bims-tremyl 2025-11-02 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–11–02
25 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML.
Differential prognostic impact of myelodysplasia-related gene mutations in a European cohort of 4978 intensively treated AML patients.
Cohesin haploinsufficiency is tolerated in Cbfb::MYH11-driven murine acute myeloid leukemia.
The XPO7-NPAT axis represents key vulnerabilities in TP53-mutated acute myeloid leukemia.
Multiselective RAS(ON) inhibition targets oncogenic RAS and overcomes RAS-mediated resistance to FLT3i and BCL2i in AML.
Final safety and efficacy results from a phase 1/2 study of tagraxofusp, a CD123-targeted therapy, for myelofibrosis.
Decitabine-cedazuridine in patients with MDS and TP53 mutations.
Upregulation of ALDH1 as an adaptive epigenetic response to anthracyclines in acute myeloid leukemia.
Unveiling prognosis in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax through novel risk stratification.
Measurable residual disease-guided interventions in patients with acute myeloid leukaemia undergoing allogeneic haematopoietic cell transplantation: best practice recommendations from the European Society for Blood and Marrow Transplantation Practice Harmonisation and Guidelines Committee.
Patient-centered care strategies for Jehovah's Witnesses with acute leukemia and high-grade myeloid neoplasms.
No clear benefit of cellular therapy consolidation for patients achieving remission after post-HCT AML relapse.
Accurate and reliable detection of clonal hematopoiesis in plasma cell-free DNA.
Metformin induces ferroptosis associated with lipidomic remodeling in AML.
Lnk Deficiency Enhances Translesion Synthesis to Alleviate Replication Stress and Promote Hematopoietic Stem Cell Fitness.
A chemical-genetic interaction between PAF1 and ENL/AF9 YEATS inhibition.
Resolving intra-tumor heterogeneity and clonal evolution of core-binding factor acute myeloid leukemia patients with single-cell resolution.
Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
Venetoclax combined with homoharringtonine, cytarabine and aclacinomycin as induction therapy in newly diagnosed Chinese acute myeloid leukaemia patients: A multicentre phase II study.
Different immunotherapeutic combinations enhance specific T cell immune responses against leukemic cells, as well as leukemic progenitor cells, in acute myeloid leukemia.
Omacetaxine and azacitidine for untreated patients with myelodysplastic syndromes and excess blasts: a phase I/II clinical trial.
Epidemiology, survival, and treatment of acute myeloid and lymphoblastic leukaemia in Germany: a nationwide population-based registry analysis.
Outcomes of patients with relapsed/refractory acute leukaemia treated with revumenib with a focus on post-revumenib therapies.
CRISPR/Cas9-mediated t(4;11) translocation in human hematopoietic stem/precursor cells demonstrates plasticity to differentiate into either the myeloid or lymphoid lineage.
Intra-leukemic interferon signaling suppresses expansion and mediates chemoresistance in human AML.

Blood. 2025 Oct 27. pii: blood.2025029712. [Epub ahead of print]

Menin inhibition enhances graft-versus-leukemia effects by T-cell activation and endogenous retrovirus induction in AML.

Viktor Fetsch, Lennard Frederik Schwöbel, Ezgi Ozyerli-Goknar, Anna-Verena Stell, Marco Punta, Thomas Plenge, Tabea Klaus, Manoj K Gupta, Geoffroy Andrieux, Khalid Shoumariyeh, Sophie Pfeiffer, Eyleen Corrales, Lina Schlenke, Hosna Baniadam, Simon M Brandl, Massimo Andreis, Michal Remen, Alina Hartmann, Kathleen Grueter, Melissa Zwick, Natalie Köhler, Monika Kuban, Eric Metzger, Christoph Rummelt, Justus Duyster, Melanie Börries, Maike Hofmann, Julian Färber, Lukas M Braun, Alexander Zähringer, Michael Lübbert, Cristina Toffalori, Luca Vago, Florian H Heidel, Susana Minguet, Petya Apostolova, Tobias Feuchtinger, Kristina Maas-Bauer, Franziska Blaeschke, Michael W M Kühn, Marc Timmers, Tobias Wertheimer, Florian Perner, Robert Zeiser.

Acute myeloid leukemia (AML) carrying chromosomal rearrangements involving the lysine methyltransferase 2A (KMT2A) gene frequently relapse after allogeneic hematopoietic cell transplantation (allo-HCT). Pharmacological blockade of the menin-KMT2A interaction disrupts the assembly of oncogenic KMT2A complexes on chromatin, thereby attenuating aberrant self-renewal and inducing myeloid differentiation. We found that beyond this anti-leukemic mechanism, menin-inhibition induced CIITA and MHC-II expression in KMT2A-rearranged and NPM1-mutated AML cells in vitro and in vivo. Increased MHC-II expression sensitized AML cells to T-cell mediated elimination after allo-HCT in mice. Menin-inhibition also increased MHC-II expression on primary human AML cells and enhanced the graft-versus-leukemia (GVL) effect in human xenograft models. Mechanistically, menin-inhibition increased expression of multiple human endogenous retroviruses (HERVs) leading to consecutive interferon-stimulated gene (ISG) upregulation and enhanced MHC-II expression. Additionally, menin-inhibition directly promoted anti-tumor effector functions of donor T-cells causing increased TNF-α, IFN-ү, perforin and granzyme A/B production and cytolytic activity. T-cell exhaustion and menin-KMT2A binding to genes encoding for negative regulators of T-cell activation were reduced by menin-inhibition. These findings indicate that menin-inhibition enhances the GVL-effect via the HERV/MHC-II axis in AML cells and promotes cytotoxicity of donor T-cells, which provides a rationale for a clinical trial using menin-inhibition as maintenance after allo-HCT.

DOI: https://doi.org/10.1182/blood.2025029712
Leukemia. 2025 Oct 27.

Differential prognostic impact of myelodysplasia-related gene mutations in a European cohort of 4978 intensively treated AML patients.

Marius Bill, Jan-Niklas Eckardt, Konstanze Döhner, Maximillian-Alexander Röhnert, Christian Rausch, Klaus H Metzeler, Karsten Spiekermann, Sebastian Stasik, Alexander A Wurm, Tim Sauer, Sebastian Scholl, Ulf Schnetzke, Andreas Hochhaus, Martina Crysandt, Tim H Brümmendorf, Utz Krug, Bernhard Wörmann, Hermann Einsele, Wolfgang Hiddemann, Dennis Görlich, Cristina Sauerland, Björn Steffen, Andreas Neubauer, Andreas Burchert, Kerstin Schäfer-Eckart, Wolfgang E Berdel, Christoph Schliemann, Stefan W Krause, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Lars Fransecky, Jan Braess, Johannes Schetelig, Jan Moritz Middeke, Lars Bullinger, Michael Heuser, Felicitas Thol, Hubert Serve, Claudia D Baldus, Uwe Platzbecker, Carsten Müller-Tidow, Jan Válka, Jiří Šrámek, Barbora Weinbergerova, Jiri Mayer, Pierre-Yves Dumas, Sarah Bertoli, Eric Delabesse, Christian Récher, Arnaud Pigneux, Tobias Herold, Arnold Ganser, Hartmut Döhner, Martin Bornhäuser, Christian Thiede, Christoph Röllig.

In the European LeukemiaNet (ELN) 2022 recommendations, myelodysplasia-related (MR) gene mutations were classified as a novel adverse prognostic category for intensively treated acute myeloid leukemia (AML). To assess the prognostic impact of individual MR genes within the ELN, clinical, cytogenetic, and molecular data from 4,978 intensively treated AML patients were analyzed. Remission rates and survival outcomes were evaluated. For analyses in context of ELN2022 classification, patients carrying an MR mutation were excluded from the adverse group and analyzed separately; those with co-occurring favorable or intermediate features remained in their respective groups. Overall, 1698 patients (34.1%) harbored at least one MR mutation. Lower complete remission rates were observed in MR-mutated cases (65.7% vs 77.7%; p < 0.001) along with shorter event-free (HR 1.45; p < 0.001), relapse-free (HR 1.33; p < 0.001), and overall survival (HR 1.45; p < 0.001) were recorded. Gene-specific prognostic patterns emerged: ASXL1, RUNX1, SF3B1, and U2AF1 mutations associated with adverse risk-like outcomes; SRSF2 and STAG2 aligned with intermediate-risk; BCOR, EZH2, and ZRSR2 did not differ significantly from intermediate or adverse risk. These findings from a large cooperative cohort highlight prognostic heterogeneity among MR mutations and suggest that SRSF2 and STAG2 mutations are associated with less adverse risk patterns, comparable to intermediate-risk.

DOI: https://doi.org/10.1038/s41375-025-02781-6
Exp Hematol. 2025 Oct 29. pii: S0301-472X(25)00576-4. [Epub ahead of print] 105287

Cohesin haploinsufficiency is tolerated in Cbfb::MYH11-driven murine acute myeloid leukemia.

Shannon E Conneely, Alexis Quezada, Kristen J Kurtz, Nenggang Zhang, Josephine De La Fuente, Nesa Mercer, Jason H Rogers, Rogelio Aguilar, Geraldo Medrano, Margaret A Goodell, Paul P Liu, Debananda Pati, Rachel E Rau.

  Cohesin gene mutations occur in many malignancies, including acute myeloid leukemia (AML). Loss-of-function mutations in the four major cohesin complex genes (RAD21, SMC3, SMC1a, STAG2) occur across most major genetic subtypes of AML but are notably absent in AML harboring CBFB::MYH11, suggesting that cohesin mutations yield distinct biological outcomes dependent on the genetic AML driver. We hypothesized that CBFB::MYH11-expressing leukemias would be dependent on intact cohesin genes given their near-mutual exclusivity. To investigate this, we combined either germline or inducible heterozygous deletions in cohesin genes Smc3 or Rad21, respectively, with an inducible murine model of Cbfb::MYH11 AML. This approach allowed us to evaluate the effects of cohesin haploinsufficiency on leukemia development, chromatin accessibility, and transcriptional output. We demonstrate that intact cohesin function is dispensable for Cbfb::MYH11-driven leukemia. Instead, Cbfb::MYH11 expression is the primary driver of the transcriptional program in transformed leukemic cells. Furthermore, we observed differential effects of Rad21 and Smc3 deletion on leukemia development and secondary engraftment despite only minor differences in gene expression. These results demonstrate that cohesin mutations are not only tolerated in Cbfb::MYH11-expressing cells, they likely do not confer a strong selective advantage and are therefore not preferentially selected for during clonal evolution of this leukemia.

Keywords:  Cohesin; acute myeloid leukemia; hematopoiesis; murine model; transcriptome

DOI:  https://doi.org/10.1016/j.exphem.2025.105287
Blood. 2025 Oct 29. pii: blood.2025028918. [Epub ahead of print]

The XPO7-NPAT axis represents key vulnerabilities in TP53-mutated acute myeloid leukemia.

Yuichiro Semba, Takuji Yamauchi, Daniel E Bauer, Seishi Ogawa, Koichi Akashi, Takahiro Maeda.

Acute myeloid leukemia (AML) with TP53 mutations is almost universally refractory to chemotherapy, molecular-targeted therapies, and hematopoietic stem cell transplantation, leading to dismal clinical outcomes. The lack of effective treatments underscores the urgent need for novel therapeutic strategies. Using genome-wide CRISPR/Cas9 dropout screens in isogenic Trp53-wild-type (WT) and knockout (KO) mouse AML models, combined with transcriptomic and proteomic analyses of mouse and human AML samples, we identify the XPO7 (exportin 7)-NPAT (nuclear protein, coactivator of histone transcription) pathway as essential for TP53-mutated AML cell survival. In TP53-WT AML, XPO7 functions as a tumor suppressor by regulating nuclear abundance of p53 protein, particularly when basal levels of functional p53 are high. However, in TP53-mutated AML, XPO7 drives leukemia proliferation by retaining NPAT, an XPO7-associated protein predominantly expressed in TP53-mutated AML, within the nucleus. NPAT depletion induces genome-wide histone loss, compromises genomic integrity, and triggers replication catastrophe in TP53-mutated AML cells. Notably, analysis of publicly available AML datasets, primary AML samples, and single-cell intra-patient mRNA profiles further reveals elevated XPO7 and NPAT expression in TP53-mutated AML. Finally, we validate the XPO7-NPAT pathway as a critical driver of leukemia progression in vivo using patient-derived xenograft (PDX) models of TP53-WT and TP53-mutant AML. Our study delineates key molecular mechanisms underlying TP53-mutated AML pathogenesis and identifies the XPO7-NPAT axis as a critical vulnerability in this refractory leukemia subtype.

DOI: https://doi.org/10.1182/blood.2025028918
Blood. 2025 Oct 27. pii: blood.2025030558. [Epub ahead of print]

Multiselective RAS(ON) inhibition targets oncogenic RAS and overcomes RAS-mediated resistance to FLT3i and BCL2i in AML.

Bogdan Popescu, Matthew F Jones, Madison Piao, Elaine Tran, Andrew Koh, Isabelle Lomeli, Cheryl A C Peretz, Natalia Murad, Sydney Abelson, Carolina E Morales, Jose M Rivera, Alexa Rane Batingana, Jeevitha D'Souza, Yana Pikman, Michael L Cheng, Aaron C Logan, Benjamin J Huang, Elliot Stieglitz, Catherine C Smith.

Aberrant activation of RAS/MAPK signaling limits the clinical efficacy of several targeted therapies in acute myeloid leukemia (AML). In FLT3-mutant AML, the selection of clones harboring heterogeneous RAS mutations drives resistance to FLT3 inhibitors (FLT3i). RAS activation is also associated with resistance to other AML targeted therapies, including the BCL2 inhibitor venetoclax. Despite the critical need to inhibit RAS/MAPK signaling in AML, no targeted therapies have demonstrated clinical benefit in RAS-driven AML. To address this unmet need, we investigated the preclinical activity of RMC-7977, a multi-selective inhibitor of GTP-bound active [RAS(ON)] isoforms of mutant and wild-type RAS in AML models. RMC-7977 exhibited potent antiproliferative and pro-apoptotic activity across AML cell lines with MAPK-activating signaling mutations. In cell line models with acquired FLT3i resistance due to secondary RAS mutations, treatment with RMC-7977 restored sensitivity to FLT3i. Similarly, RMC-7977 effectively reversed resistance to venetoclax in RAS-addicted cell line models with both RAS wild-type and mutant genetic backgrounds. In murine patient-derived xenograft models of RAS-mutant AML, RMC-7977 was well tolerated and significantly suppressed leukemic burden in combination with gilteritinib or venetoclax. Our findings strongly support clinical investigation of broad-spectrum RAS(ON) inhibition in AML to treat and potentially prevent drug resistance due to activated RAS signaling.

DOI: https://doi.org/10.1182/blood.2025030558
Blood Neoplasia. 2025 Nov;2(4): 100165

Final safety and efficacy results from a phase 1/2 study of tagraxofusp, a CD123-targeted therapy, for myelofibrosis.

Abdulraheem Yacoub, Haris Ali, Vikas Gupta, Eunice S Wang, Mrinal M Patnaik, Gary J Schiller, Minakshi Taparia, Tariq I Mughal, Ross Lindsay, Antonio Galleu, Ira Gupta, Naveen Pemmaraju.

Patients with myelofibrosis (MF) who are resistant to or relapse after Janus kinase inhibitor (JAKi) therapy have limited treatment options and typically poor prognoses. CD123 is overexpressed in various myeloid malignancies, including MF. Tagraxofusp is a first-in-class CD123-targeted therapy, and the only drug approved globally for the rare myeloid malignancy blastic plasmacytoid dendritic cell neoplasm. We conducted a phase 1/2 trial to determine optimal dosing, and evaluate safety and efficacy of tagraxofusp monotherapy in treatment-naïve (n = 5) MF and patients with MF resistant/refractory to JAKi (n = 25) and not eligible for stem cell transplant. There were no dose-limiting toxicities. The recommended phase 2 dose of tagraxofusp was 12 μg/kg per day for 3 consecutive days per cycle. In the safety population (n = 36) treated at 12 μg/kg per day, the most frequent grade ≥3 treatment-emergent adverse events were thrombocytopenia (19%), anemia (22%), and dyspnea (11%). Capillary leak syndrome occurred in 11% of patients, all during cycle 1 with resolution in all patients. Thirty patients treated at 12 μg/kg per day were efficacy evaluable. Of 18 (n = 2 treatment-naïve, n = 16 relapsed/refractory) patients with baseline splenomegaly, 2 relapsed/refractory patients had spleen volume reduction ≥35%. In relapsed/refractory patients, 40% had total symptom score (TSS) ≥50%, and median overall survival (OS) was 19.3 months. In patients who were treatment naïve, 40% had TSS ≥50%, and median OS was 26.6 months. In this trial, tagraxofusp monotherapy in MF was well tolerated, without cumulative myelotoxicity, and with symptom score improvements, warranting further investigation in combination therapy. This trial was registered at www.clincaltrials.gov as #NCT02268253.

DOI: https://doi.org/10.1016/j.bneo.2025.100165
Blood Adv. 2025 Oct 30. pii: bloodadvances.2025017745. [Epub ahead of print]

Decitabine-cedazuridine in patients with MDS and TP53 mutations.

Samuel Urrutia, Koji Sasaki, Alex Bataller, Hagop M Kantarjian, Guillermo Montalban-Bravo, James McCloskey, Elizabeth A Griffiths, Karen W L Yee, Amer M Zeidan, Michael R Savona, Aram Oganesian, Yuri Sano, Harold Neal Keer, Guillermo Garcia-Manero.

Patients with myelodysplastic syndromes (MDS) harboring TP53 mutations have poor outcomes. The objective of this study is to evaluate patients with TP53 mutations treated in the phase 2/3 studies of decitabine-cedazuridine (DEC-C) in MDS. We divided patients into three groups: TP53wt, TP53single-hit, and TP53multi-hit. We then performed propensity matching of patients who were treated with DEC-C vs a cohort of patients treated with parenteral hypomethylating agents (HMA). 180 patients were analyzed of which 73 (40.5%) had TP53 mutations, 23 (12%) with TP53multi-hit. Patients with TP53multi-hit more frequently had complex cytogenetics (69.5%), and had fewer median number of co-mutations (2.5, IQR 2-3) compared to TP53single-hit(3, IQR 1-5), or TP53wt (4, IQR 3-6) (p=0.002). Patients with TP53multi-hit had a higher chance of lack of response with 39.1% vs 28.1% for TP53single-hit (p=0.2). Patients with TP53mult-hit lost response earlier at 8.2 months, vs 13.2 months for TP53single-hit, and 15.1 months for TP53wt (p=0.1). Median overall survival (mOS) was 11.5 months (95% CI: 8.6 - 19.1) for TP53mult-hit, 22.1 months (95% CI: 14.6 - 35.9) for TP53single-hit, and 31.7 months (95% CI: 19.5 - 51.1) for TP53wt (log-rank, p < 0.005). Propensity scores matched 47 TP53mutpatients treated with DEC-C and 47 TP53mut patients treated with single agent parenteral HMA. Median survival was 13.1 months (95% CI: 8.4 - 21.3) for DEC-C vs 8.0 months (95% CI: 5.2 - 13.0) for single agent parenteral HMA (log-rank, p=0.047). In patients with MDS harboring TP53mut, DEC-C may improve overall survival compared to parenteral HMA.

DOI: https://doi.org/10.1182/bloodadvances.2025017745
Hemasphere. 2025 Oct;9(10): e70244

Upregulation of ALDH1 as an adaptive epigenetic response to anthracyclines in acute myeloid leukemia.

Francesco Leonetti, Sladjana Kosanovic, Rocio Rebollidos-Rios, Iris Manosalva, Céline Baier, Muhube Yazir, Andrada Constantinescu, Charbel Souaid, Raquel Pequerul, Miroslava Kari Adamcova, Mehak Shaikh, Magdalena Havlová, Regis Costello, Jaume Farrés, Guillaume Martin, Meritxell Alberich-Jorda, Salvatore Spicuglia, Mileidys Perez-Alea.

Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the clonal proliferation of undifferentiated myeloid precursors in the bone marrow. Although standard induction regimens based on anthracyclines often achieve initial remission, up to 25% of patients exhibit primary refractory disease and nearly 50% relapse, underscoring the urgent need to overcome therapy resistance. Aldehyde dehydrogenase 1 (ALDH1) contributes to leukemic cell survival by maintaining stemness, proliferation, and chemoresistance through aldehyde detoxification and retinoic acid synthesis. Here, we identify two enhancer elements, ALDH1A1-E3 and ALDH1A2-E1-A, that mediate transcriptional activation of ALDH1A1 and ALDH1A2 in response to the anthracycline daunorubicin. These enhancers are regulated by STAT3 and FOS/JUN transcription factors, which cooperatively link drug response to ALDH1 induction. Functional validation in AML cell lines, primary samples, and xenograft models shows that ALDH1 upregulation is part of an adaptive stress response and may contribute to reduced anthracycline sensitivity. Co-treatment with the ALDH1A1/1A2 inhibitor DIMATE synergistically enhances daunorubicin efficacy across in vitro and in vivo resistant models. Consistently, high ALDH1 expression is associated with adverse genetic risk, prior anthracycline exposure, and inferior OS, particularly in relapsed/refractory AML. These findings uncover a novel enhancer-mediated mechanism of ALDH1 induction in the context of anthracycline exposure and support the rationale for future clinical trials combining standard treatments with ALDH1-targeted approaches, including the clinical-stage inhibitor DIMATE.

DOI: https://doi.org/10.1002/hem3.70244
Leuk Res Rep. 2025 ;24 100550

Unveiling prognosis in patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax through novel risk stratification.

Jiajia Sun, Zhiping Guo.

  Several genetic risk classification systems based on response to older acute myeloid leukemia patients treated with less-intensive regimens, especially venetoclax (VEN) + hypomethylating agent (HMA), are proposed recently. VEN+HMA improved the outcome of cytogenetic adverse-risk AML, AML with some of MR mutations and/or clonal hematopoiesis (CH) related mutations. DNMT3A mut, IDH1/2 mut and NPM1 mut were defined as "VEN sensitive mutations". DDX41 mut is identified as a particularly favorable-risk group. Even multi-hit TP53 status did not negatively affect overall survival (OS) of DDX41-mutants. Signaling gene mutations (FLT3-ITDpos and K/NRAS mut) are classified as intermediate risk, consistent with their biological associations as mediators of VEN resistance.

Keywords:  Acute myeloid leukemia; Genetic risk classification; Hypomethylating agent; Venetoclax

DOI:  https://doi.org/10.1016/j.lrr.2025.100550
Lancet Oncol. 2025 Nov;pii: S1470-2045(25)00426-7. [Epub ahead of print]26(11): e586-e596

Measurable residual disease-guided interventions in patients with acute myeloid leukaemia undergoing allogeneic haematopoietic cell transplantation: best practice recommendations from the European Society for Blood and Marrow Transplantation Practice Harmonisation and Guidelines Committee.

Jaime Sanz, Gesine Bug, Fabio Ciceri, Charles Craddock, Richard Dillon, Jordi Esteve, Matteo Giovanni Della Porta, Michael Heuser, David C de Leeuw, Arnon Nagler, Francesco Onida, Gail J Roboz, Annalisa Ruggeri, Isabel Sánchez-Ortega, Micha Srour, Ibrahim Yakoub-Agha, Francesco Buccisano.

Measurable residual disease (MRD) is a key predictor of relapse, the primary cause of treatment failure after allogeneic haematopoietic cell transplantation (allo-HCT) in acute myeloid leukaemia. This Policy Review, based on guidance from the European Society for Blood and Marrow Transplantation, provides practical recommendations for incorporating MRD assessment into clinical decision making during the transplantation process, the application of which remains challenging in acute myeloid leukaemia due to technical limitations and the limited availability of standardised, evidence-based approaches. Available methods include reverse transcription quantitative PCR, digital droplet PCR, next-generation sequencing, and multiparametric flow cytometry-chimerism-based approaches are under investigation. This Policy Review highlights the importance of MRD monitoring to enable timely, risk-adapted interventions that encompass both pre-transplantation and post-transplantation periods and can include tailoring conditioning intensity, donor selection, immunosuppression management, donor lymphocyte infusions, and pharmacological therapies such as FLT3 or IDH inhibitors, hypomethylating agents, venetoclax, or menin inhibitors. These recommendations aim to harmonise MRD-driven clinical practice and improve patient outcomes, while identifying key areas for future research.

DOI: https://doi.org/10.1016/S1470-2045(25)00426-7
Haematologica. 2025 Oct 30.

Patient-centered care strategies for Jehovah's Witnesses with acute leukemia and high-grade myeloid neoplasms.

Jabra Zarka, Aref Al-Kali, Hassan B Alkhateeb, Aasiya Matin, Naseema Gangat, William J Hogan, James Foran, Hemant Murthy, Cecilia Arana Yi, Dhauna Karam Prasad, Syeda Mina, Mark R Litzow, Kebede H Begna, Antoine N Saliba.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.288622
Blood Adv. 2025 Oct 31. pii: bloodadvances.2025018139. [Epub ahead of print]

No clear benefit of cellular therapy consolidation for patients achieving remission after post-HCT AML relapse.

H Moses Murdock, Haesook T Kim, Katie Maurer, Amar H Kelkar, Roman M Shapiro, Mahasweta Gooptu, Rizwan Romee, Prashant K Nageshwar, Heather M Garrity, Shai Shimony, Marlise R Luskin, Eric S Winer, Rahul S Vedula, Maximilian F Stahl, Evan C Chen, Virginia O Volpe, Jacqueline S Garcia, Martha Wadleigh, Daniel J DeAngelo, Richard M Stone, Catherine J Wu, Corey S Cutler, John Koreth, Jerome Ritz, Joseph H Antin, Vincent T Ho, Sarah Nikiforow, Robert J Soiffer.

Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) portends a dismal prognosis. One approach for reinvigorating a graft-vs-leukemia response is consolidation with donor lymphocyte infusions (DLI) or second HSCT (HSCT2). However, the role of DLI/HSCT2 in patients who achieve complete remission (CR) after salvage therapy is unclear. In this retrospective study we evaluated the outcomes of 464 patients with post-HSCT AML relapse, focusing on those who achieved CR prior to consolidation with cellular therapy. In multivariable analysis (MVA), achieving CR after post-HSCT1 relapse was associated with improved survival (OS), HR 0.42, p<0.0001. Of 133 patients (29%) who achieved CR after post-transplant AML relapse and before cellular therapy; 64 received DLI, 28 underwent HSCT2, and 41 received neither. Four-year outcomes from CR for the entire cohort (N=133) were: OS 29%, relapse-free survival (RFS) 22%, cumulative incidence of relapse (CIR) 58%, and non-relapse mortality (NRM) 20%. In MVA, there was no association between receipt of DLI (HR 0.87, p=0.59) or HSCT2 (HR 1.08, p=0.83) and OS. Furthermore, we did not identify a benefit with DLI or HSCT2 with respect to RFS, relapse, or NRM. Patients with donor chimerism <90% at the time of CR had reduced 4-year OS (20% vs 32%, p=0.03), as did MRD-positive patients (17% vs 62%, p=0.024). Our results question the benefit of consolidation with DLI or HSCT2 in patients with AML who achieve CR, and we identify high-risk subgroups that should be the focus of future studies with larger cohorts.

DOI: https://doi.org/10.1182/bloodadvances.2025018139
Blood Adv. 2025 Oct 30. pii: bloodadvances.2025017293. [Epub ahead of print]

Accurate and reliable detection of clonal hematopoiesis in plasma cell-free DNA.

Alyssa C Parker, Joseph Van Amburg, Yash Pershad, David A Ong, Ketan J Hoey, Christopher J Farady, Philipp J Rauch, Michael M Mendelson, J Brett Heimlich, Paul Brent Ferrell, Alexander G Bick.

DOI: https://doi.org/10.1182/bloodadvances.2025017293
Blood Adv. 2025 Oct 31. pii: bloodadvances.2025016155. [Epub ahead of print]

Metformin induces ferroptosis associated with lipidomic remodeling in AML.

Dominique Sternadt, Diego A Pereira-Martins, Prodromos Chatzikyriakou, Luise Albuquerque-Simões, Ming Yang, Douglas R Silveira, Albertus Tj Wierenga, Isabel Weinhäuser, Shanna M Hogeling, Lieve Oudejans, Pilar Casares-Alaez, Jean-Emmanuel Sarry, Christian Frezza, Gerwin A Huls, Lynn Quek, Jan Jacob Schuringa.

Metabolic reprogramming is a hallmark of cancer, essential for sustaining leukemogenesis. In acute myeloid leukemia (AML), high dependency on oxidative phosphorylation (OXPHOS) is often linked to poor outcomes and inhibiting this pathway has shown to be highly effective. However, most OXPHOS inhibitors are not clinically translatable due to significant side effects. Thus, repurposing safe FDA-approved drugs that can target OXPHOS is of great interest. Here, we evaluated metformin, an antidiabetic drug that inhibits OXPHOS, in a genetically diverse panel of primary AML samples to identify metabolic profiles predicting treatment susceptibility. Using label-free quantitative proteome analysis on sorted CD34+/CD117+ AML, we performed single-sample gene set enrichment analysis focused on metabolic terms and correlated enrichment scores with metformin sensitivity, followed by functional studies. Ex vivo treatment of AML samples with metformin showed a significant increase in ROS levels and ferroptosis induction, especially in samples with disturbed lipid metabolism, such as IDH2- and FLT3-mutant AMLs. In IDH2-mutant cells, co-treatment with palmitate, a saturated fatty acid (FA), increased metformin sensitivity, which could be rescued by CD36 knockdown, rendering these cells more resistant to treatment. Lipidomic analysis revealed profound alterations upon metformin treatment, including increased production of triglycerides and polyunsaturated FAs, further supporting a metabolic shift. We observed upregulation of genes related to lipid droplet formation, including DGAT1, a key enzyme in this process. DGAT1 inhibition was strongly synergistic with metformin, while iron chelators acted antagonistically. Our results underscore the potential of leveraging metabolic vulnerabilities in AML to identify more effective and personalized therapeutic strategies.

DOI: https://doi.org/10.1182/bloodadvances.2025016155
J Clin Invest. 2025 Oct 30. pii: e191713. [Epub ahead of print]

Lnk Deficiency Enhances Translesion Synthesis to Alleviate Replication Stress and Promote Hematopoietic Stem Cell Fitness.

Brijendra Singh, Md Akram Hossain, Xiao Hua Liang, Jeremie Fages, Carlo Salas Salinas, Roger A Greenberg, Wei Tong.

  The adaptor protein LNK/SH2B3 negatively regulates hematopoietic stem cell (HSC) homeostasis. Lnk-deficient mice show marked expansion of HSCs without premature exhaustion. Lnk deficiency largely restores HSC function in Fanconi Anemia (FA) mouse models and primary FA patient cells, albeit protective mechanisms remain enigmatic. Here, we uncover a novel role for LNK in regulating translesion synthesis (TLS) during HSC replication. Lnk deficiency reduced replication stress-associated DNA damage, particularly in the FA background. Lnk deficiency suppressed single-strand DNA breaks, while enhancing replication fork restart in FA-deficient HSCs. Diminished replication-associated damage in Lnk-deficient HSCs occurred commensurate with reduced ATR-p53 checkpoint activation that is linked to HSC attrition. Notably, Lnk deficiency ameliorated HSC attrition in FA mice without exacerbating carcinogenesis during ageing. Moreover, we demonstrated that enhanced HSC fitness from Lnk deficiency was associated with increased TLS activity via REV1 and, to a lesser extent, TLS polymerase eta. TLS polymerases are specialized to execute DNA replication in the presence of lesions or natural replication fork barriers that stall replicative polymerases. Our findings implicate elevated use of these specialized DNA polymerases as critical to the enhanced HSC function imparted by Lnk deficiency, which has important ramifications for stem cell therapy and regenerative medicine in general.

Keywords:  Cell stress; DNA repair; Development; Hematology; Hematopoietic stem cells

DOI:  https://doi.org/10.1172/JCI191713
RSC Chem Biol. 2025 Oct 24.

A chemical-genetic interaction between PAF1 and ENL/AF9 YEATS inhibition.

Paige A Barta, Leopold Garnar-Wortzel, Timothy R Bishop, Rachel E Hayward, Lauren M Hargis, James B Shaum, Hui Si Kwok, Brian B Liau, Benjamin F Cravatt, Michael A Erb.

Transcriptional regulatory proteins are frequent drivers of oncogenesis and common targets for drug discovery. The transcriptional co-activator, ENL, which is localized to chromatin through its acetyllysine-binding YEATS domain, is preferentially required for the survival and pathogenesis of acute leukemia. Small molecules that inhibit the ENL/AF9 YEATS domain show anti-leukemia effects in preclinical models, which is thought to be caused by the downregulation of pro-leukemic ENL target genes. However, the transcriptional effects of ENL/AF9 YEATS domain inhibitors have not been studied in models of intrinsic or acquired resistance and, therefore, the connection between proximal transcriptional effects and downstream anti-proliferative response is poorly understood. To address this, we identified models of intrinsic and acquired resistance and used them to study the effects of ENL/AF9 YEATS domain inhibitors. We first discovered that ENL/AF9 YEATS domain inhibition produces similar transcriptional responses in naive models of sensitive and resistant leukemia. We then performed a CRISPR/Cas9-based genetic modifier screen and identified in-frame deletions of the essential transcriptional regulator, PAF1, that confer resistance to ENL/AF9 YEATS domain inhibitors. Using these drug-resistance alleles of PAF1 to construct isogenic models, we again found that the downregulation of ENL target genes is shared in both sensitive and resistant leukemia. Altogether, these data support the conclusion that the suppression of ENL target genes is not sufficient to explain the anti-leukemia effects of ENL/AF9 antagonists.

DOI: https://doi.org/10.1039/d5cb00233h
Exp Hematol Oncol. 2025 Oct 28. 14(1): 127

Resolving intra-tumor heterogeneity and clonal evolution of core-binding factor acute myeloid leukemia patients with single-cell resolution.

Raphael Hablesreiter, Paulina M Strzelecka, Klara Kopp, Natalia Estrada, Anna Dolnik, Marlon Tilgner, Coral Fustero-Torre, Felicitas Thol, Florian H Heidel, Michael Heuser, Laleh Haghverdi, Lars Bullinger, Friederike Christen, Frederik Damm.

  Reconstructing and understanding intra-tumor heterogeneity, the coexistence of multiple genetically distinct subclones within the tumor of a patient, and tumor development is essential for resolving carcinogenesis and for identifying mechanisms of therapy resistance. While bulk sequencing can provide a broad view on tumoral complexity/heterogeneity of a patient, single-cell analysis remains essential to identify rare subclones that might drive chemotherapy resistance. In this study, we performed an integrated analysis of bulk and single-cell DNA sequencing data of core-binding factor acute myeloid leukemia patients, defined by the presence of a RUNX1::RUNX1T1 or CBFB::MYH11 fusion gene. By single-cell sequencing, we inferred tumor phylogenies for 8 patients at diagnosis including patient-specific somatic variants, somatic copy-number alterations and fusion genes, and studied clonal evolution under the pressure of chemotherapy for 3 patients. As a result, we developed an approach to reliably integrate subclonal somatic copy number alterations into phylogenetic trees and clonal evolution analysis, obtaining unprecedented resolution of intra-tumor heterogeneity in CBF AML. We were able to show that the fusion gene is among the earliest events of leukemogenesis at single-cell level. We identified remaining tumor clones in 6 patients with complete remission samples indicating incomplete eradication of the tumor clones. Here, we show that identifying the order of mutation acquisition can provide valuable insights into evolutionary history, offering a framework to improve drug selection in the era of targeted therapies.

Keywords:  AML; CBF; Clonal evolution; Clonal heterogeneity; Intra-tumor heterogeneity; Single-cell DNA sequencing

DOI:  https://doi.org/10.1186/s40164-025-00718-4
Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00819-6. [Epub ahead of print]

Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.

Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Niklas B Thompson, Peter A Faull, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.

  The de novo purine synthesis pathway is fundamental for nucleotide production, yet the role of mitochondrial metabolism in modulating this process remains underexplored. Here, we identify that succinate dehydrogenase (SDH) is essential for maintaining de novo purine synthesis. Genetic or pharmacological inhibition of SDH suppresses purine synthesis, contributing to a decrease in cell proliferation. Mechanistically, SDH inhibition elevates succinate, which in turn promotes the succinylation of serine hydroxymethyltransferase 2 (SHMT2) within the mitochondrial tetrahydrofolate (THF) cycle. This post-translational modification lowers formate output, depriving cells of one-carbon units needed for purine assembly. In turn, cancer cells activate the purine salvage pathway, a metabolic compensatory adaptation that represents a therapeutic vulnerability. Notably, co-inhibition of SDH and purine salvage induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings reveal a signaling role for mitochondrial succinate in tuning nucleotide metabolism and highlight a dual-targeted strategy to exploit metabolic dependencies in cancer.

Keywords:  TCA cycle; cancer; formate; mitochondrial metabolism; nucleotide metabolism; succinate

DOI:  https://doi.org/10.1016/j.molcel.2025.10.002
Br J Haematol. 2025 Oct 28.

Venetoclax combined with homoharringtonine, cytarabine and aclacinomycin as induction therapy in newly diagnosed Chinese acute myeloid leukaemia patients: A multicentre phase II study.

Yaxian Tan, Xingli Zhao, Xiaohui Suo, Guanchen Bai, Weihua Zhao, Yunya Luo, Xinxiao Lu, Linyu Yuan, Congcong Zhang, Yinling Li, Sifeng Gao, Jilei Zhang, Zeyan Shi, Heng Li, Kaiqi Liu, Yingchang Mi, Hongling Peng, Pengxiang Guo, Zeping Zhou.

  To evaluate the efficacy and safety of the HAAV regimen (venetoclax, aclarubicin, cytarabine, homoharringtonine) as induction therapy for newly diagnosed adult acute myeloid leukaemia (AML). This multicentre, single-arm, prospective clinical trial included 84 AML patients (aged 18-60) from eight Chinese hospitals. The HAAV regimen was administered, with venetoclax dosed at 100 mg on day 1, 200 mg on day 2 and 400 mg on days 3-8, combined with homoharringtonine, cytarabine and aclarubicin on days 3-7. The overall response rate after one cycle was 95.2% (95% confidence interval [CI] 88.3-98.7), with 92.9% achieving complete remission + incomplete count recovery (95% CI 83.6-96.6). Among responders, 89.9% (95% CI 80.2-95.8) had minimal residual disease negativity. With a median follow-up of 15.5 months, the -1-year overall survival was 77.9% (95% CI 18.3-26.1), relapse-free survival was 83.9% (95% CI 19.2-22.3) and event-free survival was 71.3% (95% CI 16.9-20.5). The HAAV regimen is highly efficacious and safe for newly diagnosed AML patients.

Keywords:  AML; HAA; HAAV; adult; venetoclax

DOI:  https://doi.org/10.1111/bjh.70202
Leukemia. 2025 Oct 27.

Different immunotherapeutic combinations enhance specific T cell immune responses against leukemic cells, as well as leukemic progenitor cells, in acute myeloid leukemia.

Jochen Greiner, Patrick J Schuler, Hubert Schrezenmeier, Johanna Weiss, Christiane Bulach, Marlies Goetz, Barbara-Ann Guinn.

Immunotherapeutic approaches have become increasingly important in cancer therapy, including for patients with acute myeloid leukemia (AML). Despite being shown to be effective in the context of stem cell transplants for almost 50 years, further improvements are required to prevent relapse and its associated morbidity. The therapeutic use of immune checkpoint inhibition in AML is still under debate. We have shown some positive effects of it on cancer control ex vivo. We found that anti-programmed death-1 (PD-1) antibodies in combination with azacitidine (AZA) had the most pronounced effect on T-cell activation and control of leukemic progenitor/stem cell growth. We identified which leukemia-associated antigen (LAA) stimulated the largest IFNγ immune response by T cells from AML patients with and without the nucleophosmin 1 (NPM1) mutation and which immunotherapeutic strategy, either alone or in combination with the immune checkpoint anti-PD-1, could enhance immune responses against leukemic cells. Anti-PD-1 with AZA had a particularly strong effect with a mean colony reduction of 56%. Taken together, combinations of immunotherapeutic approaches increase antigen-specific immune responses against leukemic cells but also leukemic progenitor/stem cells. The combination of LAA-peptides with anti-PD-1 antibody and one further immunotherapeutic could be an interesting option for further clinical studies.

DOI: https://doi.org/10.1038/s41375-025-02764-7
EClinicalMedicine. 2025 Nov;89 103546

Omacetaxine and azacitidine for untreated patients with myelodysplastic syndromes and excess blasts: a phase I/II clinical trial.

Daniel A Pollyea, Brett M Stevens, Diana Abbott, Maria Amaya, Jonathan A Gutman, Andrew Kent, Christine McMahon, Marc Schwartz, Clayton Smith, Jessie Dell-Martin, Connor Sohalski, Alexandra Ellis, Mary Haag, Jeffrey Schowinsky, Zenggang Pan, Sweta B Patel, Monica Ransom, Austin Gillen, Craig T Jordan, Eric M Pietras.

   Background: Patients with myelodysplastic syndromes (MDS) with excess blasts (MDS-EB) have poor long-term outcomes. Our preclinical studies showed MDS-EB stem cells are dependent upon protein synthesis. We designed a phase 1/2 clinical trial to examine the safety/efficacy of the protein synthesis inhibitor omacetaxine mepesuccinate (oma) with the hypomethylating agent (HMA) azacitidine (aza) for patients with untreated MDS-EB.
Methods: Enrollment occurred from September 2018 to March 2024 and the study was registered at clinicaltrials.gov (NCT03564873). The phase 1 primary endpoint was to determine the maximum tolerated dose (MTD) and the phase 2 primary endpoint was to determine the overall response rate. Aza 75 mg/m2 was administered daily and oma twice daily days 1-7. Oma was escalated in three cohorts: 0.75 mg/m2, 1.0 mg/m2 and 1.25 mg/m2, with a de-escalation cohort (0.5 mg/m2), to find the maximum tolerated dose (MTD). Responders who tolerated therapy could continue sequential cycles. Those who did not respond, progressed, had significant toxicity or proceeded to allogeneic stem cell transplantation (ASCT) discontinued.
Findings: The MTD of oma was 0.5 mg/m2; dose limiting toxicities included hypoxia, respiratory failure, gastrointestinal bleed and gout. Common adverse events included thrombocytopenia, anemia, neutropenia and febrile neutropenia. Overall response rate was 13/24 (54%) with four complete remissions (CR). Ten patients were bridged to ASCT. With median follow-up time of 3.5 years, median response duration and progression-free survival were 719 and 92 days, respectively. Median overall survival was 1.5 years.
Interpretation: The MTD of oma in MDS-EB has been established. Responses, including CRs, occurred rapidly. This therapeutic combination, conceived based on data that it targets the malignant stem cell population, could be further studied for patients with MDS-EB but high toxicity needs to be taken into account.
Funding: HYPERLINCI, Edward P. Evans Foundation, Leukemia and Lymphoma Society Career Development Program, VA Merit, V-Foundation.

Keywords:  Azacitidine; Clinical trial; Myelodysplastic syndromes; Omacetaxine; Phase 1/2

DOI:  https://doi.org/10.1016/j.eclinm.2025.103546
Lancet Reg Health Eur. 2025 Dec;59 101503

Epidemiology, survival, and treatment of acute myeloid and lymphoblastic leukaemia in Germany: a nationwide population-based registry analysis.

David Baden, Nadine Wolgast, Philipp M Altrock, Sophie Steinhäuser, Jakob Voran, Thomas Beder, Manuel Hecht, Cornelia Baden, Lorenz Bastian, Cécile Ronckers, Jacqueline Müller-Nordhorn, Soo-Zin Kim-Wanner, Martin Neumann, Lars Fransecky, Gunnar Cario, Christoph Röllig, Alexander Katalinic, Claudia D Baldus.

   Background: Acute leukaemias are rare but highly aggressive malignancies, but only limited population-level data are available for Germany. We aimed to describe epidemiology, survival, and therapies of acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) in Germany using nationwide cancer registry data.
Methods: We conducted a population-based analysis of all incident cases of AML and ALL in Germany, identified via ICD codes from mandatory cancer registry reporting, to assess incidence, treatment, and survival outcomes.
Findings: We identified 25,788 patients with AML and 6480 patients with ALL diagnosed between 2016 and 2021 aged 0-101 years. The age-standardized incidence rate was 4.72/100,000 for AML (median age 72.8 years, IQR 61.0-80.3) and 1.36/100,000 for ALL (median age 19.4 years, IQR 5.2-58.6). The three- and five-year overall survival was 29.0% (95% CI: 28.3-29.7) and 23.8% (95% CI: 23.1-24.7) in AML, and 64% (95% CI: 62.2-65.9) and 58% (95% CI: 55.7-60.2) in ALL. Survival was highly dependent on age, with children (0-18 years) showing the highest three-year survival rates in AML (76.4%, 95% CI: 70.2-83.2) and ALL (91.9%, 95% CI: 89.8-94.1) compared to older adults. Moreover, area-based income and social deprivation were linked to survival, with three-year survival reduced by up to 4% in lower-income counties. Based on German federal population estimates, AML cases are expected to rise by 14.6%, while ALL cases will decline by 2.3% between 2020 and 2050.
Interpretation: We provide incidence and survival data to inform future clinical trials, guide resource allocation, and support healthcare planning to improve real-world outcomes and address disparities in acute leukaemia.
Funding: German Research Foundation (DFG).

Keywords:  Acute leukaemia; Acute lymphoblastic leukaemia (ALL); Acute myeloid leukaemia (AML); Epidemiology; Outcomes; Socioeconomic differences

DOI:  https://doi.org/10.1016/j.lanepe.2025.101503
Br J Haematol. 2025 Oct 26.

Outcomes of patients with relapsed/refractory acute leukaemia treated with revumenib with a focus on post-revumenib therapies.

Miles Thomas, Hannah Johnston, Emily Dworkin, Austin Wesevich, Gregory W Roloff, Caner Saygin, Mariam T Nawas, Michael W Drazer, Adam S DuVall, Satyajit Kosuri, Michael J Thirman, Olatoyosi Odenike, Wendy Stock, Richard A Larson, Rafael Madero-Marroquin, Anand A Patel.



Keywords:  Revumenib; acute lymphoblastic leukaemia; acute myeloid leukaemia

DOI:  https://doi.org/10.1111/bjh.70225
Leukemia. 2025 Oct 27.

CRISPR/Cas9-mediated t(4;11) translocation in human hematopoietic stem/precursor cells demonstrates plasticity to differentiate into either the myeloid or lymphoid lineage.

T Benz, P Larghero, C Meyer, T Hanewald, D Brüggmann, A-E Hentrich, F Louwen, R Marschalek.

The chromosomal translocation t(4;11)(q21;q23) is frequently diagnosed in KMT2A-r Acute Leukemia patients. Although we understand much about the function of both wildtype KMT2A and AFF1 multiprotein complexes, little is known about the molecular actions the two fusion proteins KMT2A::AFF1 and AFF1::KMT2A during the very early steps of disease onset and progression. Most published data have been generated in t(4;11) cell lines or transplanted mouse models, where exactly this process remains a black box. Here, we present the results of our efforts to establish a t(4;11) chromosomal translocation in human hematopoietic stem/precursor cells by CRISPR/Cas9. These genetically modified cells can be expanded over 5-6 months in vitro and their potential to differentiate was examined with IL-7 supplementation. The benefit of this model system is that (1) both reciprocal fusion proteins are concomitantly present, and (2) a molecular surveillance is possible at any timepoint through analysis of RNA, DNA or protein. Thus, the CRISPR/Cas9 technique allowed us to create a bona fide model system to study the very early steps of leukemia onset at the molecular level. In conclusion, this approach is the fastest way to investigate and characterize KMT2A-r fusions in primary human cells.

DOI: https://doi.org/10.1038/s41375-025-02791-4
Blood Cancer Discov. 2025 Oct 30.

Intra-leukemic interferon signaling suppresses expansion and mediates chemoresistance in human AML.

Daiki Karigane, Amy C Fan, Toshinobu Nishimura, Kensuke Kayamori, Yusuke Nakauchi, Thomas Köhnke, Athreya Rangavajhula, Asiri Ediriwickrema, Brooks A Benard, Rozario Thomas, Feifei Zhao, Melissa Stafford, Fabian P Suchy, Jonas L Fowler, Mark P Chao, Tian Yi Zhang, Kyle M Loh, Hiromitsu Nakauchi, Ravindra Majeti.

Intra-tumoral heterogeneity can impact the competitive fitness and chemoresistance of individual cancer cells. In acute myeloid leukemia (AML), both genetic and functional heterogeneity contribute to chemoresistance, resulting in relapse. While the role of cell-extrinsic factors has been described for AML relapse, whether interactions between cancer cells affects chemoresistance is not fully known. Here, we demonstrated that a dominant leukemic fraction can suppress the proliferation and expansion of other leukemic cells and that this suppression is reversible. This suppression is mediated in part by both type I and type II intra-leukemic interferon (IFN) signaling and dependent on BST2. Importantly, blocking antibodies to type II IFN receptor activated the cycling of this suppressed cell fraction and sensitized the cells to subsequent chemotherapy treatment. Our findings suggest that interactions between functionally heterogeneous leukemic fractions can affect competitive fitness and treatment response, highlighting IFN signaling as a potential therapeutic target to counter chemoresistance.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0173