bims-tremyl 2025-12-21 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2025–12–21
thirty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Pharmacological Inhibition of miR-126 Enhances Venetoclax Activity in Acute Myeloid Leukemia.
The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis.
2025 Update on MRD in Acute Myeloid Leukemia: A Consensus Document from the ELN-DAVID MRD Working Party.
Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML.
Study Backs MRD as AML Trial Endpoint.
Ribosomal protein control of hematopoietic stem cell transformation through regulation of metabolism.
Loss of Ezh2 precipitates lethal disease progression in a mouse model of Calr-mutated myeloproliferative neoplasms.
BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML.
A proteogenomic gene signature defines prognostic subgroups highlighting PI3K/AKT/mTOR signaling pathway as a therapeutic vulnerability in myeloid malignancies.
Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia.
Targeting IL-1/IRAK1/4 signaling in acute myeloid leukemia stem cells following treatment and relapse.
Assessment of measurable residual disease in ovarian tissue collected for fertility preservation in patients in remission from acute myeloid leukaemia: A pilot study.
Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome.
The glycosaminoglycan oncofetal chondroitin sulfate represents a novel target for antibody drug-conjugate therapy for AML.
Pretransplant HMA and Venetoclax in AML patients - a Real-World Analysis from the Cooperative Transplant Study Group.
Leukemia-expanded splenic CD81+ erythroblasts potentiate disease progression in mice by reshaping leukemic cell metabolism.
Characterization of chromosome 5 aberrations in TP53 mutated myeloid neoplasms with ≥5% blasts: An International TP53 Investigators Network (iTiN) study.
Transient SP140 inhibition unlocks hematopoietic stem cell fate from human pluripotent stem cells.
Integrated analysis of post-transcriptional regulations reveals insights into acute myeloid leukemia.
Dynamics of clonal hematopoiesis and cellular responses to stress-induced toxicity in autologous stem cell transplantation.
Asciminib Demonstrates Superior Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia in the ASC4FIRST Trial.
Dynamic and extensive A-to-I RNA recoding in immunoglobulin shapes myeloid neoplasms transcriptome.
NAMPT inhibition uncovers therapeutic vulnerabilities to venetoclax and chemotherapy in acute myelogenous leukemia.
Durable post-transplant survival after first-line tagraxofusp for blastic plasmacytoid dendritic cell neoplasm.
Treatment expectations and goals among patients with chronic myeloid leukemia in Germany: a patient-centered perspective.
Etiology of TP53 mutated complex karyotype acute myeloid leukemia.
Genomics of Acute Myeloid Leukemia at Diagnosis and Remission.
Microenvironmental cell interactions are essential for sustaining functionality of myelofibrosis malignant stem cells.
The role of CD38 in monocytes during fibrotic progression of myeloproliferative neoplasms.
Safety and effectiveness of the combination of 5-azacitidine and ruxolitinib in VEXAS syndrome: A single-centre experience.
RPL5 deficiency-induced ribosomal stress targets a select subset of proteins and inhibits the PI3K-Akt-mTOR signaling pathway to eradicate leukemia stem cells.
Predicting the differential diagnosis of inherited versus acquired bone marrow failure syndromes: Development of simple clinical scoring systems.
Nonionotropic action of an acid-sensing ion channel inhibits leukemogenesis in the acidic bone marrow niche.
Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.
Solving Riddles Through Sequencing (SIRIUS): unlocking hematologic diagnoses by whole genome and transcriptome sequencing.
Randomized Noninferiority Trial of a Liberalized Diet Versus the Neutropenic Diet in Hematopoietic Stem-Cell Transplant Patients and Patients With Acute Leukemia.

Blood. 2025 Dec 15. pii: blood.2025029875. [Epub ahead of print]

Pharmacological Inhibition of miR-126 Enhances Venetoclax Activity in Acute Myeloid Leukemia.

Lianjun Zhang, HyunJun Kang, Melissa Valerio, Dinh Hoa Hoang, Khyatiben V Pathak, Krystine Garcia-Mansfield, Xiyuan Lu, Wancheng Guo, Yu-Hsuan Fu, Xin He, Ying-Chieh Chen, Zhenhua Chen, Lucy Y Ghoda, Ralf Buettner, Zhuo Li, Amanda Blackmon, Ling Li, Bin Zhang, Patrick Pirrotte, Guido Marcucci, Ya-Huei Kuo, Le Xuan Truong Nguyen.

Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) depend on oxidative phosphorylation (OXPHOS) sustained by fatty acid oxidation (FAO) and mitochondrial fusion (mitofusion). We demonstrate that miR-126 maintains LSC function by promoting BCL-2-dependent FAO, OXPHOS, and mitofusion, whereas its inhibition disrupts mitochondrial metabolism, induces mitochondrial fission (mitofission), and triggers apoptosis. Mechanistically, miR-126 stabilizes BCL-2 via the SPRED1/ERK axis, which upregulates CPT1B (FAO) and NRF2 (antioxidant response) while regulating mitochondrial dynamics through DRP1 phosphorylation (inhibiting mitofission) and MFN1/2 phosphorylation (enhancing mitofusion). miRisten, a CpG-conjugated anti-miR-126 oligonucleotide now in clinical trials (NCT07025564), synergized with venetoclax (VEN) to suppress FAO/OXPHOS, promote mitofission, and impair LSC homeostasis. In vivo, miRisten potentiated the VEN/azacitidine (AZA) regimen, an FDA-approved therapy for older or unfit AML patients, significantly prolonging survival in patient-derived xenograft models. VEN/miRisten combination also reduced LSC burden and restored VEN sensitivity, establishing miR-126 inhibition as a transformative therapeutic strategy in AML.

DOI: https://doi.org/10.1182/blood.2025029875
Leukemia. 2025 Dec 17.

The pathogenesis of therapy-related myeloid neoplasms from TP53-mutant clonal hematopoiesis.

Jonas Fullin, Ebru Topçu, Karolina A Zielińska, Roman R Schimmer, Nancy Klemm, Christian Koch, Francisco Caiado, Melissa Lock, Cyril Doerdelmann, Marco M Bühler, Joelle Tchinda, Kari J Kurppa, Lubor Borsig, Philip H Jones, Massimo Lopes, Markus G Manz, Steffen Boettcher.

Therapy-related acute myeloid leukemia and myelodysplastic neoplasms (t-AML/MDS) are devastating complications of chemo- or radiation therapy in patients treated for an unrelated primary malignancy. Cancer patients with TP53-mutant hematopoietic stem and progenitor cells (HSPCs) - a condition termed clonal hematopoiesis (CH) - are at a particularly high risk for t-AML/MDS. However, the pathogenesis of TP53-mutant t-AML/MDS, especially the role of the TP53 allelic state (i.e., mono- vs. biallelic), and its prognostic impact in AML/MDS have remained only poorly understood. We developed novel in vitro and in vivo mouse models to investigate how mono- or biallelic Trp53 mutations influence clonal expansion and leukemic progression from CH to t-AML/MDS. While HSPCs with monoallelic Trp53 mutations gain clonal fitness but retain their genomic integrity under chemo- or radiation therapy, biallelic Trp53 mutations result in genomic instability and are essential for leukemic transformation. Moreover, we provide proof of concept that non-mutational p53 inactivation, such as MDM2 overexpression, can replicate the effects of biallelic TP53 mutations, providing a possible explanation for cases of TP53-mutant AML/MDS that retain one wild-type TP53 allele. Our findings elucidate the pathogenesis of TP53-mutant t-AML/MDS and support the classification of biallelic TP53-mutant AML/MDS as distinct clinical entities.

DOI: https://doi.org/10.1038/s41375-025-02839-5
Blood. 2025 Dec 15. pii: blood.2025031480. [Epub ahead of print]

2025 Update on MRD in Acute Myeloid Leukemia: A Consensus Document from the ELN-DAVID MRD Working Party.

Jacqueline Cloos, Peter J M Valk, Christian Thiede, Konstanze Döhner, Gail J Roboz, Brent L Wood, Roland B Walter, Sa A Wang, Agnieszka Wierzbowska, Andrew H Wei, David Wu, Francois Vergez, Adriano Venditti, Bert A van der Reijden, Arjan A van de Loosdrecht, Ing Soo Tiong, Felicitas R Thol, Marion Subklewe, Christophe Roumier, Tom Reuvekamp, Farhad Ravandi, Claude Preudhomme, Adriana Plesa, Jad Othman, Gert J Ossenkoppele, Yishai Ofran, Aguirre Mimoun, Luca Maurillo, Agata Majchrzak, David C de Leeuw, Wolfgang Kern, Dennis Dong Hwan Dong Hwan Kim, Maura Rosane Valério Ikoma-Colturato, Lukas H Haaksma, Monica L Guzman, Michaela Feuring, Barbara Depreter, Anna Czyz, Veit L Bücklein, Constance Baer, Costa Bachas, Sylvie D Freeman, Francesco Buccisano, Christopher S Hourigan, Richard James Dillon, Michael Heuser.

Measurable residual disease (MRD) monitoring has become a critical component in the management of acute myeloid leukemia (AML), to inform prognosis, guide therapy, and serve as a key endpoint in clinical trials. The 2025 update of the MRD guideline provides a comprehensive and refined framework for MRD assessment, aligned with the ELN 2022 genetic risk classification. Developed by members of the ELN-DAVID consortium, the guidelines incorporate expert consensus determined through a two-stage Delphi round. They address the clinical implementation of MRD methodologies, technical considerations, integration into clinical trials, and future directions. Importantly, MRD recommendations are tailored to individual prognostic and genetic subgroups. A new qualitative MRD response category, designated as optimal, warning, or high risk of treatment failure, has been introduced to facilitate contextual interpretation of the MRD burden and its clinical relevance. Notably, ultrahigh-sensitivity (UHS) NGS-based MRD assessment is now recommended for FLT3-ITD-mutated AML following intensive chemotherapy and prior to allogeneic hematopoietic cell transplantation. A total of 56 recommendations were formulated, with 53 achieving a high level of consensus (≥90%). These updated guidelines represent a major step forward toward harmonizing MRD assessments in AML and enhancing its clinical utility across diverse treatment settings.

DOI: https://doi.org/10.1182/blood.2025031480
Redox Biol. 2025 Dec 04. pii: S2213-2317(25)00471-9. [Epub ahead of print]89 103958

Redox-dependent protein S-glutathionylation governs azacitidine sensitivity and resistance in AML.

Dušan Nemes, Michaela Myšáková, Lubomír Minařík, Anna Jonášová, Tomáš Stopka, Kristýna Gloc Pimková.

  Disruption of redox metabolism is a hallmark of drug-resistant cancer cells, representing a major obstacle to the effective treatment of acute myeloid leukemia (AML). While recent studies have highlighted the importance of redox balance in AML therapy, the specific contribution of protein redox signaling to resistance remains poorly understood. Defining these mechanisms could uncover therapeutic vulnerabilities of resistant AML cells and guide the development of novel combination strategies. Here, we performed comprehensive mass spectrometry-based redox and quantitative proteomic profiling of AML cell lines and patient samples sensitive or resistant to the hypomethylating agent azacitidine (AZA). We demonstrate that AZA disrupts redox homeostasis, which inactivates the glyoxalase system and DNA damage response, and thereby induces cell death. In contrast, AZA resistance is associated with a redox reset characterized by elevated glutathione levels and diminished protein S-glutathionylation. Importantly, AZA failed to induce oxidation of proteins in these pathways in resistant cells and patient-derived AML samples. Pharmacological inhibition of glutathione synthesis restored protein S-glutathionylation and resensitized resistant AML cells to AZA.

Keywords:  Acute myeloid leukemia; Azacitidine; Cysteine oxidation; DNA damage; Drug resistance; Glyoxalase system; Hypomethylation therapy; Redox proteomics; S-glutathionylation

DOI:  https://doi.org/10.1016/j.redox.2025.103958
Cancer Discov. 2025 Dec 07. OF1

Study Backs MRD as AML Trial Endpoint.

Measurable residual disease (MRD) is associated with survival in acute myeloid leukemia (AML) but is not an accepted trial endpoint. A new study that combined data from seven clinical trials found that MRD predicted individual survival within trials and correlated with overall survival across trials. The results support use of MRD as a surrogate endpoint for AML trials.

DOI: https://doi.org/10.1158/2159-8290.CD-NW2025-0109
Cell Rep. 2025 Dec 12. pii: S2211-1247(25)01460-3. [Epub ahead of print]44(12): 116688

Ribosomal protein control of hematopoietic stem cell transformation through regulation of metabolism.

Bryan Harris, Dinesh K Singh, Billy Truong, Michele Rhodes, Rachael Price, Susan Shinton, Monika Verma, Bridget Aylward, Shawn P Fahl, Shanna R Sprinkle, Sarah Aminov, Minshi Wang, Yong Zhang, Jaqueline Perrigoue, Rachel Kessel, Suraj Peri, Joshua West, Orsi Giricz, Jacqueline Boultwood, Andrea Pellagatti, K H Ramesh, Cristina Montagna, Kith Pradhan, Jeffrey W Tyner, Brian K Kennedy, Michael Holinstat, Ulrich Steidl, Stephen Sykes, Amit Verma, David L Wiest.

  We report here that expression of the ribosomal protein RPL22 is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), and reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from altered metabolism, including increased fatty acid oxidation (FAO) and a striking induction of the stemness factor Lin28b in the resulting leukemia. Lin28b promotes a substantial increase in lipid content, upon which the survival of Rpl22-deficient leukemias depends. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSCs through regulation of FAO and promotes leukemogenesis through Lin28b promotion of lipid synthesis.

Keywords:  AML; CP: cancer; CP: molecular biology; Lin28b; MDS; Rpl22; fatty acid metabolism; hematopoietic stem cell; ribosomal protein; triglyceride

DOI:  https://doi.org/10.1016/j.celrep.2025.116688
Exp Hematol. 2025 Dec 13. pii: S0301-472X(25)00629-0. [Epub ahead of print] 105350

Loss of Ezh2 precipitates lethal disease progression in a mouse model of Calr-mutated myeloproliferative neoplasms.

Koki Ueda, Yuka Sato, Keiji Minakawa, Saori Miura, Yuko Hashimoto, Kazuhiko Ikeda.

  Patients with CALR-mutant essential thrombocythemia (ET), the myeloproliferative neoplasm (MPN) subtype with the most favorable long-term prognosis, remain at risk of developing secondary myelofibrosis (sMF) or acute myeloid leukemia (AML). Outcomes after such progression are poor. Loss-of-function mutations in the epigenetic regulator EZH2 are frequently acquired during disease evolution, but their causal contribution to CALR-driven MPN has remained uncertain. To investigate this question, we used a knock-in mouse that constitutively expresses a Calr frameshift allele and introduced conditional Ezh2 deletion triggered by tamoxifen. Ezh2 loss in Calr-mutant MPN resulted in lethal disease progression. These mice developed two terminal outcomes that mirror human disease: fibrotic MPN (sMF-like) and blast-phase MPN (AML-like). Transplantation experiments demonstrated that only the AML-like phenotype was transplantable, whereas the sMF-like phenotype did not confer lethal condition in recipients. These findings provide direct in vivo evidence that EZH2 loss drives malignant evolution of CALR-mutant MPN. Transcriptomic profiling of leukemic stem cells from AML-like mice revealed enrichment of fatty-acid-oxidation (FAO) pathways. Short-term colony assays showed that inhibition of PPARγ modestly increased the anti-proliferative effect of cytarabine on AML-derived stem and progenitor cells, suggesting a possible reliance on FAO. Reanalysis of public single-cell RNA-sequencing data from patients with MPN progressing to AML also demonstrated elevated FAO signatures in leukemic stem cells. Together, these results identify EZH2 loss as a key determinant of CALR-mutant MPN progression and point to altered metabolic wiring as a potential vulnerability in post-MPN AML. TEASER ABSTRACT: CALR-mutant myeloproliferative neoplasms occasionally progress to secondary myelofibrosis or acute myeloid leukemia, but the role of co-occurring EZH2 loss is unclear. Using a Calr-mutant knock-in mouse with inducible Ezh2 deletion, we show age-dependent evolution to either sMF-like or AML-like fatal disease. At a non-critical stage, peripheral counts remain near-normal while bone marrow HSPC compartments are already distorted. AML-like, but not sMF-like, Flk2- CD48+ LSK cells transmit leukemia and display enhanced fatty-acid-oxidation signatures, suggesting a distinct, potentially targetable metabolic bias.

Keywords:  Myeloproliferative neoplasms; leukemia stem cells

DOI:  https://doi.org/10.1016/j.exphem.2025.105350
Leukemia. 2025 Dec 19.

BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML.

Christine E Birdwell, Warren Fiskus, Christopher P Mill, Tapan M Kadia, Naval Daver, Courtney D DiNardo, Koji Sasaki, John A Davis, Kaberi Das, Hanxi Hou, Antrix Jain, Anna Malovannaya, Lauren B Flores, Rasoul Pourebrahim, Selina Yuan, Xiaoping Su, Michele Ceribelli, Kapil N Bhalla.

MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.

DOI: https://doi.org/10.1038/s41375-025-02842-w
Cell Commun Signal. 2025 Dec 16.

A proteogenomic gene signature defines prognostic subgroups highlighting PI3K/AKT/mTOR signaling pathway as a therapeutic vulnerability in myeloid malignancies.

Fan He, Shuyang Lin, Bei Gao, Varun Ramesh, Alexander B Kim, Tim Kong, Daniel A C Fisher, Christopher T Letson, Molly Brakhane, Mary Fulbright, Yanbo Yu, Marco Sardiello, Jorge Di Paola, Stephen M Sykes, Stephen T Oh.

   INTRODUCTION: Myeloid malignancies, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN), exhibit overlapping pathophysiology. Chronic MPNs can transform into secondary AML (sAML), which is associated with poor prognosis and limited treatment options. However, the process and prognostic significance of leukemic transformation remain incompletely understood.
METHOD: Through a two-sample bidirectional Mendelian randomization (MR) analysis, we showed that genetic liability to MPN significantly predicts the risk of developing AML, establishing MPN as the precursor to leukemia. To identify mediators of this risk, we integrated population-level plasma proteomics data, identifying 55 proteins associated with MPN. Upon integrative analysis with the BEAT-AML cohort, we developed a prognostic proteogenomic gene signature, showing that higher expression of CDCP1, CRISP3, and DXCR, alongside lower MPO levels, correlates with worse AML outcomes. We further performed pharmacogenomic analysis to identify vulnerability to PI3K/AKT/mTOR signaling pathway inhibition in high-risk AML. In vitro and in vivo experiments validated the efficacy of mTOR inhibition in myeloid malignancies.
RESULTS: This gene signature effectively stratified patients by risk, with significant survival differences across the BEAT-AML and TCGA-LAML cohorts, and revealed immune alterations in high-risk groups, including elevated monocyte prevalence and cytokine signaling activity. Single-cell RNA sequencing (scRNA-seq) further suggested enrichment of these genes in progenitor cells and AML blasts. Drug sensitivity predictions suggested that high-risk AML patients may be particularly responsive to PI3K/AKT/mTOR signaling pathway inhibitors. Consistently, we observed upregulation of the genes in cell line models harboring MPN and AML mutations, which was suppressible via dual PI3K/mTOR inhibitor Omipalisib. The efficiency of PI3K/mTOR inhibition in myeloid malignancies was further corroborated by results from multiple in vivo models.
CONCLUSION: Together, our findings revealed shared molecular features across MPN and AML, identified a prognostic gene signature for risk stratification, and provided rationale for PI3K/mTOR inhibition as a promising therapeutic strategy in myeloid malignancies.

Keywords:  Myeloid malignancy; PI3K/AKT/mTOR signaling; Pharmacogenomics; Prognostic model; Proteogenomic

DOI:  https://doi.org/10.1186/s12964-025-02568-3
Cell Cycle. 2025 Dec 15. 1-19

Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia.

Yolande Klootsema, Nikolaos Tsesmetzis, Sushma Sharma, Sophia Hofmann, Jonas Thier, Christopher Dirks, Femke M Hormann, Miriam Yagüe-Capilla, Anna Bohlin, Sofia Bengtzen, Sören Lehmann, Andrei Chabes, Martin Jädersten, Vanessa Lundin, Sean G Rudd, Ingrid Lilienthal, Nikolas Herold.

  Cytarabine (ara-C) and fludarabine (F-ara-A) are key drugs in leukaemia treatment. SAMHD1 is known to confer resistance to ara-C and F-ara-A, and we previously identified ribonucleotide reductase inhibitors as indirect SAMHD1 inhibitors in a phenotypic screen. The inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolic acid (MPA) was also a hit in this screen. IMPDH inhibitors (IMPDHi) have previously shown efficacy against KMT2A-rearranged (KMT2Ar) acute myeloid leukaemia (AML). We investigated whether IMPDH inhibition could enhance the effect of ara-C and F-ara-A in AML cell lines and primary AML samples, and whether this effect was linked to KMT2A status. We found that sensitivity to IMPDHi was independent of KMT2A status. IMPDHi synergized with ara-C and F-ara-A in a SAMHD1-dependent manner in a subset of AML cells, but not in acute lymphoblastic leukaemia cell lines. Mechanistically, IMPDHi depleted allosteric SAMHD1 activators GTP and dGTP, thereby increasing active triphosphate metabolites in SAMHD1-proficient, but not SAMHD1-deficient, cells. Our findings suggest that the addition of IMPDHi to ara-C and F-ara-A may have therapeutic benefits in some AML cases.

Keywords:  IMPDH; KMT2A; SAMHD1; leukemia; therapy resistance

DOI:  https://doi.org/10.1080/15384101.2025.2601796
Leukemia. 2025 Dec 19.

Targeting IL-1/IRAK1/4 signaling in acute myeloid leukemia stem cells following treatment and relapse.

Tzu-Chieh Ho, Mark W LaMere, Hiroki Kawano, Daniel K Byun, Elizabeth A LaMere, Yu-Chiao Chiu, Chunmo Chen, Li-Ju Wang, Jian Wang, Baskar Ramdas, Nikolay V Dokholyan, Laura M Calvi, Jane L Liesveld, Craig T Jordan, Rakesh K Singh, Reuben Kapur, Michael W Becker.

Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.

DOI: https://doi.org/10.1038/s41375-025-02816-y
Br J Haematol. 2025 Dec 19.

Assessment of measurable residual disease in ovarian tissue collected for fertility preservation in patients in remission from acute myeloid leukaemia: A pilot study.

Augustin Boudry, Florian Chevillon, Alice Marceau-Renaut, Thorsten Braun, Thomas Boyer, Nathalie Helevaut, Elise Fournier, Sandrine Geffroy, Nicolas Boissel, Emmanuelle Clappier, Claude Preudhomme, Nicolas Duployez, Catherine Poirot, Laurène Fenwarth.

  Allogeneic haematopoietic stem cell transplantation (ASCT) is a curative treatment for acute myeloid leukaemia (AML) but carries a high risk of gonadotoxicity. Ovarian tissue cryopreservation (OTC) offers a fertility preservation option, yet its safety in AML remains uncertain due to the risk of leukaemic cell reintroduction. The FERTILAM pilot study evaluated measurable residual disease (MRD) in ovarian tissue collected at complete remission (CR) from nine AML patients undergoing OTC before ASCT. MRD was assessed using patient-specific clonal markers via droplet digital polymerase chain reaction on DNA and RNA from bone marrow (BM), ovarian cortex and medulla. At CR, MRD-DNA was detected in ovarian cortex of four of nine patients, all with concurrent MRD positivity in BM. Three patients were negative in both BM and ovarian tissue. Paired cortex/medulla analyses showed concordant MRD-DNA results in five of six patients. BM MRD-RNA and MRD-DNA were fully concordant, whereas two discrepancies were observed between MRD-DNA and MRD-RNA in ovarian tissue. These findings suggest potential leukaemic cell persistence in ovarian tissue despite CR and highlight the need for sensitive molecular assays to assess safety prior to ovarian tissue transplantation.

Keywords:  acute myeloid leukaemia; fertility preservation; measurable residual disease; ovarian tissue cryopreservation

DOI:  https://doi.org/10.1111/bjh.70289
Nat Commun. 2025 Dec 19.

Thrombopoietin increases susceptibility for EVI1 + KMT2A-MLLT3-driven AML expressing stem cell genes linked to poor outcome.

Hugues-Étienne Châtel-Soulet, Sabine Juge, Ana Luisa Pereira, Jonathan Seguin, Athimed El Taher, Federica Valigi, Zivojin Jevtic, Rathick Sivalingam, Frederik Otzen Bagger, Paul Büschl, Marwa Almosailleakh, Alexander Tzankov, Wei Tong, Mineo Kurokawa, César Nombela Arrieta, Juerg Schwaller.

To address the cellular origin of ecotropic virus integration site 1 (EVI1)-expressing aggressive KMT2A-rearranged acute myeloid leukaemia (AML) we integrate an Evi1-GFP reporter allele in the inducible iKMT2A-MLLT3 mouse model. We observe that a single injection of thrombopoietin (TPO) selectively increases the number of cycling Evi1+ haematopoietic stem cells (HSC) and accelerates AML initiation. Comparison of mouse Evi1+ KMT2-MLLT3+ AML originating from TPO-stimulated HSC with human EVI1+AML reveals higher expression of HSC genes including IL12Rβ2 and INPP4B linked to poor disease outcome of patients of four large AML cohorts. Knockdown experiments show exclusive MECOM-dependency of human EVI1high KMT2A-rearranged OCI-AML4 cells while reduction of IL12Rβ2 also impairs clonogenic growth of EVI1low MOLM-13, THP-1 or HL-60 AML cells. Collectively, we show that exogenous factors like TPO can increase the susceptibility for iKMT2A-MLLT3-driven HSC-originating Evi1+ AML expressing stem cell genes linked to transformation maintenance of cell lines, and poor disease outcome of patients.

DOI: https://doi.org/10.1038/s41467-025-67611-w
Blood. 2025 Dec 17. pii: blood.2024028147. [Epub ahead of print]

The glycosaminoglycan oncofetal chondroitin sulfate represents a novel target for antibody drug-conjugate therapy for AML.

Joana Mujollari, Montserrat Estruch Alrich, Priya Khadgawat, Swati Choudhary, Tobias Gustavsson, Robert Dagil, Norbert Redlinger, Caroline Løppke, Elena Vidal Calvo, Mie Anemone Nordmaj, Thor Grundtvig Theander, Olaf Heidenreich, Yen Nguyen, Shuyu Qin, Anne Louise Tølbøll Sørensen, Kristen Grønbæk, Bo T Porse, Brigitte Kircher, Jan Mueller, Mette Agerbæk, Ali Salanti, Kim Theilgaard-Mönch.

Antibody-drug conjugates (ADCs) have emerged as promising targeted therapies in acute myeloid leukemia (AML). However, most ADCs exhibit off-target binding to normal hematopoietic stem and myeloid progenitor cells, resulting in adverse hemato-toxicity and narrow therapeutic windows, limiting their clinical application to young and fit AML patients eligible for intensive curative therapies. Proteoglycans with high levels of the glycosaminoglycan oncofetal chondroitin sulfate (ofCS), are abundantly expressed in solid cancers while being absent or lowly expressed in normal adult tissues. Here, we report high ofCS levels on bone marrow (BM) cells of AML patients and AML patient-derived xenografts (PDXs), while BM cells of healthy subjects showed low or undetectable ofCS levels. Consistently, an anti-ofCS antibody demonstrated binding and internalization into AML cells, and anti-ofCS ADCs effectively killed AML cells in vitro. Moreover, anti-ofCS ADC treatment significantly prolonged survival of AML PDXs compared to controls and was associated with low toxicity. Hence, anti-ofCS ADC could represent an effective therapy with acceptable toxicity applicable for all AML patients, including those ineligible or unresponsive to current intensive curative therapies. In conclusion, our study for the first time demonstrates that a glycosaminoglycan like ofCS represents a druggable target for development of effective antibody-based AML therapies.

DOI: https://doi.org/10.1182/blood.2024028147
Transplant Cell Ther. 2025 Dec 15. pii: S2666-6367(25)02601-6. [Epub ahead of print]

Pretransplant HMA and Venetoclax in AML patients - a Real-World Analysis from the Cooperative Transplant Study Group.

Christina Rautenberg, Matthias Stelljes, Gesine Bug, Udo Holtick, Edgar Jost, Sara Jennrich, Annemarie Mohring, Johanna Tischer, Alessia Fraccaroli, Christoph Schliemann, Laura K Schmalbrock, Lars Bullinger, Judith Metzdorf, Krischan Braitsch, Mareike Verbeek, Katharina Götze, Fabian Acker, H Christian Reinhardt, Nicolaus Kröger, Thomas Schroeder.

  The combination of hypomethylating agents (HMA) and the BCL2 inhibitor venetoclax (VEN) has become standard first-line therapy for AML patients ineligible for intensive treatment and is also used as salvage therapy in relapsed/refractory (R/R) AML. Data on outcomes after subsequent allogeneic stem cell transplantation (allo-SCT) are limited. We retrospectively analyzed 91 patients with newly diagnosed (ND, n=34) or R/R (n=57) AML who received HMA/VEN followed by allo-SCT between 2020 and 2022. Overall response rate (ORR) to HMA/VEN was 67% with no significant difference between ND (73%) and R/R (64%) patients. Pre-transplant MRD negativity was achieved in 49% of responders. Post-transplant 2-year overall survival (OS) and relapse-free survival (RFS) were 52% and 42% for the entire cohort, with similar outcomes for ND (2-year OS 47%, RFS 38%) and R/R (2-year OS 56%, RFS 45%) patients. In patients with high-risk features, such as TP53 mutation or complex karyotype (cKT), ND patients still achieved promising responses (TP53mut 75%, cKT 80%) and acceptable post-transplant outcomes (TP53mut 2-year OS 36%; cKT 2-year OS 45%). In contrast, R/R patients showed lower response rates (TP53mut 14%, cKT 29%) and inferior outcomes (TP53mut 2-year OS 29%; cKT 2-year OS 29%). In conclusion, HMA/VEN is a feasible induction or salvage strategy enabling allo-SCT with encouraging outcomes in high-risk populations. In ND AML, this approach may expand transplant eligibility in older or frail patients. R/R patients with adverse molecular features may require alternative novel therapies or direct transplantation.

Keywords:  AML; HMA; Venetoclax; allogeneic transplantation; measurable residual disease

DOI:  https://doi.org/10.1016/j.jtct.2025.12.943
J Clin Invest. 2025 Dec 15. pii: e193082. [Epub ahead of print]135(24):

Leukemia-expanded splenic CD81+ erythroblasts potentiate disease progression in mice by reshaping leukemic cell metabolism.

Yue Li, Jiaxuan Cao, Jingyuan Tong, Peixia Tang, Haoran Chen, Guohuan Sun, Zining Yang, Xiaoru Zhang, Fang Dong, Shangda Yang, Jie Gao, Xiangnan Zhao, Jinfa Ma, Di Wang, Lei Zhang, Lin Wang, Tao Cheng, Hui Cheng, Lihong Shi.

  During the progression of acute myeloid leukemia (AML), extramedullary hematopoiesis (EMH) compensates for impaired bone marrow hematopoiesis. However, the specific cellular dynamics of EMH and its influence on AML progression remain poorly understood. In this study, we identified a substantial expansion of the CD81+ erythroblast subpopulation (CD81+ Erys) in the spleens of AML mice, which promoted AML cell proliferation and reduced survival. Mechanistically, CD81+ Erys secrete elevated levels of macrophage migration-inhibitory factor (MIF), which interacted with the CD74 receptor on AML cells, activating the mTORC1 signaling pathway and upregulating Egln3. Consequently, AML cells cocultured with CD81+ Erys exhibited reprogrammed phospholipid metabolism, characterized by an increased phospholipid-to-lysophospholipid ratio. Modulating this metabolic shift, either by supplementing exogenous lysophospholipids or depleting Egln3 in AML cells, restored the phospholipid balance and mitigated the protumorigenic effects induced by CD81+ Erys. Overall, our findings elucidate the molecular crosstalk between erythroblasts and AML cells, extend our insights into the mechanisms driving AML progression, and suggest potential therapeutic strategies.

Keywords:  Cell biology; Hematology; Leukemias; Metabolism

DOI:  https://doi.org/10.1172/JCI193082
Cancer. 2026 Jan 01. 132(1): e70210

Characterization of chromosome 5 aberrations in TP53 mutated myeloid neoplasms with ≥5% blasts: An International TP53 Investigators Network (iTiN) study.

Irfan Yasin, Anna Stengel, Haipeng Shao, Amandeep Kaur, Emily F Mason, Pranav P Patwardhan, Nathanael G Bailey, Sharmila Ghosh, Kedar V Inamdar, Anand A Patel, Madhavi Pandiri, Jingjing Zhang, Payal Sojitra, Hamza Tariq, Zenggang Pan, Danica Wiredja, Peng Wang, Melissa Y Tjota, Jeremy P Segal, Hong Chang, David A Sallman, Daniel A Arber, Ayalew Tefferi, Talha Badar, Anamarija M Perry, Claudia Haferlach, Angela M Lager, Girish Venkataraman.

   BACKGROUND: Isolated chromosome 5/5q losses (-5/5q) without TP53 mutations are associated with favorable outcomes in myeloid neoplasms (MN) with <5% blasts. However, the clinical implication of concurrent -5/5q and TP53 aberrations in MN with ≥5% blasts is poorly understood.
METHODS: Patients with TP53-mutated MN carrying ≥5% blasts assessing the prognostic impact of -5/5q on 24-month overall survival (OS24) were examined.
RESULTS: Of 587 patients, 515 (88%) exhibited -5/5q overwhelmingly in the context of a complex karyotype (98.3% vs. 61.1% complex karyotype without -5/5q; p < .0001) and multihit TP53 allelic state (88.3% vs. 56.9%; p < .0001). Proportions of patients with blasts ≥20% were comparable between groups with and without -5/5q; p = 0.26. Notably, patients with -5/5q exhibited significantly fewer coalterations; p < .0001. Looking at outcomes, presence of -5/5q was associated with shorter median 24-month overall survival (7.8 months vs. 11.2 months; pLog-rank = .012), an effect restricted to subgroups with blasts <20% (p = .039; N = 163), absent -7/7q (p = .007; N = 225), or WHO5-defined single hit allelic state (p = 0.030; N = 91). Importantly, -5/5q retained independent adverse prognostic significance regardless of TP53 allelic state in a multivariable model. Furthermore, among the subset of 75 (13%) patients undergoing allogeneic stem cell transplantation, -5/5q predicted significantly shorter median 5-year posttransplant survival (16.2 months vs. median not reached; pLog-rank = .009).
CONCLUSIONS: These findings emphasize the independent prognostic relevance of chromosome 5/5q losses underscoring the clinical relevance of cytogenetic testing for -5/5q even in this high-risk cohort.

Keywords:  AML; MDS; TP53; cytogenetics; outcomes; pathology

DOI:  https://doi.org/10.1002/cncr.70210
Blood. 2025 Dec 15. pii: blood.2025032084. [Epub ahead of print]

Transient SP140 inhibition unlocks hematopoietic stem cell fate from human pluripotent stem cells.

Xingjie Liu, Zhiwei Zhang, Xinyu Cui, Rui Guo, Xiaoyan Ding, Liyang Ma, Pentao Liu, Yong Yu.

Efficient derivation of transplantable hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is constrained by epigenetic silencing. Through a CRISPR/Cas9 screen with a BCL11A-eGFP reporter, we identified epigenetic reader SP140 suppressing hematopoiesis. Transient genetic or pharmacologic inhibition of SP140 in hPSC-derived teratoma and embryoid body cultures promoted robust multilineage hematopoiesis and accelerated production of HSCs with serial transplantability and durable reconstitution in immunodeficient mice. Mechanistically, SP140 blockade unlocked transcription at endothelial-to-hematopoietic transition (EHT) loci through topoisomerase 1-dependent chromatin remodeling, activating key hematopoietic and stem cell programs. Transcriptomic analysis showed activation of these regulators upon SP140 inhibition, which was prevented by topoisomerase 1 blockade. CUT&Tag profiling identified SP140 binding at EHT and HSC-specification gene loci. SP140's function as an epigenetic gatekeeper was conserved in diverse hPSCs and murine embryo models, where its downregulation enhanced physiological HSC emergence. Importantly, selective SP140 inhibition in a chemically defined, scalable protocol enabled rapid in vitro generation of bona fide human HSCs suitable for transplantation. These findings identify transient SP140 inhibition as an effective strategy to overcome epigenetic barriers and unlock clinically relevant HSC specification from hPSCs, advancing regenerative hematopoiesis and cell therapy.

DOI: https://doi.org/10.1182/blood.2025032084
Commun Biol. 2025 Dec 17. 8(1): 1768

Integrated analysis of post-transcriptional regulations reveals insights into acute myeloid leukemia.

Elissa Khadra, Zoaila Iqbal, Morgane Le Gall, Guilhem Clary, Francoise Levavasseur, Zubaidan Tuerdi, Charles Dussiau, David Rombaut, Marie Temple, Chloe Friedrich, Romain Vazquez, Justine Decroocq, Clément Larrue, Didier Bouscary, Olivier Kosmider, Nicolas Chapuis, Yannick Simoni, Jerome Tamburini, Evelyne Lauret, Michaela Fontenay, Rudy Birsen, Emilie-Fleur Gautier, Ismael Boussaid.

Post-transcriptional regulations play crucial roles in gene expression, but their global impact in acute myeloid leukemia (AML) remains poorly understood. Here, we perform an integrative analysis of transcriptomic and proteomic data from 44 AML samples to uncover the determinants of protein-to-mRNA-ratios (PTRs), a metric summarizing post-transcriptional regulatory processes. Using over a thousand proxies related to mRNA sequestration, translation efficiency, and RNA/protein stability, multivariate regression reveals key features driving PTRs. Our findings show that PTRs are conserved between AML samples and human tissues, underscoring the universality of underlying mechanisms. Furthermore, we show that the shadow proteome, consisting of genes frequently undetectable by mass spectrometry, can be partially attributed to low predicted PTRs.Due to the lack of existing tools, these post-transcriptional mechanisms remained in the blind spot of proteogenomic analysis. To bridge this gap, we developed POSTCODE, a tool for annotating omics datasets with PTR-related proxies, enabling the detection of post-transcriptional regulation changes. Applying this tool to AML datasets enables a better understanding of the mechanisms underlying differential expression, including alterations in proteostasis, translation, RNA stability or transcript localization. Our study provides a comprehensive resource for monitoring post-transcriptional regulation, paving the way for the identification of new precision medicine strategies.

DOI: https://doi.org/10.1038/s42003-025-09156-8
Leukemia. 2025 Dec 19.

Dynamics of clonal hematopoiesis and cellular responses to stress-induced toxicity in autologous stem cell transplantation.

Catarina M Stein, Raphael Hablesreiter, Friederike Christen, Pelle Löwe, Coral Fustero-Torre, Klara Kopp, Benjamin N Locher, Lena Nitsch, Robert Altwasser, Johanna Franziska Kerschbaum, Lars Bullinger, Leif S Ludwig, Paulina M Strzelecka, Frederik Damm.

Autologous stem cell transplantation (ASCT) involves harvesting hematopoietic stem and progenitor cells (HSPCs) prior to chemotherapy and subsequent repopulation of the bone marrow. This process imposes a bottleneck, providing a framework to dissect the unresolved short- and long-term clonal dynamics during hematopoietic reconstitution. By integrating bulk error-corrected targeted sequencing of clonal hematopoiesis (CH)-associated genes with mitochondrial single-cell Assay for Transposase-Accessible Chromatin sequencing (mtscATAC-seq), we characterized mutational trajectories in frequently altered hematological genes and traced clonal evolution through somatic mitochondrial DNA variants, revealing post-transplant cellular heterogeneity and clonal architecture. Among 60 patients (multiple myeloma, n = 51; non-Hodgkin lymphoma, n = 6; Hodgkin lymphoma, n = 3), CH-associated mutations were identified in 53% pre-ASCT, predominantly involving DNMT3A. A transient increase in mutation counts and gene diversity occurred 10-25 days post-ASCT, with a gradual clonal expansion two years post-transplantation. Tandem ASCT amplified clonal complexity, with a twofold increase in mutation count and gene-level diversity, while preserving clonal trajectories across both transplant courses. Mitochondrial single-cell profiling in longitudinal samples of 3 patients showed patient-specific immune reconstitution and clonal dynamics, with balanced multilineage output from graft HSPCs. Collectively, our findings provide a firsthand comprehensive view of ASCT-induced clonal dynamics and immune reconstitution, paving the way for targeted gene-specific post-transplant monitoring.

DOI: https://doi.org/10.1038/s41375-025-02823-z
Blood. 2025 Dec 15. pii: blood.2025029210. [Epub ahead of print]

Asciminib Demonstrates Superior Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia in the ASC4FIRST Trial.

Jorge E Cortes, Timothy P Hughes, Jianxiang Wang, Dong-Wook Kim, Dennis Dong Hwan Kim, Jiri Mayer, Yoew-Tee Goh, Philipp le Coutre, Gabriel Etienne, Inho Kim, David Andorsky, Felice Bombaci, Ghayas C Issa, Naoto Takahashi, Shruti Kapoor, Rajendra Jinwal, Kamel Malek, Tracey McCulloch, Lillian Yau, Richard A Larson, Andreas Hochhaus.

Many patients receiving frontline tyrosine kinase inhibitors (TKIs) for chronic phase chronic myeloid leukemia (CML-CP) experience inadequate disease control and/or adverse events (AEs) that impair quality of life. Treatments offering optimal efficacy, safety, and tolerability will support long-term therapy. In the primary analysis from ASC4FIRST, a phase 3 randomized trial comparing asciminib with investigator-selected TKIs (IS-TKIs) in newly diagnosed CML-CP, asciminib demonstrated superior efficacy vs all IS-TKIs and vs imatinib in the imatinib stratum, meeting both primary objectives. In the secondary analysis (2.2 years median follow-up), major molecular response (MMR) rate at week 96 was 74.1% with asciminib vs 52.0% with IS-TKIs (treatment difference, 22.4%; 95% CI, 13.6%-31.3%; 1-sided P<.001), and 76.2% with asciminib vs 47.1% with imatinib in the imatinib stratum (treatment difference, 29.7%; 95% CI, 17.6%-41.8%; 1-sided P<.001), meeting both key secondary objectives. MMR rate was 72.0% with asciminib vs 56.9% with second-generation (2G) TKIs (treatment difference, 15.1%; 95% CI, 2.3%-28.0%; 1-sided P<.05), suggesting possible clinical benefit although the study was not designed to formally confirm statistical significance for this secondary endpoint. Safety/tolerability remained favorable with asciminib vs IS-TKIs. Dose reductions and interruptions, respectively, occurred with asciminib (18.5% and 46.5%), imatinib (23.2% and 47.5%), and 2G TKIs (54.9% and 63.7%). The hazard ratio for time to discontinuation of treatment due to AEs for asciminib vs 2G TKIs was 0.46 (95% CI, 0.215%-0.997%). With longer follow-up, asciminib continued to demonstrate a favorable benefit-risk profile over IS-TKIs and imatinib, supporting its potential as a treatment option for newly diagnosed CML-CP.

DOI: https://doi.org/10.1182/blood.2025029210
J Biol Chem. 2025 Dec 17. pii: S0021-9258(25)02918-7. [Epub ahead of print] 111066

Dynamic and extensive A-to-I RNA recoding in immunoglobulin shapes myeloid neoplasms transcriptome.

Qi Cao, Yuqing Wang, Yuange Duan.

  Functional adenosine-to-inosine (A-to-I) mRNA editing sites are continuously identified in cellular organisms. Despite that several editing sites have been linked to various human cancers, the dynamic RNA editing in the progression of myeloid neoplasms remains less known, preventing a clearer understanding of the functional repertoire of RNA editing in blood diseases. By analyzing transcriptomes from healthy controls (HC), low-risk myelodysplastic syndrome (MDS), high-risk MDS, and acute myeloid leukemia (AML), we reveal widespread and dynamic RNA editing events accompanying disease progression. Immunoglobulin genes are enriched for nonsynonymous editing sites with significantly altered editing levels in myeloid neoplasms, and such recoding sites often show genomic substitutions to hardwired G during mammalian evolution. Collectively, our findings broaden the functional spectrum of RNA editing in human and highlight its potential as a driver, responsor, or biomarker of myeloid neoplasms, underscoring its significance in human disease evolution.

Keywords:  A-to-I mRNA editing; differential editing; immunoglobulin; myeloid neoplasms; nonsynonymous

DOI:  https://doi.org/10.1016/j.jbc.2025.111066
Leuk Lymphoma. 2025 Dec 16. 1-11

NAMPT inhibition uncovers therapeutic vulnerabilities to venetoclax and chemotherapy in acute myelogenous leukemia.

John R Sanchez, Chaomei Liu, Vishakha Pawar, Yanqing Huang, Daisy Diaz-Rohena, Jyotsana Singh, Priya Koppikar, Tzung-Huei Lai, Lisa St John, Vinay Puduvalli, Jeffrey Molldrem, Palaniraja Thandapani, Nitin Jain, Rosa Lapalombella, Deepa Sampath.

  Acute myeloid leukemia (AML) cells depend on nicotinamide adenine dinucleotide (NAD+) biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) for survival. Single-cell RNA sequencing revealed robust NAMPT expression across diverse AML subtypes. Proteomic profiling showed that NAMPT inhibition with KPT-9274 induced adaptive upregulation of BCL2, an anti-apoptotic protein, highlighting a survival mechanism. BH3 profiling confirmed that AML cells hierarchically depend on BCL2, followed by MCL1 and BCLxL, for survival. Combining KPT9274 with the BCL2 inhibitor venetoclax synergistically enhanced mitochondrial dysfunction, cytochrome C release, and apoptotic death in AML blasts. Additionally, NAMPT inhibition reduced PARP activity and impaired DNA repair pathways, sensitizing AML cells to cytarabine and hypomethylating agents. Together, these results demonstrate that NAMPT inhibition both potentiates venetoclax activity and enhances the cytotoxic effects of standard chemotherapies by targeting metabolic and DNA repair vulnerabilities. These findings provide strong preclinical support for evaluating NAMPT and BCL2 dual inhibition strategies in future AML clinical trials.

Keywords:  AML; BCL-2 dependency; DNA repair impairment; KPT-9274; NAMPT inhibition; metabolic vulnerability

DOI:  https://doi.org/10.1080/10428194.2025.2571199
Leuk Lymphoma. 2025 Dec 17. 1-5

Durable post-transplant survival after first-line tagraxofusp for blastic plasmacytoid dendritic cell neoplasm.

Naveen Pemmaraju, Marina Konopleva, Muzaffar Qazilbash, Anthony S Stein, David A Rizzieri, Eunice S Wang, Sumithira Vasu, Ira Gupta, Andrew A Lane.

DOI: https://doi.org/10.1080/10428194.2025.2595226
Leukemia. 2025 Dec 19.

Treatment expectations and goals among patients with chronic myeloid leukemia in Germany: a patient-centered perspective.

Philipp Ernst, Cera Lohse, Michael Lauseker, Jan Geißler, Philipp le Coutre, Tim H Brümmendorf, Susanne Saußele, Andreas Burchert, Georg-Nikolaus Franke, Paul La Rosée, Annamaria Brioli, Thomas Schenk, Christian Fabisch, Thomas Ernst, Guido Mehlkop, Andreas Hochhaus.

Chronic myeloid leukemia (CML) is a chronic condition with excellent long-term survival under tyrosine kinase inhibitor (TKI) therapy. However, patient priorities regarding treatment goals and quality of life remain insufficiently understood. We conducted a nationwide online survey among German CML patients in collaboration with the German CML Alliance and patient organizations to assess treatment goals at diagnosis, during therapy, and in the treatment-free remission phase. The questionnaire included validated measures of treatment satisfaction, fear of progression, and quality-of-life priorities, supplemented by newly developed items. Between November 2024 and February 2025, 582 patients (median age 56 years, 48.8% female) completed the survey. Overall TKI tolerability was rated positively (median 4/5), particularly in first-line therapy and among patients with shorter disease duration, whereas long-term survivors reported more daily-life limitations. Younger patients ( < 45 years) emphasized fertility, sexuality, and work-related concerns, while older patients prioritized tolerability, independence, and mental health. Treatment history shaped expectations: those with discontinuation experience were more willing to accept adverse effects for the prospect of remission. Overall, patient priorities diverged between achieving deep molecular response and maintaining optimal tolerability. Integrating patient-reported preferences into shared decision-making may enhance satisfaction, adherence, and long-term outcomes of patients with CML.

DOI: https://doi.org/10.1038/s41375-025-02826-w
Leukemia. 2025 Dec 19.

Etiology of TP53 mutated complex karyotype acute myeloid leukemia.

Anna Fedenko, Honorata Czapinska, Alwin Krämer, Friedrich Stölzel, Tilmann Bochtler, Matthias Bochtler.

SCHEMATIC VIEW OF THE DEVELOPMENT OF CK-AML DRIVEN BY THE TP53 ABSENCE.: The occurrence of the first, often dominant negative TP53 mutation is quickly followed by the loss of the second TP53 allele and numerous further chromosomal aberrations.

DOI: https://doi.org/10.1038/s41375-025-02835-9
medRxiv. 2025 Dec 07. pii: 2025.12.04.25340141. [Epub ahead of print]

Genomics of Acute Myeloid Leukemia at Diagnosis and Remission.

Kai Yu, Laura W Dillon, Jesse M Tettero, Gege Gui, Rasha W Al-Ali, Michael R Grunwald, Elizabeth F Krakow, Elizabeth A Griffiths, Alexandra Gomez-Arteaga, Rahul S Vedula, Melhem Solh, Amandeep Salhotra, Nelli Bejanyan, Lori Muffly, Antonio M Jimenez-Jimenez, Michael W Drazer, Yi-Bin Chen, Aaron Logan, Reena V Jayani-Kosarzycki, Sophia R Balderman, James S Blachly, Brian C Shaffer, Lawrence J Druhan, Cecilia Cs Yeung, Vanessa E Kennedy, Amir T Fathi, Hetty E Carraway, Sandeep Gurbuxani, Melissa Y Tjota, Farah Sahoo, Max Smith, Dylan Barfield, Jim Guo, James Han, Jason Hu, Heejon Jo, Vidya Kudlingar, Wilfred Li, Yutong Qiu, Pratheesh Sathyan, Sean Truong, Severine Catreux, Sam Ng, Khai Luong, Yunjiao Zhu, Reem Bahr, Jamie Diemer, Christina K Ferrone, Allison J Getker, Jackie Bjerke, Stephanie Bo-Subait, Steven M Devine, Bergetta Dietel, Gabrielle Giammarino, Emily Heying Chihak, Jianqun Kou, Emily Kolb, Danielle O'Donnell Vitali, Stephen R Spellman, Brenna K Tesch, Jenny Vogel, Stephanie Waldvogel, Syreeta Weatherspoon, Jeffery J Auletta, Christopher S Hourigan.

Accurate and comprehensive genetic characterization of acute myeloid leukemia (AML) is essential for diagnosis, prognostication, and treatment selection. We report here, in 255 adults with AML enrolled in a prospective clinical protocol at 18 major cancer centers across the USA, the results of whole genome DNA-sequencing (WGS) at diagnosis and post-treatment remission. WGS effectively recapitulated, and frequently identified genetic alterations missed by, conventional standard of care clinical testing. These new findings included important prognostic and predictive biomarkers, copy number alterations, regulatory element, splicing, and structural variants including partial tandem duplications within KMT2A. All patients had a pathogenic variant detected at diagnosis, and approximately ten percent also had evidence of a potential inherited myeloid malignancy predisposition. This comprehensive atlas of adult AML genomics provides novel insights into disease biology, creates an evidentiary basis to support clinical testing improvements, and is a resource for both diagnostics and drug development. <This work is embargoed, with agreement of medRxiv, until 7th December 2025> .
Statement of Significance: Acute myeloid leukemia is a diagnostic category encompassing multiple rare hematological malignances. We show, in this nationwide multicenter study, that standardized unbiased whole genome DNA-sequencing and disease-optimized bioinformatics can replicate conventional "standard of care" AML clinical testing results, while also revealing currently underdiagnosed AML disease biology and potential genetic predisposition.

DOI: https://doi.org/10.64898/2025.12.04.25340141
Blood. 2025 Dec 15. pii: blood.2025031454. [Epub ahead of print]

Microenvironmental cell interactions are essential for sustaining functionality of myelofibrosis malignant stem cells.

Min Lu, Md Babu Mia, Lijuan Xia, Gohar Mosoyan, Momina Hayat, Christoph Schaniel, Ronald Hoffman.

Cancer develops through the interactions between cancer stem cells and the components of tumor microenvironment (TME). To model in vivo cancer stem cell/TME interactions and elucidate their functional consequences, we focused on myelofibrosis (MF), a stem cell driven myeloproliferative neoplasm. We co-cultured MF hematopoietic stem and progenitor cells (HSPCs) with normal donor endothelial cells (ECs) and mesenchymal stromal cells (MSCs) to investigate the consequences of interactions between malignant MF HSPCs and non-malignant microenvironmental cells. This tri-cultivation system proved to be a simple and reproducible platform, which promoted malignant clone dominance and the persistence of MF HSPCs that recapitulate the MF phenotype upon transplantation into immunodeficient mice, including splenomegaly and marrow fibrosis. Transcriptional profiling revealed extensive reprogramming of not only the co-cultured MF HSPCs, but also MSCs and ECs. Although numerous disease-relevant pathways were upregulated, the pro-inflammatory response stood out as a key consequence of MF HSPC/TME interactions. We validated these findings through quantitation of pro-inflammatory transcript upregulation and cytokine production. This human multicellular model system has proven useful in demonstrating the multidirectional interactions of MF HSPCs with TME cells that are essential for sustaining fully functional MF stem cells.

DOI: https://doi.org/10.1182/blood.2025031454
Blood. 2025 Dec 17. pii: blood.2025028703. [Epub ahead of print]

The role of CD38 in monocytes during fibrotic progression of myeloproliferative neoplasms.

Yiru Yan, Jinqin Liu, Songyang Zhao, Fuhui Li, Lin Yang, Zefeng Xu, Tiejun Qin, Xiaofan Zhu, Wenbin An, Zhongxun Shi, Wenyi Shen, Peihong Zhang, Gang Huang, Raajit K Rampal, Zhijian Xiao, Bing Li.

Proinflammatory signaling is a hallmark of myeloproliferative neoplasms (MPNs). Several studies have shown that monocytes are a major source of proinflammatory cytokines and monocyte-derived fibrocytes play a pivotal role in the pathogenesis of myelofibrosis (MF). To further explore the role of monocytes in MF, we generated inducible NrasG12D/+Jak2V617F/+ (NJ) mice. Recipients transplanted with NJ BM cells developed MF with an early onset of anemia and monocytosis. In vitro, NJ recipients' BM nucleated cells exhibited increased quantity of CD45+CollagenI+ fibrocytes, which were mainly derived from the Ly6chigh monocytes. RNA sequencing identified a significant elevated expression of CD38 (a nicotinamide adenine dinucleotide (NAD)+ hydrolase) in Ly6chigh monocytes from NJ mice, which results in pronounced lower level of NAD+. In humans, CD14+ monocytes from MF patients showed significantly higher expression of CD38 than controls and monocytes from polycythemia vera (PV) patients with grade 1 fibrosis had higher CD38 expression than those without fibrosis. Finally, boosting NAD+ via pharmacological CD38 targeting or NAD+ precursor supplementation inhibited the differentiation of fibrocytes in vitro and targeting CD38 can effectively prevent the onset of fibrosis in vivo. Collectively, our findings shed light on the role of CD38 in monocytes and suggest potential clinical applications such as use of CD38 as a biomarker of fibrotic progression and potential clinical utility of CD38 inhibition in patients with MF.

DOI: https://doi.org/10.1182/blood.2025028703
Br J Haematol. 2025 Dec 14.

Safety and effectiveness of the combination of 5-azacitidine and ruxolitinib in VEXAS syndrome: A single-centre experience.

Gregorio Maria Bergonzi, Enrico Cozzo, Alessandro Tomelleri, Costanza Piccolo, Gianluca Scorpio, Carmelo Gurnari, Francesca Romano, Marco Matucci-Cerinic, Lorenzo Dagna, Massimo Bernardi, Luca Vago, Fabio Ciceri, Corrado Campochiaro, Elisa Diral.



Keywords:  VEXAS; myelodysplastic syndrome

DOI:  https://doi.org/10.1111/bjh.70285
Cell Death Dis. 2025 Dec 18.

RPL5 deficiency-induced ribosomal stress targets a select subset of proteins and inhibits the PI3K-Akt-mTOR signaling pathway to eradicate leukemia stem cells.

Xiaofei He, Daijiao Ye, Jiayao He, Gangfeng Ding, Zihan Lin, Yaqian Qin, Bin Zhou, Liuzhi Shi, Xuanyu Yu, Chen Meng, Min Li, Chongyun Xing, Shenmeng Gao.

Ribosomal protein L5 (RPL5) is considered a haplo-insufficient tumor suppressor by upregulating p53 expression or promoting the inactivation of c-Myc in solid tumors upon tumor initiation. However, its detailed effect and mechanism in tumor maintenance were more complicated. Particularly, the specific role of RPL5 in acute myeloid leukemia (AML) remains unclear. In this study, we found that RPL5 expression was increased in primary AML blasts compared with normal controls, regardless of TP53 mutation. RPL5 knockdown reduced the survival and colony-forming ability of AML cells in vitro, as well as inhibited the engraftment of leukemia stem cells (LSCs) in vivo. It indicated that RPL5 was required for the survival of AML cells, especially for maintaining the stemness of LSCs. The data analysis of RNA-seq and proteomics revealed that RPL5 deficiency eradicated LSC by inducing a cellular stress response, i.e., ribosomal stress, rather than a specific function relating to RPL5. The inhibited PI3K-Akt-mTOR signaling pathway played a central role in the ribosomal stress induced by RPL5 deficiency. To investigate the selectivity of RPL5 depletion in eradicating LSCs, we found that RPL5 expression was highest in LSCs compared to AML cells and healthy controls. Moreover, ribosomal stress specifically affected transcripts with longer exon lengths and proteins with a lower isoleucine (Ile) to valine (Val) ratio. Ile and Val are glycogenic branched-chain amino acids (BCAAs) that regulate fundamental cell processes by affecting mTOR activation through BCAA metabolism. In conclusion, RPL5 depletion-induced ribosomal stress disrupted stemness maintenance by affecting BCAA metabolism in AML, specifically inhibiting the PI3K-Akt-mTOR signaling pathway, which resulted in LSC eradication.

DOI: https://doi.org/10.1038/s41419-025-08379-1
Br J Haematol. 2025 Dec 18.

Predicting the differential diagnosis of inherited versus acquired bone marrow failure syndromes: Development of simple clinical scoring systems.

Marta Bortolotti, Bruno Fattizzo, Simona Stella, Jie Jiang, Francesco Versino, Clair Engelbrecht, Roochi Trikha, Joanna Large, Shreyans Gandhi, Katie Snape, Dario Consonni, Francesco Passamonti, Wilma Barcellini, Austin G Kulasekararaj.



Keywords:  differential diagnosis; inherited and acquired bone marrow failure syndromes

DOI:  https://doi.org/10.1111/bjh.70291
J Clin Invest. 2025 Dec 15. pii: e189051. [Epub ahead of print]135(24):

Nonionotropic action of an acid-sensing ion channel inhibits leukemogenesis in the acidic bone marrow niche.

Hao Gu, Lietao Weng, Chiqi Chen, Xiaoxin Hao, Rongkun Tao, Xin Qi, Xiaoyun Lai, Ligen Liu, Tinghua Zhang, Yiming Jiang, Jin Wang, Wei-Guang Li, Zhuo Yu, Li Xie, Yaping Zhang, Xiaoxiao He, Ye Yu, Yi Yang, Dehua Wu, Yuzheng Zhao, Tian-Le Xu, Guo-Qiang Chen, Junke Zheng.

  The metabolic microenvironment plays important roles in tumorigenesis, but how leukemia-initiating cells (LICs) response to the acidic BM niche remains largely unknown. Here, we show that acid-sensing ion channel 3 (ASIC3) dramatically delays leukemogenesis. Asic3 deletion results in a remarkably enhanced self-renewal, reduced differentiation, and 9-fold greater number of murine acute myeloid LICs. We developed an ultrasensitive, ratiometric, genetically encoded fluorescent pH sensor (pHluorin3) and demonstrated that LICs prefer localizing in the endosteal niche with a neutral pH range of 7.34-7.42, but not in the vascular niche with a lower pH range of 6.89-7.22. Unexpectedly, acid-ASIC3 signaling inhibits both murine and human LIC activities in a noncanonical manner by interacting with the N-terminal of STIM1 to reduce calcium-mediated CAMK1-CREB-MEIS1-LDHA levels, without inducing cation currents. This study reveals a pathway in suppression of leukemogenesis in the acidic BM niche and provides insight into targeting LICs or other cancer stem cells through pH-dependent ASICs.

Keywords:  Hematology; Leukemias; Metabolism; Oncology; Stem Cells

DOI:  https://doi.org/10.1172/JCI189051
Cell Rep. 2025 Dec 17. pii: S2211-1247(25)01507-4. [Epub ahead of print]45(1): 116735

Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.

Meng Zhang, Xiashiyao Zhang, Yandan Chen, Mengmeng Li, Qingwei Ding, Liang Zheng, Junke Zheng, Jun Wan, Bin Guo.

  Mitochondrial proteostasis is essential for hematopoietic stem cell (HSC) maintenance, yet how proteolytic regulation coordinates with metabolic pathways remains unclear. Here, we identify Afg3l2 as a key regulator of cobalamin metabolism and amino acid homeostasis in HSCs through its mediation of Mmadhc degradation. Loss of Afg3l2 leads to Mmadhc accumulation, driving excessive mitochondrial cobalamin import and its conversion to adenosylcobalamin. Elevated adenosylcobalamin levels hyperactivate methylmalonyl-CoA mutase, diverting branched-chain amino acid catabolism toward excessive succinyl-CoA production. This overstimulates the tricarboxylic acid cycle and creates a compensatory dependency on anaplerotic amino acid replenishment. Consequently, Afg3l2-deficient HSCs exhibit increased oxidative stress due to mitochondrial hyperactivation and reactive oxygen species accumulation, ultimately impairing their maintenance and engraftment capacity. Remarkably, Mmadhc overexpression phenocopies these defects, whereas Mmadhc knockdown partially restores HSC function in Afg3l2-deficient models. Our work defines a proteostatic-metabolic circuit in which Afg3l2-mediated Mmadhc degradation regulates cobalamin flux to maintain amino acid and energy balance in HSCs.

Keywords:  CP: Metabolism; CP: Stem cell research; TCA cycle; amino acid metabolism; cobalamin metabolism; hematopoietic stem cell; mitochondrial protease

DOI:  https://doi.org/10.1016/j.celrep.2025.116735
Leukemia. 2025 Dec 19.

Solving Riddles Through Sequencing (SIRIUS): unlocking hematologic diagnoses by whole genome and transcriptome sequencing.

Marietta Truger, Manja Meggendorfer, Wencke Walter, Stephan Hutter, Winfried Alsdorf, Gero Massenkeil, Uwe M Martens, Wolfgang Kern, Katharina Hörst, Constanze Kühn, Andreas Reiter, Andreas Hochhaus, Torsten Haferlach.

In the rapidly evolving field of hematology, the diagnosis of leukemias and lymphomas poses major challenges, despite significant genetic advancements. Although established diagnostic methods comprise a multidisciplinary approach and are considered gold standard, in some cases they fall short in conclusively identifying hematological neoplasms. In this context, the current SIRIUS study (NCT05046444) delves into the potential of whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) to bridge diagnostic gaps. By analyzing 106 patients with an unclear diagnosis or clinical condition following gold standard diagnostics, our study demonstrates that WGS and WTS can uncover a broader range of somatic alterations, including rare single-nucleotide variants (SNVs), small copy number variations (CNVs), and aberrant gene expression patterns not detected by conventional diagnostics. WGS and WTS provided additional diagnostic insights in 25% of cases, suggesting their value not only in enhancing diagnostic accuracy but also in contributing to more informed prognostic assessments and personalized treatment strategies. Therefore, our study underscores the importance of integrating WGS and WTS into the diagnostic toolbox for hematological neoplasms. This approach promises not only to improve patient outcomes but also to do so in a manner that is both financially sustainable and ethically sound.

DOI: https://doi.org/10.1038/s41375-025-02820-2
J Clin Oncol. 2025 Dec 17. JCO2500889

Randomized Noninferiority Trial of a Liberalized Diet Versus the Neutropenic Diet in Hematopoietic Stem-Cell Transplant Patients and Patients With Acute Leukemia.

John R Wingard, Ji-Hyun Lee, Derek Li, Zeina Al-Mansour, Nosha Farhadfar, Jack Hsu, John Hiemenz, Erin A Dean, Randy Brown, Gaurav Trikha, Jenna N Schulz, Christina L Cline, Helen Leather, Michele W Sugrue, Wendy J Dahl, Kristina H McGee, Alex Leggett, Debra Lynch Kelly.

PURPOSE: Patients undergoing hematopoietic stem-cell transplantation (HSCT) or induction chemotherapy for acute leukemia (AL) generally receive a low-bacterial neutropenic diet (ND) to minimize infection from ingested microbes. Recent studies suggest that a more liberalized diet (LD) might be safe. However, those studies lacked robust designs to demonstrate noninferiority and did not address whether an LD improves caloric intake or nutritional status. This trial aimed to determine whether the rate of major infections in LD patients was noninferior to that in ND patients and whether an LD improved caloric intake and nutritional status.
METHODS: In this phase III noninferiority trial, patients were randomly assigned to either an ND or LD, containing fresh fruits and vegetables. The primary end point was the development of any major infection during neutropenia. The noninferiority margin was set at a difference of ≤10% in the major infection rate.
RESULTS: The trial was halted at the second interim analysis after enrolling 214 evaluable patients, because of the LD arm's major infection rate surpassing the predefined stopping boundary. In the LD arm, major infections occurred in 31.4% of patients compared with 20.2% of patients in the ND arm, a difference of 11.2% ([95% CI, -0.4 to 22.9]; P = .58). Furthermore, the caloric intake in the LD arm was not improved and nearly two thirds of patients on both diets reported critical nutritional problems. There was no advantage in symptoms, quality of life, or survival for the LD arm.
CONCLUSION: These findings suggest that LD is not a safe alternative to ND in HSCT patients and patients with AL because of increased infection risk without nutritional or other benefit. Further dietary strategies are needed to improve nutrition without compromising safety.

DOI: https://doi.org/10.1200/JCO-25-00889