 24-91). With a median follow-up time of 11.8 months, the median overall survival (OS) was 12.8 months (95% CI, 5-NE) with a 2-year OS of 34% (95% CI, 10-61). Patients with MR mutations had a median OS of 17.9 months versus 5.1 months in patients without MR mutations (P = 0.039). Twelve (86%) of 14 responding patients proceeded to stem cell transplant (SCT); the median recurrence-free survival and OS landmarked from date of SCT were 14.7 months (95% CI, 1-32) and 14.7 months (95% CI, 4-25), respectively. The 4-week mortality was 0% and the 8-week mortality was 17%. The most common adverse events were related to myelosuppression. CPX + VEN resulted in high remission rates and enabled progression to allogenic SCT for the majority of a highly adverse group of ND AML patients.
    DOI:  https://doi.org/10.1002/hem3.70214
  5. Exp Hematol Oncol. 2025 Oct 21. 14(1): 123
      KMT2A-altered acute myeloid leukemia (AML) comprises rearrangements (KMT2A-r), partial tandem duplications (KMT2A-PTD), and dual alterations (KMT2A-r/PTD). In this study of 125 patients, these subgroups exhibited distinct molecular profiles: KMT2A-r cases were enriched in RAS pathway mutations, whereas KMT2A-PTD showed a higher burden of epigenetic alterations. Although overall survival (OS) and event-free survival (EFS) did not differ significantly between subgroups, prognosis was strongly influenced by fusion partners. MLLT3/ELL-rearranged cases showed superior outcomes, but concurrent KMT2A-PTD abrogated this survival advantage, AFDN and other fusions showed poor outcomes. We therefore propose a revised three-tier risk model integrating fusion partner and PTD status, which significantly stratified patient outcomes. The intermediate-risk group (MLLT3/ELL without PTD) had a 3-year OS of 78.1%, compared to 50.5% in the high-risk group (all PTD), and 34.9% in the very high-risk group (other KMT2A-r) (P = 0.044). For EFS, the rates were 71.0%, 40.1%, and 24.9%, respectively (P = 0.003). Allogeneic hematopoietic cell transplantation significantly improved survival, with 3-year OS rates of 75.2% in transplant recipients versus 22.5% in non-transplanted patients (P < 0.001), particularly in high-risk groups and when performed in first complete remission. These findings support the use of molecularly guided, risk-adapted therapy in KMT2A-altered AML.
    Keywords:   KMT2A partial tandem duplication (KMT2A-PTD); KMT2A rearrangement (KMT2A-r); Acute myeloid leukemia (AML); Allogeneic hematopoietic cell transplantation (allo-HCT); Risk stratification
    DOI:  https://doi.org/10.1186/s40164-025-00714-8
  6. Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2509412122
      Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here, we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. Linker histones package nucleosomes and compact chromatin. HSPCs expressing a doxycycline (dox)-inducible H1.0 transgene favor the lymphoid fate, display strengthened nucleosome organization, and reduced chromatin accessibility at subsets of genomic regions. The genomic regions showing reduced chromatin accessibility host many known marker genes of myeloid-biased HSCs. The transcription factor Hlf is located in one of the most differentially closed regions, whose chromatin accessibility and gene expression are reduced in H1.0high HSPCs. Failure to reduce Hlf expression in multipotential HSPCs abrogates the H1.0-endowed lymphoid potential. Furthermore, HSPCs display aspartyl protease-dependent H1.0 decreases, especially in response to interferon alpha (IFNα). Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work elucidates a molecular scenario of how myeloid bias arises and uncovers a point of intervention for correcting myeloid skewed hematopoiesis.
    Keywords:  inflammation; linker histone; myeloid bias
    DOI:  https://doi.org/10.1073/pnas.2509412122
  7. Mol Cancer Ther. 2025 Oct 22.
      Histone deacetylase (HDAC) inhibitors have been considered as anti-leukemic agents, but have shown poor efficacy in clinical trials. Here, we investigated the immediate transcriptional response to the HDAC inhibitor SAHA (Vorinostat) in healthy CD34+ blood stem/progenitor cells and primary acute myeloid leukemia (AML) patient myeloblasts, carrying TET2 and NPM1 mutations. We found that although healthy CD34+ and AML cells differed substantially at the transcriptional level, they responded very similarly to 10 min SAHA-treatment. HDAC inhibition led to a global increase in histone acetylation, however only 150-250 genes were up-regulated. These were involved in oxidative stress, metabolism, chromatin regulation, cell-cycle control and cell death, and the vast majority were up-regulated in both healthy and AML cells. Up-regulated genes were more highly acetylated compared to average expressed genes, and had higher levels of promoter-proximal paused RNA polymerase II (Pol II) before treatment. Upon HDAC inhibition, up-regulated genes increased BRD4 occupancy the most and released paused Pol II into transcription elongation. Our results suggest that the immediate effect of HDAC inhibition is to trigger release of paused Poll II into elongation. We speculate that the similar transcriptional response in healthy and leukemic cells may contribute to the poor efficacy of HDAC inhibitors in patients with hematological malignancies.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0150
  8. Br J Haematol. 2025 Oct 24.
      Treatment with pegylated interferon α resulted in a molecular response in 91% of patients with an average decrease in JAK2V61F VAF of 48.5% from baseline. In patients that discontinued treatment, the JAK2V617F VAF at the time of treatment discontinuation was the best indicator of durable remission over the 6-month follow-up period. Created with SMART Servier Medical Art (https://smart.servier.com/).
    Keywords:   JAK2 ; myeloproliferative neoplasm; pegylated interferon alpha
    DOI:  https://doi.org/10.1111/bjh.70198
  9. Exp Hematol Oncol. 2025 Oct 22. 14(1): 126
      MLL (KMT2A)-rearranged leukemia (MLL-r) is a highly aggressive hematologic malignancy driven by transcriptional dysregulation. Here, we identify EYA family phosphatase activity, particularly EYA1 and EYA3, as key vulnerabilities in MLL-r leukemia. The small molecule benzbromarone (BBR) selectively reduced viability in MLL-r and EYA-expressing MLL-nonrearranged (MLL-nr) leukemia cells. Inhibition of EYA PTP activity increased global RNA Pol II CTD Tyr1 phosphorylation, linking aberrant EYA PTP activity in responsive leukemia cells to transcriptional dysregulation. In vivo, BBR treatment significantly prolonged survival and reduced leukemia burden without overt toxicity. Furthermore, BBR synergized with the menin-MLL inhibitor VTP50469 and showed additive effects with the DOT1L inhibitor EPZ5676, the latter of which restored BBR sensitivity in previously BBR-unresponsive cells. These findings establish EYA PTP activity as a therapeutic target in MLL-r leukemia, support the use of EYA expression for identifying patients likely to benefit from BBR treatment, and highlight the potential of BBR-based combinations to improve response in this high-risk leukemia subtype.
    DOI:  https://doi.org/10.1186/s40164-025-00717-5
  10. Cancer Cell. 2025 Oct 23. pii: S1535-6108(25)00406-4. [Epub ahead of print]
      Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage defined by mutations activating mitogen-activated protein kinase (MAPK) signaling. Recently, the MEK1/2 inhibitor cobimetinib was FDA-approved for patients with adult histiocytoses. Here, aided by a prospective registry of patients with histiocytoses (NCT03329274), we identify that MEK1/2 mutations which constitutively activate MEK independently of RAF are associated with worse progression-free survival with MEK1/2 inhibition as compared to patients with other MEK1/2 mutational classes. The most common RAF-independent MEK1 mutation (MEK1E102_I103del) drove a lethal histiocytic-like neoplasm in mice, which was sensitive to the ERK1/2 inhibitor ulixertinib. We subsequently treated five MEK1E102_I103del-mutant patients with ulixertinib on prospective protocols, four of whom were refractory to MEK inhibition. Four of five patients experienced objective responses to ulixertinib. These data reveal the impact of oncogenic MEK mutations in vivo, identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition to overcome resistance to MEK inhibition in histiocytoses.
    Keywords:  BRAF; ERK; Erdheim-Chester disease; Langerhans cell histiocytosis; MEK; cobimetinib; histiocytoses; macrophage; trametinib; ulixertinib
    DOI:  https://doi.org/10.1016/j.ccell.2025.09.014
  11. Blood Adv. 2025 Oct 22. pii: bloodadvances.2025017837. [Epub ahead of print]
      Myeloid leukemia of Down syndrome (ML-DS) is a distinct form of pediatric acute myeloid leukemia (AML) that responds to reduced intensity chemotherapy as compared to non-DS AML that requires intensive chemotherapy and often stem cell transplant. While most patients with ML-DS have a favorable prognosis, outcomes for those with refractory or relapsed disease are dismal. Children's Oncology Group (COG) study AAML1531 introduced the use of minimal residual disease measured by multi-parameter flow cytometry at the end of the first course of induction therapy (EOI-1 MRD) for risk stratification of treatment intensity. Of 280 ML-DS patients enrolled, 41 were classified as high risk (HR) due to positive EOI-1 MRD and treated with intensified chemotherapy similar to that used for pediatric non-DS AML. Treatment intensification did not improve the 2-year event-free survival compared to MRD-positive patients treated with reduced intensity therapy in predecessor study AAML0431(80.5 + 12.4% vs. 76%, p=0.247) or overall survival (80.5 + 12.4% vs. 76.2 + 18.6%, p=0.819), but significantly increased the frequency of febrile neutropenia and sepsis events. While stratification of treatment intensity based on MRD was not beneficial, molecular markers of relapse risk proposed by the Japan Children's Cancer Group for ML-DS (alterations of CDKN2A, ZBTB7A, JAK2, TP53) proved prognostic. Relapse risk was 50% in AAML1531 HR patients with any high risk molecular marker compared to 6.7% in those without. Similar relapse results were obtained in the MRD-negative AAML1531 group, suggesting molecular risk markers can predict outcome and thus be used to stratify therapy in ML-DS. https://clinicaltrials.gov/study/NCT02521493.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017837
  12. J Clin Oncol. 2025 Oct 24. JCO2501369
      On June 6, 2024, the US Food and Drug Administration (FDA) approved imetelstat (RYTELO, Geron) for adults with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring ≥4 red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents. The approval was based on a randomized (2:1), double-blind, placebo-controlled multicenter trial, Study MDS3001. In the protocol-specified primary analysis, the ≥8-week RBC transfusion independence (RBC-TI) rate was 39.8% (95% CI, 30.9 to 49.3) in the imetelstat group versus 15% (95% CI, 7.1 to 26.6) in the placebo group (P < .001). This was supported by the rate of ≥24-week RBC-TI of 28% (95% CI, 20.1 to 37) in the imetelstat group versus 3.3% (95% CI, 0.4 to 11.5) in the placebo group (P < .001). However, there was no major difference between arms regarding the key secondary end point of erythroid response (HI-E) per International Working Group 2006 criteria or secondary end points reflective of a disease-modifying effect such as complete remission rate and overall survival. The most common adverse reactions were thrombocytopenia, leukopenia, neutropenia, increased liver enzymes, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19, and headache. The rate of grade 3 to 4 neutropenia and thrombocytopenia were 72% and 65%, respectively, in the imetelstat arm compared with 7% and 8% in the placebo arm. Despite the high incidence of neutropenia and thrombocytopenia, the FDA determined that the benefits outweighed the risks in this patient population with high unmet need. Postmarketing requirements were issued to evaluate long-term safety and to conduct a randomized trial comparing at least two dosages of imetelstat to potentially minimize risks of imetelstat treatment and improve tolerability.
    DOI:  https://doi.org/10.1200/JCO-25-01369
  13. Cell Death Discov. 2025 Oct 20. 11(1): 470
      Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of myeloid blasts in the bone marrow. Despite the availability of potential curative treatments, patients frequently experience unfavorable outcomes. One crucial aspect contributing to relapse is the plasticity of leukemic clones, which enables them to switch between active proliferation and dormancy. The adaptability of AML underscores the need for novel therapies targeting AML-specific proteins. To address this, genome-wide CRISPR screens can be utilized to identify cancer entity-specific vulnerabilities. Leveraging publicly available functional genomics datasets and comparing AML with non-AML cancer cell lines, we identified a significant dependency on the cell cycle-regulating gene MYBL2 in AML. We describe MYBL2 as a key driver of AML cell growth and proliferation, highlighting its established role as a cell cycle regulator. Also, our findings uncover its previously unrecognized function as an inhibitor of cellular senescence. A knockdown of MYBL2 induces cell cycle arrest in the G2/M phase with subsequent induction of apoptosis in vitro, and reduces leukemic burden in a patient-derived xenograft (PDX) model in vivo. Interestingly, some AML cells evade apoptosis and enter a senescent-like phenotype upon MYBL2-knockdown, which is reversible upon re-expression of MYBL2. Finally, analyses of clinical data from two publicly available patient cohorts demonstrate a lower probability of survival in patients with higher MYBL2 expression, further hinting at the potential relevance of MYBL2 in AML. In conclusion, our findings demonstrate the essential role of MYBL2 in AML, governing the balance between cell proliferation, cell survival and senescence, ultimately influencing the fate of AML cells.
    DOI:  https://doi.org/10.1038/s41420-025-02810-4
  14. Blood Cancer J. 2025 Oct 24. 15(1): 178
      Accumulation of genetic mutations in malignant myeloid precursor cells leads to an extremely poor prognosis for patients with acute myeloid leukemia (AML). Immunogenic neoantigens recognized by T cell receptor (TCR) can elicit effective immune responses against malignant cells with corresponding somatic mutations. To broaden the range of targeted treatments for AML, in this study, we explored the feasibility of immunotherapy targeting neoantigens arising from recurrent mutations, which are exclusively present on leukemic cells. We used data-driven methods to select seven neoantigens from four frequently mutated genes (NPM1, FLT3, TP53, and DNMT3A) associated with HLA-A*02:01-positive AML patients. Functional assays demonstrated that neoantigens derived from NPM1/W288fs, FLT3/D835H, and FLT3/D835Y were shown to induce specific T cell responses in AML patients. We further identified the specific TCR sequences from healthy donors capable of recognizing these neoantigens. In-depth studies of their specific T cells revealed the presence of dominant αβTCRs that could specifically recognize NPM1/W288fs and FLT3/D835H in an HLA-A*02:01-restricted manner. T cells engineered with each αβTCR selectively recognized and killed HLA-A*02:01-positive AML targets endogenously expressing corresponding mutations. Overall, our findings support the clinical translation of adoptive neoantigen-specific TCR-engineered T cells as a novel therapeutic strategy for treating AML.
    DOI:  https://doi.org/10.1038/s41408-025-01370-1
  15. Mol Metab. 2025 Oct 19. pii: S2212-8778(25)00182-6. [Epub ahead of print] 102275
      T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy commonly driven by NOTCH1 activating mutations. A concomitant feature associated with NOTCH1 mutations is heightened oxidative metabolism enabling the exponential proliferation of T-ALL blasts. As such, targeting mitochondrial metabolism in T-ALL is an attractive therapeutic avenue. Related to this, canagliflozin (cana), is an FDA-approved sodium glucose co-transporter 2 inhibitor with known off-target effects on complex I and glutamate dehydrogenase, but its potential anti-leukaemic effects remain unexplored. Here, we show that cana possesses potent anti-leukaemic effects underpinned by proliferative defects, cell cycle disruption and apoptosis. These anti-leukaemic effects driven by cana, are attributed to a perturbed tricarboxylic acid (TCA) cycle and mitochondrial metabolism, and elevated mitochondrial ROS. Proteomic analysis revealed that cana treatment resulted in a compensatory increase in the expression of ATF4 targets, including upregulation of serine biosynthesis pathway and one-carbon metabolism enzymes. As such, restriction of serine and glycine synergized with cana treatment, further enhancing its anti-leukaemic effects. Collectively, our study reveals a cana-driven metabolic vulnerability that can be further exploited via dietary manipulation to treat T-ALL.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102275
  16. Bone Marrow Transplant. 2025 Oct 18.
      We assessed pGF in 2497 AML patients undergoing HSCT from 8-10/10 HLA-matched UD with PTCy. pGF was defined as failure to achieve an ANC ≥ 0.5 × 109/L by day +30 after HSCT. The day +30 cumulative incidence of ANC was 92.6% (95%CI: 91.5-93.6), and the incidence of death without ANC recovery was 1.8% (95% CI: 1.3%-2.3%), corresponding to 141 (5.6%) patients not achieving an ANC ≥ 0.5 × 109/L by day +30. PB was the graft source in 89.4% of the patients, and 56% received reduced-intensity conditioning. 21 patients underwent a second HSCT (15 in the absence of ANC recovery and 6 after ANC recovery). 1-y NRM and RI post-pGF were 22.1% and 22.4%, respectively. 1-y LFS and OS post-pGF were 59% and 55.5%, respectively. ANC recovery evaluated as a time-dependent covariate, KPS ≥ 90, and being in CR at the time of HSCT were associated with improved OS. In conclusion, the incidence of pGF post-unrelated HSCT with PTCy was 5.6%. Of the patients who failed to engraft by day +30, 70.9% did so by day +60. A second transplant can save some of the patients with pGF.
    DOI:  https://doi.org/10.1038/s41409-025-02726-8
  17. Cell Death Dis. 2025 Oct 21. 16(1): 750
      Leukemia cells are consistently subjected to higher oxidative stress than normal cells. To mitigate reactive oxygen species (ROS) overload, which can trigger various forms of cell death, leukemia cells employ a robust antioxidant defense system and maintain redox homeostasis. Recent evidence suggests that dimethyl fumarate (DMF), a derivative of fumarate, inactivates the antioxidant glutathione (GSH), thereby inducing oxidative stress and metabolic dysfunction, eventually leading to cell death in cancer cells. In this study, we observed that DMF decreases the GSH/oxidated GSH ratio and increases intracellular ROS levels, the extent of which is closely correlated with cell death, in acute myeloid leukemia (AML) cell lines. DMF reduced the mitochondrial membrane potential and oxidative phosphorylation (OXPHOS), effects that were almost fully restored by the antioxidant N-acetylcysteine, suggesting that these responses are ROS-dependent. Electron microscopy and inhibition assays revealed that apoptosis, rather than necroptosis or ferroptosis, is the predominant form of cell death of AML cells following DMF treatment. Notably, the combination of DMF and the BCL-2 selective BH3-mimetic venetoclax induced marked cell death in AML cells, including venetoclax-refractory BCL-2 low expressing U937 and acquired venetoclax-resistant MOLM-14 cells. This combination also caused greater mitochondrial depolarization and a more profound reduction in OXPHOS activity than either agent alone. Collectively, our findings indicate that DMF exerts potent anti-leukemia activity in AML cells and sensitizes cells to venetoclax treatment by synergistically disrupting mitochondrial integrity through ROS accumulation.
    DOI:  https://doi.org/10.1038/s41419-025-08040-x
  18. Nat Immunol. 2025 Oct 22.
      Large-scale, unbiased single-cell genomics studies of complex developmental compartments, such as hematopoiesis, have inferred novel cell states and trajectories; however, further characterization has been hampered by difficulty isolating cells corresponding to discrete genomic states. To address this, we present a framework that integrates multimodal single-cell analyses (RNA, surface protein and chromatin) with high-dimensional flow cytometry and enables semiautomated enrichment and functional characterization of diverse cell states. Our approach combines transcription factor expression with chromatin activity to uncover hierarchical gene regulatory networks driving these states. We delineated and isolated rare bone marrow Lin-Sca-CD117+CD27+ multilineage cell states ('MultiLin'), validated predicted lineage trajectories and mapped differentiation potentials. Additionally, we used transcription factor activity on chromatin to trace and isolate multilineage progenitors undergoing multipotent to oligopotent lineage restriction. In the proposed model of steady-state hematopoiesis, discrete states governed developmental trajectories. This framework provides a scalable solution for isolating and characterizing novel cell states across different biological systems.
    DOI:  https://doi.org/10.1038/s41590-025-02307-3
  19. Leuk Lymphoma. 2025 Oct 24. 1-9
      Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive, orphan hematologic malignancy characterized by cells expressing CD123 and other markers. The only drug approved for BPDCN is tagraxofusp, a first-in-class CD123-targeted therapy. Tagraxofusp has a boxed warning for capillary leak syndrome (CLS) in the US prescribing information. CLS symptoms include hypoalbuminemia, weight gain, edema, and in severe cases, hypotension and hemodynamic instability. In the tagraxofusp registrational trial, 21% of patients receiving 12 µg/kg/day developed CLS. Most events were grade 2; higher grade CLS events including 2% grade 3, 2% grade 4, and two deaths occurred. During tagraxofusp treatment, strict monitoring for early recognition of CLS symptoms and directed intervention is essential for managing CLS; with this approach CLS is typically mild and occurs mostly in cycle 1, without recurrence. We discuss patient selection and optimization, monitoring, and early intervention for successful identification and optimized management of CLS in real-world practice.
    Keywords:  Blastic plasmacytoid dendritic cell neoplasm; adverse effects; capillary leak syndrome; monitoring; symptom management; tagraxofusp
    DOI:  https://doi.org/10.1080/10428194.2025.2557505
  20. Blood Rev. 2025 Oct 16. pii: S0268-960X(25)00085-2. [Epub ahead of print] 101340
      This review summarizes applications of machine learning (ML) in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), spanning diagnosis, prognostication, treatment prediction, and research tools. In diagnostics, deep learning applied to bone marrow smears, peripheral blood films, and flow cytometry has shown high sensitivity and specificity, outperforming conventional methods. ML-driven unsupervised clustering and consensus classification have refined disease taxonomies, identifying genomic subtypes with prognostic value. Prognostic models and neural networks enable dynamic, personalized survival predictions. In treatment, ML assists in predicting responses to hypomethylating agents and venetoclax-based regimens, supporting clinical decision-making. In research, generative approaches create privacy-preserving synthetic cohorts and digital twins, facilitating trial design and overcoming data limitations. Future integration into clinical practice will require rigorous validation, explainable algorithms, seamless workflow incorporation, and regulatory oversight to ensure trust, equity, and safety. ML has potential to enhance multiple aspects of AML and MDS management.
    Keywords:  Acute myeloid leukemia; Artificial intelligence; Digital twins; Machine learning; Myelodysplastic syndromes; Prognostication
    DOI:  https://doi.org/10.1016/j.blre.2025.101340
  21. Transplant Cell Ther. 2025 Oct 18. pii: S2666-6367(25)01444-7. [Epub ahead of print]
       BACKGROUND: Data on transplant outcomes of obese patients undergoing allogeneic hematopoietic cell transplant (alloHCT) have demonstrated conflicting results both in regard to the prognostic significance of obesity and appropriate dosing of chemotherapy to balance toxicity and efficacy.
    OBJECTIVES: We retrospectively evaluated 751 acute myeloid leukemia (AML) patients who underwent alloHCT at the Moffitt Cancer Center from 2010-2021 to compare transplant outcomes of obese (BMI ≥ 30 kg/m2) and non-obese patients (BMI < 30 kg/m2). Transplant related outcomes included time to engraftment, acute graft-versus-host disease (aGVHD), moderate-severe chronic graft-versus-host disease (cGVHD), relapse, non-relapse mortality (NRM), relapse free survival (RFS), and overall survival (OS).
    STUDY DESIGN: Data was collected via internal database supplemented by direct records review. Univariate Cox regression models were developed using baseline variables, and multivariate Cox regression models were built using significant variables from univariate analysis and backwards selection. Similarly, Fine & Gray subdistribution hazard models were built when competing risks were present. Kaplan Meier curves were utilized to show RFS and OS. The time-to-event outcomes with competing risks were summarized by cumulative incidence curves. In the subgroup of patients with BMI ≥ 30 kg/m2 receiving melphalan based conditioning (n=78), we compared outcomes in patients who received melphalan dosed on total body weight vs. adjusted body weight.
    RESULTS: The cohort of 751 patients included 246 (32.8%) with BMI ≥ 30 kg/m2, and 505 (67.2%) with BMI < 30 kg/m2. Median follow up time was 50 months. Engraftment did not differ between groups. The cumulative incidence of grade 2-4 aGVHD was 49% for patients with BMI ≥ 30 kg/m2 and 44% for patients with BMI < 30 kg/m2, (p=0.28), while the cumulative incidence of moderate to severe cGVHD was 24% vs 25% (p=0.56). The cumulative incidence of relapse at 2 years was 23% vs 27% for patients with BMI ≥ 30 kg/m2 and BMI < 30 kg/m2 respectively (p=0.41), and cumulative incidence of NRM at 1 year was 14% vs 15% (p=0.94). OS at 2 years was 64% vs 59% for patients with BMI ≥ 30 kg/m2 and BMI < 30 kg/m2, respectively (p=0.35). In multivariable analysis, BMI was not shown to affect aGVHD, moderate to severe cGVHD, NRM, RFS, relapse, or OS. In the analysis of obese patients who received melphalan, no significant differences in outcomes were found between those receiving melphalan dosed by total body weight vs adjusted body weight.
    CONCLUSIONS: In this study of North American AML patients receiving alloHCT with varying conditioning and GVHD prophylaxis, including post-transplant cyclophosphamide, there were no significant differences in clinical outcomes between patients with BMI ≥ 30 kg/m2 compared to patients with BMI < 30 kg/m2.
    Keywords:  Allogeneic hematopoietic cell transplant; body mass index; chemotherapy dosing; melphalan; obesity
    DOI:  https://doi.org/10.1016/j.jtct.2025.09.022
  22. Haematologica. 2025 Oct 23.
      Driver mutations in KMT2A-rearranged (KMT2A-r) have been identified in acute myeloid leukemia (AML); however, age-related differences in their frequency and prognostic factors remain unclear. In this study, we report age-specific mutation profiles and outcomes in pediatric patients with KMT2A-r AML. In 239 cases of KMT2A-r AML, infants (<1 year, n = 59) showed a significantly higher event-free survival (EFS) and overall survival (OS) compared with children (≥1 year, n = 180). Conversely, in 538 cases of non-KMT2A-r AML, infants exhibited a significantly lower EFS and OS than children. KMT2A::MLLT4 was only detected in children with KMT2A-r AML and was associated with a poor prognosis. In KMT2A-r AML, mutations in signaling pathway genes, such as KRAS, were frequently detected in infants and children. However, the frequency of non-signaling pathway mutations was significantly higher in children. Moreover, non-signaling pathway mutations had no significant effect on the prognosis in infants and children, whereas KRAS mutations were associated with poor prognosis in both groups. Multivariate analysis identified older age, a high white blood cell count, KMT2A::MLLT4, and KRAS mutations as independent adverse prognostic factors for both EFS and OS. These age-specific mutation profiles suggest distinct disease mechanisms across age groups and may help refine risk stratification and treatment strategies for pediatric KMT2A-r AML.
    DOI:  https://doi.org/10.3324/haematol.2025.288481