bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–05–25
35 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London



  1. Am J Hematol. 2025 May 22.
      Outcomes in patients with relapsed/refractory (RR) AML are poor. We sought to investigate if CPX-531 in combination with venetoclax (CPX + VEN) was tolerable and effective in RR AML. This was a single institution phase 1b/2 trial of CPX + VEN. Patients aged ≥ 18 years with RR AML who were fit for intensive chemotherapy were eligible. Prior venetoclax exposure was allowed. The phase 1b portion followed a 3 + 3 design to identify the recommended phase 2 dose (RP2D) for the expansion cohort. At the starting dose level of -1, prolonged myelosuppression was observed, leading to dose level -2 (CPX-351 dosed at daunorubicin 44 mg/m2 on days 1,3, and 5 and venetoclax 300 mg days 2-8) being chosen as the RP2D. Thirty three patients with a median age of 58 years (range, 26-72) were treated. Patients were heavily pretreated, with 58% with prior venetoclax exposure, 44% in the second salvage or later, and 30% with prior stem cell transplant (SCT). Adverse cytogenetics were present in 51% of patients, with myelodysplasia-related mutations in 64%, and TP53mut in 21%. The overall response rate (ORR) was 46% (95% CI, 30-62), with a composite CR rate (CRc) of 39% (95% CI, 25-56). Patients in first salvage with wildtype TP53 had a CRc rate of 70% (95% CI, 40-89), with undetectable MRD in 71% (95% CI, 36-92) and a 2-year OS of 49% (95% CI, 23-100). Eleven (73%) responding patients underwent SCT. The 30-day mortality was 9%, with a 60-day mortality of 21%. The most common adverse events were related to myelosuppression. CPX + VEN has activity in RR AML, particularly when used in first salvage and in patients who do not harbor TP53 mutations. ClinicalTrials.gov Identifier: NCT03629171.
    Keywords:  AML; CPX‐VEN; clinical trial
    DOI:  https://doi.org/10.1002/ajh.27723
  2. Cancer Metab. 2025 May 19. 13(1): 22
       BACKGROUND: Enhanced glycolysis plays a pivotal role in fueling the aberrant proliferation, survival and therapy resistance of acute myeloid leukemia (AML) cells. Here, we aimed to elucidate the extent of glycolysis dependence in AML by focusing on the role of lactate dehydrogenase A (LDHA), a key glycolytic enzyme converting pyruvate to lactate coupled with the recycling of NAD+.
    METHODS: We compared the glycolytic activity of primary AML patient samples to protein levels of metabolic enzymes involved in central carbon metabolism including glycolysis, glutaminolysis and the tricarboxylic acid cycle. To evaluate the therapeutic potential of targeting glycolysis in AML, we treated AML primary patient samples and cell lines with pharmacological inhibitors of LDHA and monitored cell viability. Glycolytic activity and mitochondrial oxygen consumption were analyzed in AML patient samples and cell lines post-LDHA inhibition. Perturbations in global metabolite levels and redox balance upon LDHA inhibition in AML cells were determined by mass spectrometry, and ROS levels were measured by flow cytometry.
    RESULTS: Among metabolic enzymes, we found that LDHA protein levels had the strongest positive correlation with glycolysis in AML patient cells. Blocking LDHA activity resulted in a strong growth inhibition and cell death induction in AML cell lines and primary patient samples, while healthy hematopoietic stem and progenitor cells remained unaffected. Investigation of the underlying mechanisms showed that LDHA inhibition reduces glycolytic activity, lowers levels of glycolytic intermediates, decreases the cellular NAD+ pool, boosts OXPHOS activity and increases ROS levels. This increase in ROS levels was however not linked to the observed AML cell death. Instead, we found that LDHA is essential to maintain a correct NAD+/NADH ratio in AML cells. Continuous intracellular NAD+ supplementation via overexpression of water-forming NADH oxidase from Lactobacillus brevis in AML cells effectively increased viable cell counts and prevented cell death upon LDHA inhibition.
    CONCLUSIONS: Collectively, our results demonstrate that AML cells critically depend on LDHA to maintain an adequate NAD+/NADH balance in support of their abnormal glycolytic activity and biosynthetic demands, which cannot be compensated for by other cellular NAD+ recycling systems. These findings also highlight LDHA inhibition as a promising metabolic strategy to eradicate leukemic cells.
    Keywords:  Acute myeloid leukemia; Cancer metabolism; Glycolysis; Lactate dehydrogenase A; NAD+ ; Redox balance
    DOI:  https://doi.org/10.1186/s40170-025-00392-4
  3. Blood Adv. 2025 May 22. pii: bloodadvances.2025015797. [Epub ahead of print]
      Most patients with acute myeloid leukemia (AML) may obtain remission upon induction chemotherapy, but relapse is frequent and associated with poor survival. Previous prognostic models for outcomes after relapse lacked analysis of comprehensive molecular data. A validated prognostic model integrating clinical, cytogenetic, and molecular variables may support treatment decisions. We studied 943 AML patients who relapsed after first-line intensive induction treatment in a development cohort (HOVON-SAKK). A random survival forest algorithm was used to evaluate the association of clinical parameters, cytogenetic abnormalities, and molecular variables at diagnosis with overall survival (OS). Relapsing patients (n=377) who were enrolled in the NCRI-AML18 trial were used for model validation. In the development cohort, the median age at relapse was 58 years, and patients were classified as 2022 ELN favorable (22%), intermediate (31%), and adverse (48%) risk. One-third underwent allogeneic transplantation in first complete remission. Variable selection yielded nine variables significantly associated with 1-year OS, including relapse-free interval, age, white blood cell count, mutated TP53, FLT3-ITD, core-binding factor abnormalities, t(v;11q23)/KMT2A-rearranged and complex/monosomal karyotype, which were assigned points according to their estimated hazard ratios. Three prognostic groups were defined with distinct 1-year OS in both development (favorable: 51±3%, intermediate: 29±3% and poor: 14±2%, respectively) and validation cohorts (51±4%, 26±5% and 14±3%, respectively). Independent validation confirmed the improved accuracy in predicting outcomes for AML patients in first relapse. The revised AML relapse model improved on previous classification systems for prognostication of outcomes after first AML relapse. It provides stratification which might support tailoring second line treatment.
    DOI:  https://doi.org/10.1182/bloodadvances.2025015797
  4. Cell Stem Cell. 2025 May 21. pii: S1934-5909(25)00179-1. [Epub ahead of print]
      Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine.
    Keywords:  IDH inhibitors; IDH1/2 mutations; acute myeloid leukemia; cellular hierarchy; clonal architecture; clonal evolution; relapse; single-cell transcriptomics; targeted therapy; treatment resistance
    DOI:  https://doi.org/10.1016/j.stem.2025.04.012
  5. Leukemia. 2025 May 22.
      Metabolic rewiring is a hallmark of malignant transformation in leukemic cells and the potential offered by its therapeutic targeting has garnered significant attention. The development of clinically relevant metabolic targeted therapies in acute myeloid leukemia (AML) has mostly focused on targeting mitochondrial energy production, but progress has been hampered by generalized toxicities. An alternative strategy is to shift the focus from targeting energy production to targeting more specialized metabolic functions, such as energy storage, the regulation of oxidative stress and availability of cofactors needed for the function of specific metabolic reactions. Lipid metabolism plays a role in many of these metabolic functions and its importance in AML maintenance and response to therapy is being increasingly recognized but needs to be adequately interpreted in the context of its interaction with the microenvironment, particularly the adipose niche. In this review, we provide an overview of our current understanding of AML cellular metabolic dependencies on fatty acid and lipid metabolism and discuss their relevance in the context of functional interactions with adipocytes. We highlight unresolved questions about how to best target lipid metabolism and suggest approaches needed to fully understand the interplay between malignant cells and their niche in the context of metabolic dependencies.
    DOI:  https://doi.org/10.1038/s41375-025-02645-z
  6. Nat Commun. 2025 May 19. 16(1): 4656
      Nucleoporin 98 (NUP98) fusion oncoproteins are strong drivers of pediatric acute myeloid leukemia (AML) with poor prognosis. Here we show that NUP98 fusion-expressing AML harbors an epigenetic signature that is characterized by increased accessibility of hematopoietic stem cell genes and enrichment of activating histone marks. We employ an AML model for ligand-induced degradation of the NUP98::KDM5A fusion oncoprotein to identify epigenetic programs and transcriptional targets that are directly regulated by NUP98::KDM5A through CUT&Tag and nascent RNA-seq. Orthogonal genome-wide CRISPR/Cas9 screening identifies 12 direct NUP98::KDM5A target genes, which are essential for AML cell growth. Among these, we validate cyclin-dependent kinase 12 (CDK12) as a druggable vulnerability in NUP98::KDM5A-expressing AML. In line with its role in the transcription of DNA damage repair genes, small-molecule-mediated CDK12 inactivation causes increased DNA damage, leading to AML cell death. Altogether, we show that NUP98::KDM5A directly regulates a core set of essential target genes and reveal CDK12 as an actionable vulnerability in AML with oncogenic NUP98 fusions.
    DOI:  https://doi.org/10.1038/s41467-025-59930-9
  7. Leukemia. 2025 May 22.
      Acute myeloid leukemia (AML) is a common hematopoietic malignancy with high recurrence rates, and there is an urgent need for new therapeutic agents. T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the surface of both LSCs and blasts in most AML patients, but not in normal hematopoietic stem cells (HSCs). We have developed KK2845, an antibody drug conjugate (ADC) that consists of an anti-TIM-3 fully human IgG1 antibody, a valine-alanine linker and a highly potent DNA cross-linking pyrrolobenzodiazepine (PBD) dimer SG3199. KK2845 exhibited potent cytotoxicity against AML cells both in vitro and in vivo. The cytotoxicity against AML cells was almost comparable between KK2845 and CD33-ADC, an anti-CD33 antibody conjugated with PBD dimer that has shown high remission rates in clinical studies. In addition to the cytotoxicity depending on PBD dimer, KK2845 also showed potent antibody-dependent cell cytotoxicity (ADCC) activity against AML cells. KK2845 showed less cytotoxicity against human normal bone marrow cells than CD33-ADC. The pharmacokinetics of KK2845 in cynomolgus monkey after intravenous infusion demonstrated a favorable profile. Taken together, these data suggest that KK2845 could be a novel ADC therapeutic in AML.
    DOI:  https://doi.org/10.1038/s41375-025-02642-2
  8. Blood. 2025 May 22. pii: blood.2024026940. [Epub ahead of print]
      The majority of calreticulin (CALR) mutations in myeloproliferative neoplasms (MPNs) are classified as either type 1, a 52 base-pair deletion (CALRdel52), or type 2, a 5 base-pair insertion (CALRins5). Both are gain-of-function (GOF) mutations that generate an identical mutant C-terminal tail, which mediates the binding to and activation of the thrombopoietin receptor MPL. We recently reported that despite this shared GOF, CALRdel52 but not CALRins5 mutations cause loss of calcium binding function, leading to activation of and dependency on the IRE1a/XBP1 pathway of the unfolded protein response (UPR). This led us to ask whether CALRins5 mutations activate and depend on a different UPR pathway, and whether this is likewise mediated by a mutation type-specific loss-of-function (LOF). Here, we show that CALRins5 mutations lead to activation of the ATF6 pathway of the UPR due to loss of CALR chaperone function. This LOF is caused by interference of the CALRins5 mutant C-terminus with key chaperone residue H170. Further, we show that CALRins5 cells are partially dependent on ATF6 for cytokine-independent growth, and identify BCL-xL as a transcriptional target of ATF6 that promotes type 2 CALR mutant cell survival.
    DOI:  https://doi.org/10.1182/blood.2024026940
  9. Blood Cancer Discov. 2025 May 21.
      Resistance to venetoclax-based therapy in acute myeloid leukemia (AML) includes genetic (i.e., mutations in N/KRAS, FLT3-ITD, TP53) and phenotypic (i.e., monocytic differentiation) features. Whether monocytic differentiation contributes to clinical venetoclax resistance secondary to a genetic bias remains unknown. This multimodal, multicenter, international analysis inclusive of 678 patients comprehensively characterized the prognostic role of monocytic differentiation in AML patients treated with hypomethylating agents combined with venetoclax. AML genetics and monocytic differentiation (HR: 1.89, 95% CI: 1.35-2.66, p < 0.001) in NPM1 wild-type cases correlated with an increased risk of death. Clustering of centralized quantitative multiparameter flow cytometry data, evaluation of RNA sequencing-derived AML maturation stage, and single-cell proteogenomics linked driver mutations with AML phenotype and anti-apoptotic gene expression. This comprehensive analysis of AML genetics, phenotype, and anti-apoptotic protein expression highlights the complementary role these factors impart following venetoclax-based therapy.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-24-0256
  10. Blood Cancer J. 2025 May 20. 15(1): 97
      Acute myeloid leukemia (AML) and DNMT3A mutations (DNMT3Amut) are considered to carry intermediate risk under the 2022 European LeukemiaNet (ELN-2022) classification in the absence of other co-mutations or cytogenetic abnormalities. However, this group is highly heterogeneous. In this study, the genomic and transcriptomic features influencing outcomes in DNMT3A-mutated AML were examined in a cohort of 884 patients with AML receiving standard chemotherapy. Stratification by NPM1 and FLT3-ITD status revealed worse survival among patients with NPM1 mutations and wild-type FLT3-ITD (NPM1mut/FLT3-ITDwt) than patients in the ELN-2022 favorable risk group. The other three subgroups (NPM1mut/FLT3-ITDmut, NPM1wt/FLT3-ITDmut, and NPM1wt/FLT3-ITDwt) exhibited worse prognoses than patients in the ELN-2022 intermediate risk group. Additionally, the presence of TET2mut in patients with AML and DNMT3Amut/NPM1mut/FLT3-ITDwt led to reclassification from favorable risk to intermediate risk in the ELN-2022. RNA-sequencing analysis revealed a distinct transcriptomic profile in patients with TET2mut, highlighting the enrichment of leukemic stem cell signatures and dendritic cell migration, with MMP14, CD200, and CT45A5 identified as key differentially expressed genes. In conclusion, co-mutation patterns strongly affected AML outcomes in patients with DNMT3Amut. Patients with TET2mut constituted a unique subgroup within the ELN-2022 favorable DNMT3Amut/NPM1mut/FLT3-ITDwt group, characterized by distinct transcriptomic features and an unfavorable prognosis.
    DOI:  https://doi.org/10.1038/s41408-025-01287-9
  11. Cancer Genet. 2025 May 15. pii: S2210-7762(25)00056-0. [Epub ahead of print]294-295 181-183
      This study explores the molecular distinctions between myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) with RUNX1 mutations (RUNX1mut), aiming to elucidate factors influencing the progression from MDS to AML. Analyzing 1520 patients (773 AML and 747 MDS cases), RUNX1mut were present in 10 % of MDS and 13 % of AML cases. Interestingly, RUNX1mut were associated with higher blast counts in MDS, suggesting a potential role in disease progression. Despite similar overall survival across subgroups, significant differences in variant allele frequency (VAF) were observed, correlating with blast count. Our study highlights a unique genetic signature in both RUNX1mut MDS and AML: Cytogenetic analysis showed a higher frequency of normal karyotypes in RUNX1mut-MDS compared to RUNX1mut-AML. While only trisomy 8 was found in MDS, trisomies 8, 11, and 13 were detected in RUNX1mut-AML. Notably, MECOM rearrangements, KMT2A-PTD, and FLT3-ITD alterations were exclusive to RUNX1mut-AML. RUNX1 mutations were strongly associated with spliceosome gene mutations, especially in RUNX1mut-MDS. Copy neutral loss of heterozygosity (CN-LOH) involving RUNX1 was detected in 22 % of RUNX1mut-AML cases but was absent in RUNX1mut-MDS. These findings highlight the distinct genetic landscape of RUNX1mut-MDS and AML. Understanding these molecular determinants may enhance monitoring and early intervention strategies for MDS patients at risk of progression to AML.
    DOI:  https://doi.org/10.1016/j.cancergen.2025.05.003
  12. Nat Aging. 2025 May 23.
      During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration. This work uncovered that cell surface presentation of P-selectin (CD62P, encoded by Selp) increases in a large fraction of aging HSCs driven by a proinflammatory milieu in mice. Notably, expression of P-selectin molecularly and functionally dichotomized the aging HSC pool; stem cells presenting with highly abundant P-selectin were hallmarked by aging-associated gene expression programs and reduced repopulation capacity upon regenerative stress. Ectopic expression of Selp in young HSCs was sufficient to impair long-term reconstitution potential and impair erythropoiesis. Mechanistically, we uncovered that P-selectin receptor activation by its primary ligand, P-selectin glycoprotein ligand-1, suppressed aging-associated gene expression, and, reversely, lack of P-selectin signaling led to HSC premature aging. Collectively, our study uncovered a functional role of P-selectin engagement in regulating HSC regeneration and driving stem cell aging when perturbed.
    DOI:  https://doi.org/10.1038/s43587-025-00880-8
  13. Res Sq. 2025 May 07. pii: rs.3.rs-6377810. [Epub ahead of print]
      Recurrent somatic mutations in the spliceosome genes SF3B1 , SRSF2 , and U2AF1 are frequently identified in patients with myeloid neoplasms, such as myelodysplastic syndromes. We characterized the in vivo consequences of expressing two hotspot mutations in U2AF1 that code for the S34F and Q157R substitutions. Our results indicate that the two mutations induce distinct hematopoietic phenotypes in mice, suggesting that the U2AF1 S34F and U2AF1 Q157R mutations should not be conflated as they may impact disease pathogenesis differently in patients. Mice expressing U2af1 S34F have a more severe reduction in their blood and bone marrow cell counts and reduced stem cell repopulating ability, compared to mice expressing U2af1 Q157R . The expression and splicing of target genes are largely unique between the mutations, in both mouse and human samples, potentially driving the phenotypic differences induced by either mutation. The two mutations co-occur with different gene mutations in patients and are not equally represented across myeloid neoplasms, suggesting that multiple mechanisms likely drive U2AF1-mutant disease pathogenesis. Collectively, our results support that U2AF1 S34F and U2AF1 Q157R mutations induce distinct hematopoietic, gene expression, and RNA splicing phenotypes in vivo . Larger population studies will be needed to determine if these phenotypic changes translate into clinico-pathologic differences in patients warranting separate classification.
    DOI:  https://doi.org/10.21203/rs.3.rs-6377810/v1
  14. Nat Commun. 2025 May 20. 16(1): 4678
      With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed CHIP. How these mutations result in increased risk for numerous age-related diseases remains poorly understood. We conduct a multiracial meta-analysis of EWAS of CHIP in the Framingham Heart Study, Jackson Heart Study, Cardiovascular Health Study, and Atherosclerosis Risk in Communities cohorts (N = 8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. We functionally validate the EWAS findings using human hematopoietic stem cell models of CHIP. We then use expression quantitative trait methylation analysis to identify transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses reveal 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value < 0.05). Taken together, our study reports the epigenetic changes impacted by CHIP and their associations with age-related disease outcomes.
    DOI:  https://doi.org/10.1038/s41467-025-59333-w
  15. Nature. 2025 May 21.
      Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.
    DOI:  https://doi.org/10.1038/s41586-025-09041-8
  16. Transplant Cell Ther. 2025 May 14. pii: S2666-6367(25)01170-4. [Epub ahead of print]
       BACKGROUND: While donor age significantly impacts allogeneic hematopoietic cell transplantation (HCT) outcomes, the effect of donor cytomegalovirus (CMV) serostatus, particularly in CMV-seronegative recipients, remains a critical consideration. Donor CMV seropositivity is linked to increased CMV viremia and non-relapse mortality (NRM) in these recipients. Given the limited scope of novel antiviral prophylaxis drugs e.g., letermovir solely for CMV-seropositive recipients and the association of post-transplant cyclophosphamide (PTCy) with increased CMV reactivation, this study investigates the impact of donor CMV serostatus on outcomes in CMV-seronegative acute myeloid leukemia (AML) patients undergoing HLA-matched or mismatched unrelated donor HCT with PTCy.
    METHODS: We retrospectively analyzed data from the Center for International Blood and Marrow Transplant Research, including adult CMV-seronegative AML patients who underwent unrelated donor HCT with PTCy between 2017 and 2021. Primary outcome was overall survival (OS). Secondary outcomes included relapse, NRM, and acute/chronic graft-versus-host disease (GVHD). Donor age was dichotomized at ≤32 and >32 years. Multivariable Cox proportional hazards (PH) models, stratified by donor age, and Restricted Mean Survival Time (RMST) and Restricted Mean Time Lost (RMTL) analyses were performed.
    RESULTS: Of 408 CMV-seronegative recipients, 127 received transplants from CMV-seropositive donors. Baseline characteristics were well-balanced between groups. Multivariable analysis demonstrated that recipients of CMV-seropositive donors had a significantly higher hazard of mortality (HR 1.51, 95% CI 1.07-2.14, p = 0.019). Donor age and donor type did not significantly impact OS in this CMV seronegative patient population. RMST analysis showed that recipients with CMV-seronegative donors lived on average 2.95 months longer (p=0.045), while RMTL ratio was 1.34 (p=0.037), indicating that recipients of CMV-seropositive donors experienced a 34% higher risk of loss of survival time. The difference in OS was primarily driven by a trend toward increased relapse risk in the CMV-seropositive donor group (HR 1.42, 95% CI: 0.95-2.08, p = 0.06) rather than NRM (HR 1.19, 95% CI: 0.66-2.13, p = 0.56).
    CONCLUSIONS: In CMV-seronegative adult AML patients undergoing unrelated donor HCT with PTCy, CMV-seropositive donors are associated with worse OS than CMV-seronegative donors, likely linked to higher relapse risk. These findings underscore the importance of considering donor CMV serostatus in donor selection for CMV-seronegative recipients undergoing HCT with PTCy. Further investigation is necessary to optimize donor selection strategies and improve outcomes in this patient population.
    Keywords:  CMV; CMV-negative recipient; Cytomegalovirus; Donor age; HLA matched unrelated donor; Haploidentical; MMUD; MUD; Mismatched unrelated donor; PTCy; post-transplantation cyclophosphamide CMV-positive donor
    DOI:  https://doi.org/10.1016/j.jtct.2025.05.005
  17. Br J Haematol. 2025 May 21.
      The appropriate salvage regimen followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT) for relapsed/refractory (R/R) acute myeloid leukaemia (AML) patients remains unclear. Three hundred and fifty R/R AML patients receiving venetoclax and azacitidine (VA) regimen or VA plus homoharringtonine (VAH) regimen as salvage therapy were enrolled in this study, with a higher composite complete remission rate in the VAH group (69.9%) than in the VA group (46.1%). A total of 105 patients underwent allo-HSCT, with a median follow-up post-transplantation of 37.2 months. The 3-year cumulative incidence of transplant-related mortality was 18.2% in the VA group and 9.8% in the VAH group. The 3-year cumulative incidence of relapse was lower in the VAH group (19.7%) than in the VA group (43.2%). The 3-year overall survival and event-free survival (EFS) were 82.0% and 70.5%, respectively, in the VAH group, which were higher than 59.1% and 38.6%, respectively, in the VA group. Multivariate analysis revealed the VAH regimen and MRD-negative at transplantation were protective factors for relapse (HR = 0.427 and HR = 0.368) and EFS (HR = 0.469 and HR = 0.384). In conclusion, the VAH regimen is an effective and safe salvage therapy bridge to allo-HSCT for R/R AML patients compared with the VA regimen.
    Keywords:  acute myeloid leukaemia; allogeneic haematopoietic cell transplantation; azacitidine; homoharringtonine; venetoclax
    DOI:  https://doi.org/10.1111/bjh.20147
  18. Res Sq. 2025 May 09. pii: rs.3.rs-6580439. [Epub ahead of print]
      Treatment of JAK2V617F driven myeloproliferative neoplasms (MPNs) with Ruxolitinib (JAK inhibitor, JAKi) has shown limited disease-modifying benefits and has led to the search for other pathways as potential therapeutic targets for this disease. We investigated the effects of Smoothened inhibition (SMOi) using the small-molecule inhibitor PF-04449913 (PF-13) in a JAK2V617F transgenic mouse model that recapitulates many of the phenotypes of MPNs including bone marrow fibrosis and splenomegaly. We show both that hedgehog (Hh) signaling pathway is activated in JAK2V617F cells and that SMOi reduces splenomegaly in JAK2V617F mice. In a murine bone marrow transplant model, we show that SMOi also reduces JAK2V617F allelic burden. JAK2V617F mice show increased pERK and NF-κB signaling, which is reduced with SMOi. Finally, we found that SMO inhibitor blocks bone marrow fibrosis by reducing TGF-β signaling. In conclusion, this report provides critical insight into the mechanism of action of SMO inhibitors in JAK2V617F associated MPN.
    DOI:  https://doi.org/10.21203/rs.3.rs-6580439/v1
  19. Sci Rep. 2025 May 17. 15(1): 17179
      The bone marrow microenvironment (BMM) plays a crucial role in the pathogenesis and progression of acute myeloid leukemia (AML). AML cells can modify the BMM to establish a more favorable environment for their survival. However, the mechanism about the complex regulatory interplay between the BMM and AML cells remains unclear. In this study, we used proteomic analysis to elucidate the potential mechanisms underlying the interaction between bone marrow stromal cells (BMSCs) and AML cells. We found that the co-culture of AML cells and BMSCs facilitated the proliferation of AML cells, suppressed the proliferation of BMSCs and triggered their senescence. Furthermore, we show the aberrant expression of S100A8 that plays a crucial role in the communication between AML cells and BMSCs. In the co-culture system, overexpression of S100A8 in AML cells activated NOX2 and induced the production of reactive oxygen species (ROS) in the supernatant, thereby suppressing the proliferation of BMSCs and facilitating the senescence of BMSCs. Subsequently, aging BMSCs secreted a variety of cytokines, including IL-6, CXCL5, MIP-1b, etc. as shown by Cytokine Array and qPCR analysis, which had stimulatory effects on the progression of AML. In conclusion, the present study reveals the crucial involvement of the S100A8-NOX2-ROS signaling pathway in mediating communication between AML cells and BMSCs, suggesting that targeting S100A8 may constitute an efficient strategy for AML therapy.
    Keywords:  Acute myeloid leukemia; Bone marrow microenvironment; Bone marrow stromal cells; Cytokines; S100A8-NOX2-ROS signaling pathway
    DOI:  https://doi.org/10.1038/s41598-025-01711-x
  20. Clin Cancer Res. 2025 May 19.
       PURPOSE: In a multicenter prospective cohort-study we assessed the diagnostic yield of the Nordic guidelines for germline investigation in myeloid neoplasms (MN) and mapped the spectrum of inherited and somatic variants.
    EXPERIMENTAL DESIGN: Eighty-five patients (acute myeloid leukemia (AML): n=38; myelodysplastic syndromes (MDS): n=26; thrombocytopenia: n=14; other: n=7) fulfilling the Nordic criteria for germline investigation: (1) medical history (MH) or family history (FH) suggestive of a germline condition; (2), relevant findings from the somatic diagnostic work-up (CytoMol), were recruited. The genetic analysis included enhanced whole-exome sequencing (WES, n=69) or sequencing of specific variants of interest (n=16).
    RESULTS: Pathogenic or likely pathogenic (P/LP) germline variants were identified in 35% of patients (30/85). The diagnostic yield varied from 6% (1/16) in the FH group to 52% (17/33) in the CytoMol group. Germline DDX41 P/LP variants were the most frequent finding (13/30, 43% of all positive cases), almost exclusively found within the CytoMol group (12/13). Seven variants of unknown significance (VUS) were also detected (TERT n=2; DDX41, RTEL1, ETV6, PARN and SAMD9: n=1). Five patients carried a P/LP variant in genes associated with another hereditary cancer syndrome (BRCA1 n=3; PALB2 n=1; CHEK2; n=1). Survival analysis showed a trend for longer survival among patients with AML and confirmed or suspected germline predisposition that underwent allogeneic stem cells transplantation (allo-HSCT).
    CONCLUSIONS: The implementation of the Nordic guidelines in a prospective Swedish cohort, results in a high overall diagnostic yield (35%), proving the feasibility and utility of these or similar guidelines in a clinical setting.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-4251
  21. Cell Death Discov. 2025 May 17. 11(1): 240
      Recently, some methyltransferase-like (METTL) proteins have been found to play crucial roles in the development of acute myeloid leukemia (AML) through mediating RNA modifications, such as METTL3/14/16 mediated N6-methyladenosine (m6A) and METTL1 mediated N7-methylguanosine (m7G). However, the roles of other METTL proteins in AML progression remain unknown. Here, we examined the expression levels of all METTL members in AML samples and showed that METTL13 was increased in AML and positively correlated with poor prognosis. Moreover, METTL13 deficiency impaired AML cell proliferation capability in vitro, improved the survival of AML cell line xenograft immune-deficient mice, and reduced tumor infiltration in vivo. Mechanistically, MYC was downregulated after METTL13 knockdown and forced expression of MYC rescued the cell proliferation defect in METTL13-deficient AML cells. Our findings uncover the critical role of METTL13 in the survival of AML cells and identify MYC as a potential downstream target of METTL13. This work highlights METTL13 as a promising candidate target for AML therapy.
    DOI:  https://doi.org/10.1038/s41420-025-02512-x
  22. Blood Adv. 2025 May 22. pii: bloodadvances.2024015627. [Epub ahead of print]
      Cell progenitor to progeny transitions depend on precise transcriptional mechanisms to adjust gene expression. The sterile alpha motif-containing 1 protein (SAMD1) regulates a shift in transcriptional activity during embryonic stem cell exit from pluripotency. SAMD1 interacts with and facilitates the activity of the histone H3 lysine demethylating enzyme LSD1. SAMD1 is expressed throughout many biological systems, but its role in hematopoiesis is unknown. In human and mouse hematopoietic stem/progenitor cells, we tested the role of SAMD1 in hematopoiesis and erythropoiesis using loss-of-function approaches. SAMD1 promoted expression of critical drivers of hematopoiesis, including the GATA2 transcription factor, while opposing erythroid programs. Loss of SAMD1 in ex vivo differentiating cells increased erythroid and megakaryocyte differentiation and altered the landscape of histone H3K4 methylation genome-wide. Cohorts of SAMD1-repressed genes are linked to erythropoietic activities. SAMD1 expression promoted ERK signaling via SCF/Kit stimulation in progenitor populations. In erythroid precursor cells, SAMD1 co-occupies chromatin with LSD1 and GATA factors. Whereas SAMD1 downregulates H3K4me2 levels genome-wide, contributing to gene repression, SAMD1 also elevates transcription at select sites. To test Samd1 function in hematopoiesis, we performed competitive transplant experiments in mice. Samd1 knockdown hematopoietic stem cells (HSCs) contributed more to peripheral blood mononuclear cells versus control HSCs. Our results establish SAMD1 as a coordinator of H3K4 methylation and stem/progenitor activity in hematopoiesis and erythropoiesis.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015627
  23. Exp Hematol Oncol. 2025 May 22. 14(1): 78
      Menin inhibitors (MENINis) represent a novel and promising class of therapeutic agents for acute leukemia (AL). AL subtypes driven by overexpressed HOXA9/MEIS1, such as those characterized by KMT2A-rearranged (KMT2Ar) or NPM1-mutated (NPM1m) AL, display sensitivity to MENINi. Consequently, approximately 40-50% of acute myeloid leukemia (AML) and 5-15% of acute lymphoblastic leukemia (ALL) patients may potentially benefit from MENINi-based therapy. At the 2024 ASH annual meeting, updated clinical data regarding monotherapy with MENINis in AL, including revumenib, bleximenib, enzomenib and BN104, were presented. Moreover, combination therapies based on MENINis were also reported to be highly effective in refractory/relapsed, or newly diagnosed KMT2Ar- and NPM1m-AML patients. Evidently, MENINis have demonstrated a considerable efficacy in KMT2Ar- and NPM1m-AML patients with a well-tolerance. Furthermore, the therapeutic effects of venetoclax plus azacitidine or "3 + 7" regimens were further enhanced by the addition of MENINis in KMT2Ar- and NPM1m-AML patients. Therefore, MENINis offer new therapeutic prospects for AML patients, particularly for those with high-risky and poor-prognostic on-target subtypes.
    Keywords:  Acute leukemia; MENIN inhibitor; The 2024 ASH annual meeting
    DOI:  https://doi.org/10.1186/s40164-025-00668-x
  24. Ann Hematol. 2025 May 20.
      The aim of this study was to assess the safety, response, and survival outcomes of cladribine (CLAD) + low-dose cytarabine (LDAC) + venetoclax (CAV) in patients with relapsed/refractory (R/R) and newly diagnosed acute myeloid leukemia (AML). This single-center, retrospective, non-randomized study included 46 adult patients with 29 R/R AML and 17 newly diagnosed AML who were unfit for intensive chemotherapy. All patients received the CAV regimen at our center. In the R/R group (median age 55 years, range 21-77), complete response (CR) was achieved in 44.8%, CR with incomplete blood count recovery (CRi) in 24.1%, composite complete remission (CRc, CR + CRi) and measurable residual disease (MRD) negativity in 51.7%. The median follow-up was 10.9 months, with median overall survival (OS) of 16.4 months (95% CI, 10.9-21.8). Leukopenia (62.1%) was the most common hematologic toxicity, and infection (44.8%) was the most common non-hematologic toxicity. The 30-day mortality rate was 0%, and one patient died within 60 days. In the newly diagnosed group, CR was 76.5%, CRi 17.6%, CRc 94.1%, and MRD negativity 82.3% after one induction cycle. The median OS was 15.5 months (95% CI, 11.1-19.9). Common grade 3/4 hematologic toxicities were leukopenia (76.5%), with infection (52.9%) as the most common non-hematologic toxicity. The CAV regimen demonstrated a high CRc rate and MRD negativity in R/R AML with manageable toxicity. In newly diagnosed acute myeloid leukaemia, this regimen has also demonstrated favourable efficacy, as previously reported, with tolerable haematological toxicity.
    Keywords:  Acute myeloid leukemia; Cladribine; Efficacy; Venetoclax
    DOI:  https://doi.org/10.1007/s00277-025-06389-9
  25. Leuk Res. 2025 May 14. pii: S0145-2126(25)00076-1. [Epub ahead of print]154 107716
      Tyrosine kinase inhibitors of the BCR::ABL1 oncoprotein can be stopped without subsequent molecular relapse or major safety concerns in 40-80 % of adult patients with P210BCR::ABL1 positive chronic myeloid leukemia with sustained deep molecular responses. In contrast, ending treatment in patients with rare rearrangements located outside the major BCR region or within the exon 3 of ABL1 remains to be explored. Twenty-four patients with chronic phase disease and diverse uncommon BCR::ABL1 transcripts who obtained sustained molecular residual disease negativity and stopped therapy in a real-life setting for various reasons were retrospectively evaluated for treatment-free remission determinants. Six patients relapsed after a median time of 6 months (range; 3-49), relapse being defined as a rise in molecular residual disease above the 3-log threshold. Treatment-free remission probabilities at 12 and 60 months were 83.3 % (95 % CI: 68.4-98.2 %) and 70.6 % (95 % CI: 49.5-91.6), respectively. The type of BCR::ABL1 transcript was the only relevant baseline factor associated with durable treatment-free remission and patients with fusions lacking exon a2 sequences had the best outcome. To conclude, treatment-free remission is a reasonably achievable goal in patients with rare ABL1 fusion transcripts. Our results pave the way for recommendations in clinical practice. Nevertheless, further research is needed to determine which patients have highest chances to reach deep molecular response levels and become free from therapy and to decipher the biological impact of the different molecular rearrangements of BCR::ABL1 on treatment-free remission.
    Keywords:  Chronic myeloid leukemia – rare transcripts – tyrosine kinase inhibitor- treatment-free remission
    DOI:  https://doi.org/10.1016/j.leukres.2025.107716
  26. Clin Cancer Res. 2025 May 21. OF1-OF14
       PURPOSE: Myelodysplastic syndrome and acute myeloid leukemia with complex and monosomy karyotypes show a high prevalence of TP53 mutations (TP53m), poor response to induction chemotherapy, and adverse outcomes. These diseases may respond to decitabine, but the mechanisms are presently unclear.
    EXPERIMENTAL DESIGN: Patients with myelodysplastic syndrome and acute myeloid leukemia were treated with decitabine for 10 days in a phase II clinical study. In this study, we collected serial samples from patients before and at the completion of decitabine treatment, morphologic remission, and relapse. The samples were interrogated with targeted myeloid panel sequencing, nanopore DNA cytosine methylation sequencing, and single-cell transcriptomics to investigate potential interactions between leukemic and immune populations.
    RESULTS: The integrative analysis allowed for the characterization of shifting dynamics within leukemic and immune cell populations in individual patients. Single-cell transcriptomic analyses confirmed immune activation in TP53m responders after decitabine treatment. At relapse, leukemic populations showed upregulation of MYC signaling and heat shock response, whereas T cells showed an exhaustion signature.
    CONCLUSIONS: Our work highlighted the complex interplay between leukemic and immune populations in TP53m patients upon decitabine treatment that might account for clinical responses and subsequent relapses.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-3192
  27. Am J Hematol. 2025 May 23.
      Although second allogeneic hematopoietic cell transplantation HCT (HCT2) is a potentially curative treatment for patients relapsing after their first HCT (HCT1), it is associated with higher non-relapse mortality (NRM) compared with HCT1. Furthermore, while reduced-intensity conditioning (RIC) in HCT2 might decrease NRM, there is no consensus on which patients may benefit from RIC. We retrospectively analyzed 2478 patients who underwent HCT2 for relapse of hematologic malignancies after HCT1. In a multivariate analysis, older recipient age, short duration between HCT1 and HCT2, RIC in HCT1, HCT-CI ≥ 2, and ECOG PS ≥ 2 were associated with an increased risk of NRM. RIC in HCT2 was associated with better NRM compared to myeloablative conditioning (MAC) (hazard ratio [HR] 0.83, 95% confidence interval [CI]: 0.72-0.97; p = 0.018), but was not significantly associated with overall survival (OS) (HR 0.91, 95% CI: 0.82-1.01; p = 0.075). We observed a significant interaction for NRM between extensive cGVHD in HCT1 and the conditioning intensity of HCT2 (interaction p < 0.001), meaning that the benefit of RIC in HCT2 was seen in patients with extensive cGVHD in HCT1, but not in those without cGVHD. RIC in HCT2 was also associated with superior OS in patients with extensive cGVHD in HCT1 (HR 0.68, 95% CI: 0.49-0.93; p = 0.02), with significant interaction between the conditioning intensity and the prior history of extensive cGVHD (interaction p = 0.01). This study suggests that RIC in HCT2 reduces NRM for HCT2 and improves OS, especially in patients with a history of extensive cGVHD.
    Keywords:  conditioning; graft‐versus‐host disease; stem cell transplantation
    DOI:  https://doi.org/10.1002/ajh.27709
  28. Blood Cancer Discov. 2025 May 22.
      Ionizing radiotherapy (RT) is a widely used treatment strategy for malignancies. In solid tumors, RT-induced double-strand breaks lead to the accumulation of indels, and their repair by non-homologous end-joining has been linked to the ID8 mutational signature in surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored. Here, we interrogated 580 whole-genome sequence samples (WGS) from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet, ID8 was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum and melphalan). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode we demonstrate that a single RT-surviving cell may seed distant relapse.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-24-0328
  29. Cancer Discov. 2025 May 22.
      To explore how early can cancers be detected prior to clinical signs or symptoms, we assessed prospectively collected serial plasma samples from the Atherosclerosis Risk in Communities (ARIC) study, including 26 participants diagnosed with cancer and 26 matched controls. At the index time point, eight of these 52 participants scored positively with a multicancer early detection (MCED) test. All eight participants were diagnosed with cancer within 4 months after blood collection. In six of these 8 participants, we were able to assess an earlier plasma sample collected 3.1 to 3.5 years prior to clinical diagnosis. In four of these six participants, the same mutations detected by the MCED test could be identified, but at 8.6 to 79-fold lower mutant allele fractions. These results demonstrate that it is possible to detect circulating tumor DNA more than three years prior to clinical diagnosis, and provide benchmark sensitivities required for this purpose.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0375
  30. Nature. 2025 May 21.
      Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.
    DOI:  https://doi.org/10.1038/s41586-025-08996-y