bims-tremyl 2026-08-02 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2026–08–02
25 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Phase 1 clinical trial of S64315, an intravenous MCL1 inhibitor, in patients with myeloid malignancies.
Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance.
Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.
OPTI-AML: Prospective Comparison of 28 vs.14 days of Venetoclax Induction with Azacitidine in Older Adults with AML.
Clinical and Genomic Convergence of High-Risk CCUS and Lower-Risk Myelodysplastic Syndromes/Neoplasms.
Regional practice differences significantly impact benefit from post-HCT gilteritinib for FLT3-ITD AML.
Ribonucleotide Reductase Inhibition Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia.
Menin inhibitors as a treatment for acute leukemia: from bench to the clinic.
Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes.
Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis.
Statin Use and Genetically Predicted HMG-CoA Reductase Inhibition in Relation to Clonal Hematopoiesis.
Single cell multi-omics enables high-resolution identification and functional purification of human acute myeloid leukemia stem cells.
Human HSPCs clones balance stochastic diversification with cytokine-induced differentiation.
PROTAC-mediated targeting of IKKβ and NR4A1 for AML therapy.
Loss of DNA methylation is not associated with venetoclax-hypomethylating agents synergy in acute myeloid leukaemia cells.
TIAR-dependent coordination of alternative splicing and lipid peroxidation is required for CML cell resistance to imatinib in the bone marrow stroma.
FLT3-ITD signals for CEBPA and p53 proteolysis by the ubiquitin-proteosome pathway.
Targeting cellular senescence alleviates bone marrow aging.
ASSESSMENT OF THE IPSS-M IN CHRONIC MYELOMONOCYTIC LEUKEMIA.
Adaptor-mediated rewiring of FLT3 signaling engages p38 MAPK to sustain gilteritinib resistance in acute myeloid leukemia.
ZMAT3 alleviates cell death in Fanconi anemia via adaptation of sphingolipid metabolism.
Real-world investigation of germline predisposition to myelodysplastic syndromes.
Low-dose ruxolitinib for graft-versus-host disease prevention in haploidentical haematopoietic stem-cell transplantation: a multicentre, open-label, randomised, controlled, phase 3 trial.
Mitochondrial metabolism and epigenetic crosstalk drive SASP.
Donor age as a dual-risk factor for donor safety and recipient survival in allogeneic haematopoietic stem cell transplantation.

Leuk Lymphoma. 2026 Jul 26. 1-8

Phase 1 clinical trial of S64315, an intravenous MCL1 inhibitor, in patients with myeloid malignancies.

Norbert Vey, Olga Salamero, Ashish Bajel, Pau Montesinos, Naval Daver, Thomas Prebet, Ollivier Legrand, Christian Récher, Aline Maillard, Agnès Hemon, Valerie de Burgat, Annette Ervin-Haynes, Alberto Broniscer, Andrew H Wei.

  Preclinical data support myeloid cell leukemia 1 (MCL1) inhibition in the treatment of acute myeloid leukemia (AML). Patients with relapsed/refractory myelodysplastic syndrome (n = 1) or AML (n = 32) or older patients with untreated AML ineligible to receive intensive chemotherapy (n = 5) were treated in this phase 1 study of S64315, an MCL1 inhibitor (NCT02979366). Seven dose levels (50, 100, 200, 250, 300, 400, and 500 mg) were tested. The most common toxicities were nausea and vomiting, diarrhea, and increased transaminases and troponin levels. Seven patients experienced dose-limiting toxicities (DLTs), including increased cardiac biomarkers (n = 3), grade 3 increased transaminases with hyperbilirubinemia (n = 2), and decreased cardiac ejection (n = 1). Three DLTs occurred at the 500-mg dose, which was intolerable; a maximum tolerated dose was not determined since fewer than six patients were treated at doses between 100 and 400 mg. Exposure to S64315 increased in a dose-dependent manner between 50 and 500 mg. There were no objective responses to therapy.

Keywords:  Myeloid leukemias and dysplasia; cell cycle and apoptosis changes; pharmacotherapeutics

DOI:  https://doi.org/10.1080/10428194.2026.2699287
Leukemia. 2026 Jul 27.

Cohesin haploinsufficiency and inv(16) cooperate to reinforce Fli1 gene transcriptional programs during acute myeloid leukemia initiation and maintenance.

Alison E Meyer, Katelyn E Heimbruch, Kirthi Pulakanti, Cary Stelloh, Nataly Cruz-Rodriguez, Josiah Murray, Dandan Wang, Lisa Latzko, Sebastian Vosberg, Philipp A Greif, Lucio H Castilla, John A Pulikkan, Subramaniam Malarkannan, Sridhar Rao.

Core binding factor (CBF) acute myeloid leukemias typically harbor the translocations t(8;21) or inv(16). As cohesin mutations are less commonly observed with inv(16) than with t(8;21), we hypothesized that they may negatively impact inv(16)-driven AML. Using a mouse model of inv(16) with haploinsufficiency of the cohesin subunit Smc3, we paradoxically found that inv(16); Smc3Δ/+ mice have a reduced leukemic latency compared to inv(16); Smc3+/+ mice, disproving our initial hypothesis and instead suggesting a role for cohesin loss in enhancing inv(16)-driven disease. Consistent with the known role of cohesin haploinsufficiency in altering chromatin accessibility, we demonstrated an increase in chromatin accessibility in inv(16); Smc3Δ/+ hematopoietic stem and progenitor cells (HSPCs) prior to leukemia development, with an enrichment for Fli1 DNA binding motifs. Through scRNA-seq on pre-leukemic HSPCs, we observe an increase in Fli1 expression and enhanced Fli1 target expression in ST-HSCs. We further show that Fli1 is essential for the maintenance stage of inv(16); Smc3Δ/+ AML. Our data demonstrate a role for cohesin loss in enhancing the aggressiveness of inv(16)-driven AML and identify Fli1 as a previously unrecognized therapeutic vulnerability in cohesin-mutated AML.

DOI: https://doi.org/10.1038/s41375-026-03070-6
bioRxiv. 2026 Jul 13. pii: 2026.07.10.737821. [Epub ahead of print]

Specific F 1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia.

Matthew T Villaume, Haley E Ramsey, Valeria Impedovo, Michael Davidson, Maria P Arrate, Anand K Singh, Yujin Lee, Anna Skwarska, Yara F Almadani, Natalia Baran, Sovira Chaudhry, Benjamin J Reisman, Eden G TenBarge, Ming Jiang, Sarah Olmstead, Agnieszka E Gorska, Zhiguo Zhao, Andrew J Monteith, Peter M Grace, Brian O Bachmann, Marina Konopleva, Stefano Tiziani, Michael R Savona.

Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F 1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD⁺/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo , a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F 1 -selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.

DOI: https://doi.org/10.64898/2026.07.10.737821
Blood. 2026 Jul 28. pii: blood.2026034611. [Epub ahead of print]

OPTI-AML: Prospective Comparison of 28 vs.14 days of Venetoclax Induction with Azacitidine in Older Adults with AML.

Uma M Borate, Ying Huang, Tara L Lin, Shivani Handa, Ronan Swords, Curtis A Lachowiez, Elie Traer, Wendy Stock, Olatoyosi Odenike, Anand A Patel, Maria R Baer, Vu H Duong, Eytan M Stein, William Blum, Colin Anthony Vale, Emily Curran, Yazan F Madanat, Rebecca L Olin, Gary J Schiller, Angela D Nichols, Lacey Williams, Nyla A Heerema, Mary F Johnson, Timothy L Chen, Sonja Marcus, Molly Martycz, Mona Stefanos, Leonard Rosenberg, Louis James DeGennaro, Lore Gruenbaum, Amy Burd, John C Byrd, Brian J Druker, Ross L Levine, Ashley O Yocum, Alice S Mims, Joshua F Zeidner.

Azacitidine (Aza) plus venetoclax (Ven) is standard treatment for older/unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). The approved 28-day (D) Ven schedule is associated with prolonged cytopenias, causing frequent dose reductions and cycle delays. Retrospective studies show similar efficacy and reduced toxicity with abbreviated Ven dosing, but prospective data is lacking. We conducted OPTI-AML(NCT03013998), a prospective randomized phase 2 trial comparing 28D Ven (AV28) versus 14D (AV14) with Aza (75mg/m²x7D) for C1-2 in genomically agnostic ND-AML patients ≥60 years. The primary endpoint was complete remission (CR) rate achieved at any time with two cycles of therapy. Between 2023-2025, 169 patients received AV28 (n=83) or AV14 (n=86). CR across two cycles was 49.4% (AV28) versus 43% (AV14); difference of 6.4% [90%CI:-6.1% to 19.0%], not meeting non-inferiority criteria. Patients with NPM1/ IDH2 mutations had higher CR rates with AV28 (60.9% vs. 33.3%), while CR rates were equivalent (45%) for other subgroups. Composite CR rates were 80.7% (AV28) versus 68.6% (AV14) and MRD negativity was similar (77.6% vs. 76.5%). Although AV28 had more frequent treatment interruptions, count recovery after C2, grade ≥3 adverse events and early mortality were similar. In conclusion, the study did not demonstrate non-inferiority of AV14 compared with AV28 during C1-2 in an unselected ND-AML cohort. However, as the confidence interval for the difference covered 0, CR rate for AV28 was not significantly different than AV14. Certain subgroups may benefit from prolonged Ven exposure, but these findings require validation in larger studies, especially as triplet regimens evolve.

DOI: https://doi.org/10.1182/blood.2026034611
Blood. 2026 Jul 29. pii: blood.2026033085. [Epub ahead of print]

Clinical and Genomic Convergence of High-Risk CCUS and Lower-Risk Myelodysplastic Syndromes/Neoplasms.

Zhuoer Xie, Zena R Komrokji, Michael Otterstatter, Ling Zhang, Lynn C Moscinski, Najla Al-Ali, David A Sallman, Jeffrey E Lancet, Gregory A Abel, R Coleman Lindsley, Rafael Bejar, Matthew J Walter, Amy E DeZern, Mikkael A Sekeres, Rami S Komrokji, Nancy Gillis, Eric Padron.

Clonal cytopenia of undetermined significance (CCUS) is defined by unexplained cytopenias with myeloid-associated somatic mutations not meeting diagnostic criteria for myelodysplastic syndromes/neoplasms (MDS) yet carries a highly risk-stratified probability of progression to myeloid neoplasms. The clinical distinction between CCUS and lower-risk MDS (LR-MDS) is challenging because current criteria rely heavily on semi-quantitative morphologic thresholds, despite substantial clinical and molecular overlap. In this prospective study of 409 patients with CCUS and 241 with LR-MDS, we applied harmonized diagnostic and progression criteria, rigorous centralized pathology review, and uniform genomic profiling to compare clinical, molecular, and outcome data. Risk stratification was performed using two independent models-the Clonal Hematopoiesis Risk Score (CHRS) and the Clonal Cytopenia Risk Score (CCRS). Patients with high-risk CCUS, as defined by CHRS or CCRS, exhibited clinical features and event rates comparable to those with LR-MDS. In contrast, patients with low- or intermediate-risk CCUS had markedly improved outcomes, supporting conservative management. These findings underscore that CHRS and CCRS are clinically informative tools that extend beyond morphology-based classification and enable a risk-adapted approach to the management of CCUS. Importantly, a subset of patients with high-risk CCUS demonstrated substantial clinical and genomic convergence with LR-MDS, supporting their consideration for enrollment in prospective clinical trials designed for LR-MDS. These observations highlight the need for further study of risk-adapted therapeutic approaches in this population and underscore the importance of prospective clinical evaluation.

DOI: https://doi.org/10.1182/blood.2026033085
Blood Adv. 2026 Jul 30. pii: bloodadvances.2026020327. [Epub ahead of print]

Regional practice differences significantly impact benefit from post-HCT gilteritinib for FLT3-ITD AML.

Mark J Levis, Mehdi Hamadani, Brent R Logan, Richard J Jones, Anurag K Singh, Mark R Litzow, John R Wingard, Esperanza B Papadopoulos, Alexander E Perl, Robert J Soiffer, Celalettin Ustun, Masumi Ueda Oshima, Geoffrey L Uy, Edmund K Waller, Sumithira Vasu, Melhem M Solh, Asmita Mishra, Lori S Muffly, Hee-Je Kim, Matthias Stelljes, Yuho Najima, Masahiro Onozawa, Kirsty J Thomson, Caroline Chen, Nahla Hasabou, Matt Rosales, Jason E Hill, Stanley C Gill, Rishita Nuthethi, Denise King, Adam M Mendizabal, Steven M Devine, Mary M Horowitz, Yi-Bin Chen.

BMT CTN 1506 ("MORPHO") was a phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib versus placebo for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) in first remission. Subgroup analysis indicated a significant benefit of post-HCT gilteritinib for participants in North America, but no benefit for those in Europe or Asia. We conducted a post-hoc analysis of the data focusing on days from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD measurable residual disease (MRD). Participants transplanted < 120 days from AML diagnosis and/or those treated with FLT3 inhibition pre-HCT were more likely to have improved survival from post-HCT gilteritinib. Pre-HCT MRD levels were higher (P = 0.001) in participants transplanted within 120 days from diagnosis and in those treated with a FLT3 inhibitor pre-HCT and transplanted within 120 days (P = 0.008). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, as participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Time from AML diagnosis to HCT and pre-HCT FLT3 inhibitor use both appeared to impact MRD levels immediately prior to HCT, and geographic differences in these two practice patterns likely accounted for the observed regional differences in benefit from post-HCT gilteritinib. Increasing the number of courses of treatment pre-HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition, but with a presumed risk of some patients experiencing early progression. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

DOI: https://doi.org/10.1182/bloodadvances.2026020327
bioRxiv. 2026 Jul 22. pii: 2026.07.21.736123. [Epub ahead of print]

Ribonucleotide Reductase Inhibition Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia.

Zhen Tian, Xiaoyu Wei, Srinivas Chatla, Yang Liu, Dongwook Kim, Yahui Li, Peng Wang, Yun Liao, Xiaolei Liu, Dan Yang, Stacia Octaviani, Gui Ma, Anthony Pompetti, Gennaro Calendo, Martin P Keough, Wei Xu, Jing Zhang, Hong Zheng, Elliot Stieglitz, Catherine Smith, Jian Huang.

Internal tandem duplication mutations in FLT3 ( FLT3 ITD ) occur in approximately 30% of patients with acute myeloid leukemia (AML) and are among the most common genetic alterations in this disease. FLT3 ITD is a major driver of AML and is associated with poor clinical outcomes. Although FLT3 inhibitors (FLT3is) have significantly improved outcomes for patients with FLT3 ITD + AML, acquired resistance remains a major barrier to durable clinical benefit. Reactivation of RAS/MAPK signaling, often driven by activating NRAS mutations, is a major mechanism of FLT3i resistance in AML; however, effective strategies to overcome this resistance remain lacking. Here, we identify ribonucleotide reductase (RNR) as a critical therapeutic vulnerability in NRAS -driven FLT3i-resistant FLT3 ITD + AML. Activation of RAS signaling through SPRY3 loss or oncogenic NRAS mutations confers robust resistance to FLT3is, whereas pharmacologic inhibition of RNR with multiple inhibitors, as well as siRNA-mediated RNR suppression, reverses FLT3i resistance and restores FLT3i sensitivity across multiple FLT3 ITD + AML models in vitro . In vivo , clofarabine, an FDA-approved RNR inhibitor (RNRi), significantly overcomes NRAS mutation-driven FLT3i resistance. In combination with FLT3 inhibition, clofarabine markedly suppresses the progression of FLT3i-resistant AML and significantly prolongs survival in cell line-derived xenograft (CDX) models. Importantly, the therapeutic efficacy of the gilteritinib/clofarabine combination was independently validated in two genetically distinct patient-derived xenograft (PDX) models harboring different NRAS mutations, demonstrating robust reduction of leukemia burden and confirming the generalizability of RNR inhibition in primary FLT3i-resistant AML. Together, these findings identify a previously unrecognized therapeutic vulnerability in FLT3i-resistant FLT3 mut + AML and establish RNR inhibition as an effective strategy to overcome FLT3i resistance, providing a strong rationale for the clinical evaluation of RNRis in combination with FLT3is in patients with resistant AML.
Significance: Although FLT3 inhibitors (FLT3i) are an important therapeutic advance in FLT3 ITD + AML, resistance commonly develops. We identified ribonucleotide reductase (RNR) as a new key vulnerability in NRAS -driven FLT3i-resistant AML and demonstrated that multiple RNRis, including the FDA-approved agent clofarabine, restore FLT3i sensitivity and enhance antileukemic activity, supporting a clinically actionable combination strategy.

DOI: https://doi.org/10.64898/2026.07.21.736123
Blood Neoplasia. 2026 Aug;3(3): 100253

Menin inhibitors as a treatment for acute leukemia: from bench to the clinic.

Justin Watts, Ellen Madarang, Tomasz Cierpicki, Jolanta Grembecka.

Menin inhibitors exploit the key biological mechanism behind KMT2A-rearranged (KMT2A-r) and nucleophosmin 1-mutated (NPM1-mut) leukemias by targeting the menin-KMT2A interaction and disrupting KMT2A/KMT2A fusion complexes binding to chromatin, thereby preventing transcriptional activation of fundamental leukemogenic programs (HOXA9/MEIS1). A series of remarkable discoveries, from the cloning and identification of the MLL1 (KMT2A) gene in 1991, to the first discovery of menin's role in leukemia in 2005, to the development of the first small-molecule menin inhibitor in 2012, and to the initiation of the first-in-human clinical trials in 2019, led to the US Food and Drug Administration (FDA) approval of the first menin inhibitor (revumenib) in 2024 for in the treatment of relapsed or refractory (R/R) KMT2A-r acute leukemia, representing a significant scientific achievement for the rapid clinical translation of molecularly targeted therapy. The menin inhibitors revumenib and ziftomenib have subsequently been FDA approved for R/R NPM1-mut acute myeloid leukemia (AML) in 2025, and at least 5 other menin inhibitors are in clinical development for leukemia. Here, we review the discovery, preclinical and clinical development, and safety and efficacy of menin inhibitors through 2025. Menin inhibitors hold promise as one of the most powerful single-agent targeted therapies in acute leukemia, with response rates of ∼50% or higher in R/R AML with KMT2A-r or NPM1-mut disease. Despite this notable clinical activity, response duration to menin inhibitors remains short-lived for most patients, which has resulted in an explosion of combination therapy trials in both R/R and newly diagnosed AML, including intensive chemotherapy and nonintensive (venetoclax-based) approaches, as well as combinations with targeted therapies and novel differentiation therapies.

DOI: https://doi.org/10.1016/j.bneo.2026.100253
bioRxiv. 2026 Jul 14. pii: 2026.07.13.737885. [Epub ahead of print]

Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes.

Anagha Deshpande, Cho-Ying Chiang, Marlenne Perales, Neha Niranjan, Neelam Sinha, Darren Finlay, Alexandra Stevens, Emily Zahn, Benjamin A Garcia, Irmela Jeremias, Mark Wunderlich, Kristen Jensen-Pergakes, Akshata Udyavar, Amy Carr, Andrew R Nager, Yanling Yang, Rabi Murad, Courtney Jones, Shawn O'Connell, Thomas Paul, Kristiina Vuori, Aniruddha J Deshpande.

Transcriptional condensates anchored by chromatin readers are increasingly recognized as organizing hubs for gene expression, but how their assembly and stability are regulated remains poorly understood. Here, we identify an acetylation-dependent feed-forward circuit that controls the integrity of the Super Elongation Complex (SEC), a key driver of transcriptional elongation. We show that the SAGA histone acetyltransferase catalytic subunits KAT2A/KAT2B license acetylation of both histone H3 lysine 9 (H3K9ac) and SEC components themselves, including ENL, AFF1, and AFF3. Loss of this dual acetylation activity, achieved via a cereblon-recruiting PROTAC (GSK983/GSK699), displaces the chromatin reader ENL from target loci, dissolves ENL-anchored transcriptional condensates, and disrupts SEC-dependent transcriptional output - linking histone and non-histone acetylation to the physical integrity of a core transcriptional machine. Using genome-scale dependency data, we show that the SAGA complex is a selective chromatin dependency in acute myeloid leukemia (AML) AML and hematological malignancies and disrupting this feed-forward transcriptional circuit in AML demonstrates subtype independent antileukemia effects. KAT2A/B degradation drives potent, broad-spectrum antileukemic activity across genetically diverse AML cell lines, primary patient samples, and an isogenic KMT2A-rearranged model bearing cooperating oncogenic mutations, with H3K9ac loss concentrated asymmetrically at core AML oncogene loci such as MYC, MYB, and the HOXA cluster. Together, these findings define an acetylation-dependent circuit governing SEC integrity and establish KAT2A/B degradation as a mechanism-based, pan-AML therapeutic strategy, with implications for transcriptional condensate regulation beyond leukemia.
HIGHLIGHTS: The SAGA complex is a selectively essential chromatin dependency across hematological malignancies and particularly in AMLKAT2A/B degradation drives broad anti-leukemic activity across genetically diverse AML subtypes including chemo-refractory diseaseKAT2A/B degradation depletes H3K9ac at AML oncogene loci and dismantles ENL-anchored condensatesKAT2A/B licenses regulation of super elongation complex acetylation and ENL interaction with SEC complex components.

DOI: https://doi.org/10.64898/2026.07.13.737885
Leukemia. 2026 Jul 31.

Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis.

Chenxi Liao, Jin Wen, Xiao Ma, Nan Wang, Ying Chen, Lei Li, Lingbo Liu, Danyue Peng.

Therapeutic resistance to cytarabine (Ara-C), a cornerstone of acute myeloid leukemia (AML) therapy, remains an unmet clinical need. Here, we identify ACSF2 as a key metabolic determinant of Ara-C resistance. ACSF2 inhibition suppresses Ara-C-resistant AML cell proliferation, restores Ara-C sensitivity in vitro and in vivo. Mechanistically, ACSF2 inhibition impairs cholesterol esterification. Therefore, the increased cholesterol accumulation on mitochondrial membranes results in mitochondrial dysfunction, elevated mitochondrial reactive oxygen species (ROS), and suppression of pro-survival ERK signaling. Furthermore, we first established SREBF1 as a direct transcriptional activator of ACSF2 in this context. Notably, the SREBF1 inhibitor fatostatin synergizes with Ara-C against resistant AML with downregulation of ACSF2. These findings define a crucial role of ACSF2 in Ara-C resistance and highlight the SREBF1-ACSF2 axis as a promising therapeutic target for relapsed/refractory AML.

DOI: https://doi.org/10.1038/s41375-026-03053-7
medRxiv. 2026 Jul 13. pii: 2026.07.08.26357595. [Epub ahead of print]

Statin Use and Genetically Predicted HMG-CoA Reductase Inhibition in Relation to Clonal Hematopoiesis.

Paul R Carter, Malgorzata Gozdecka, Sean Wen, Pedro M Quirós, Samuel M Lockhart, Monika Dudek, Laura Bond, George Richenberg, Susanna C Larsson, Daniel Bromage, Jonathan Mitchell, Brian Huntly, Peter Libby, Murray C H Clarke, Margarete Fabre, George S Vassiliou, Stephen Burgess, Siddhartha P Kar.

Background: Clonal hematopoiesis (CH) is associated with increased risks of diverse cardiovascular diseases, hematologic malignancies and mortality, yet no preventive therapies are approved. As emerging data implicate lipid pathways in CH pathogenesis, we investigated the association of statin use and genetically proxied inhibition of HMG-CoA reductase (HMGCR) with CH risk, and validated findings using primary peripheral blood mononuclear cells (PBMCs).
Methods: We performed an observational analysis of 416,118 UK Biobank participants of European ancestry using multivariable logistic regression to compare CH prevalence among statin users and nonusers. Mendelian randomization (MR) analyses evaluated the causal association of genetically proxied lowering of low-density lipoprotein cholesterol (LDL-C) with risk of CH using two instruments; (i) the lead HMGCR variant (rs12916) which proxied LDL-C lowering by statins, and, (ii) 303 genome-wide LDL-C-lowering variants representing polygenic mechanisms. Summary statistics were obtained from the Global Lipid Genetics Consortium genome-wide association study (N = 842,634). Experimentally, primary PBMCs from a DNMT3A R882 hotspot mutation carrier were cultured in methylcellulose with pravastatin or vehicle control to evaluate colony-forming dynamics.
Results: Among 416,118 individuals, 20,488 had CH, including 11,550 with single DNMT3A-mutant and 4,375 with single TET2-mutant CH. Pre-recruitment statin users had reduced odds of DNMT3A-mutant CH (OR=0.93; 95% CI:0.88-0.98; P=0.009), driven primarily by associations with DNMT3A R882-mutant (OR=0.78; 95% CI:0.66-0.92; P=0.003), but not TET2-mutant CH (OR=1.05; 95% CI:0.97-1.14; P=0.20). Similarly, genetically predicted HMG-CoA-reductase inhibition equivalent to a 1 SD reduction in circulating LDL-C levels was associated with lower odds of DNMT3A-mutant CH (OR=0.66; 95% CI:0.45-0.95; P=0.03) but not TET2-mutant CH (OR=1.34; 95% CI:0.76-2.36; P = 0.31). By contrast, polygenic estimation of LDL-C lowering was not associated with DNMT3A-mutant CH (OR=1.05; 95% CI:0.97-1.14; P=0.20), suggesting protective effects were independent of LDL-C lowering per se. Genetically predicted HMG-CoA reductase inhibition had wide effects on blood cell counts and indices, suggesting effects on bone marrow cell dynamics. In vitro, pravastatin selectively suppressed colony formation of primary human DNMT3A R882-mutant relative to wild-type cells (P=0.031).
Conclusions: Statin therapy and genetically predicted lifelong inhibition of HMG-CoA reductase were significantly associated with reduced risk of DNMT3A-mutant CH, likely via LDL-C-independent mechanisms, which may be specific to DNMT3A-mutant CH. This provides a strong rationale for prospective trials evaluating the effect of statins on risk of developing DNMT3A-mutant CH, subsequent clonal expansion, and associated clinical sequelae.

DOI: https://doi.org/10.64898/2026.07.08.26357595
bioRxiv. 2026 Jul 13. pii: 2026.07.12.737989. [Epub ahead of print]

Single cell multi-omics enables high-resolution identification and functional purification of human acute myeloid leukemia stem cells.

Asiri Ediriwickrema, Yusuke Nakauchi, Thomas Köhnke, Amy C Fan, Xiaoyi Hu, Brooks A Benard, Daiki Karigane, Miles H Linde, Aaron M Newman, Andrew J Gentles, Ravindra Majeti.

In human acute myeloid leukemia (AML), a sub-population of leukemia stem cells (LSCs) drive disease initiation, therapeutic resistance, and relapse. However, the lack of reliable markers to distinguish LSCs from bulk leukemia cells has impeded progress in studying LSC pathogenesis and developing meaningful LSC-specific diagnostics and therapeutics. Existing LSC gene signatures, derived from bulk populations, cannot definitively identify LSCs at single-cell resolution. To address this, we analyzed large patient cohorts with bulk gene expression data and single-cell multi-omic assays to identify a prognostic gene signature that is specifically enriched in a clinically adverse AML sub-population. Using this signature, we defined and prospectively isolated CD34+CD90-CLL1-CD69+CD53- immunophenotypic LSCs that are significantly enriched for LSC content based on limiting dilution xenotransplantation assays. Our findings demonstrate the power of single-cell multi-omics to precisely identify a clinically relevant LSC population and establish a clear framework for future translational research in AML.
Key Points: Single cell multi-omics identifies human AML LSCs at high resolution. HOPX and SOCS2 co-expression (hrLSC2) defines a prognostic gene signature in de novo acute myeloid leukemia. hrLSC2 marks an AML subpopulation (iLSCs) with a distinct immunophenotype.iLSCs can be purified using flow cytometry and are significantly enriched for LSCs.

DOI: https://doi.org/10.64898/2026.07.12.737989
Blood. 2026 Jul 28. pii: blood.2026033834. [Epub ahead of print]

Human HSPCs clones balance stochastic diversification with cytokine-induced differentiation.

Elia Colin, Dror Brook, Jonathan Izraeli, Oren Milman, Aviezer Lifshitz, Tal Bacharach, Noa Chapal-Ilani, Liran I Shlush, Amos Tanay.

Hematopoietic stem and progenitor cells (HSPCs) balance self-renewal with on-demand differentiation of blood lineages. Modern bone marrow atlases specify static transcriptional states, but not HSPC dynamics, which are only partly understood, particularly in humans. Here, we introduce cHSPCTrack (clonal HSPC tracker), an in vitro framework for serially tracking clonal differentiation and fate acquisition from human HSPCs extracted from circulation. By following thousands of single-cell-derived clones stimulated by different cytokine combinations, cHSPCTrack reconstructs the balance between stochasticity and directed differentiation in human HSPCs. Single HSPCs stochastically yield multiple lineages under a uniform cytokine environment, with stimulatory inputs modulating differentiation probabilities by introducing biases toward preferred fates. In parallel, differentiation rates vary stochastically across and within clones. Clonal memory stabilizes the induction of a few genes per clone over otherwise archetypical differentiation trajectories. Within clones, multiple fates can interact with each other, as shown for clones mixing basophils, eosinophils, and mast cells with other fates. cHSPCTrack opens avenues for understanding hematopoietic clonal dynamics in health and disease.

DOI: https://doi.org/10.1182/blood.2026033834
Oncogene. 2026 Jul 30.

PROTAC-mediated targeting of IKKβ and NR4A1 for AML therapy.

Chandra K Maharjan, Yi Liu, Yufeng Xiao, Bristy R Podder, Tyler H Montgomery, Lei Wang, Myung-Chul Kim, Zeng Jin, Seyedehalaleh Anvar, Tanzia Islam Tithi, Vivek M Shastri, Alexandra M Stevens, Ryan Kolb, Chen Zhao, Zhijian Qian, Jatinder K Lamba, Guangrong Zheng, Weizhou Zhang.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor clinical outcomes and limited therapeutic options. Aberrant activation of the IKKβ-NF-κB pathway occurs in approximately 40% of AML cases and contributes to leukemogenesis. However, pharmacological inhibition of IKKβ has been limited by serious toxicities, including neutrophilia. Here we identify IKKβ and NR4A1 as critical drivers of AML progression in certain models and develop a proteolysis-targeting chimera (PROTAC) capable of degrading the proteins. Although NR4A1 has previously been described as a tumor suppressor in AML, our findings demonstrate that NR4A1 exhibits oncogenic functions in some AMLs of the (pro)monocytic lineage. Notably, elevated expression of IKKβ and NR4A1 in AML is associated with poor clinical outcomes, playing non-redundant oncogenic roles in AML. To therapeutically target IKKβ and NR4A1, we designed and synthesized a series of celastrol-based PROTACs that exploit celastrol's ability to bind both IKKβ and NR4A1. Among these compounds, the lead A9 induces potent cytotoxicity in multiple AML cell lines and primary AML samples through cereblon E3 ligase-dependent degradation of IKKβ and/or NR4A1. In vivo, A9 suppresses leukemia progression in a KMT2A::MLLT3 AML mouse model without inducing neutrophilia, supporting PROTAC-mediated degradation of IKKβ and NR4A1 as a promising therapeutic strategy.

DOI: https://doi.org/10.1038/s41388-026-03925-3
Br J Haematol. 2026 Jul 27.

Loss of DNA methylation is not associated with venetoclax-hypomethylating agents synergy in acute myeloid leukaemia cells.

Aida Selimović-Pašić, Lisa Haglund, Maike Bensberg, Júlia Goldmann, Padraig D'arcy, Sandra Hellberg, Colm E Nestor.



Keywords:  DNA damage; DNA methylation; acute myeloid leukaemia; drug synergy; hypomethylating agents; venetoclax

DOI:  https://doi.org/10.1111/bjh.70729
bioRxiv. 2026 Jul 15. pii: 2026.05.29.728710. [Epub ahead of print]

TIAR-dependent coordination of alternative splicing and lipid peroxidation is required for CML cell resistance to imatinib in the bone marrow stroma.

Paulina Podszywalow-Bartnicka, Ewa Kozlowska, Remigiusz Serwa, Joanna Idaszek, Ewa Walejewska, Agnieszka Kepczynska, Anna Mietelska-Porowska, Paulina Pilanc-Kudlek, Magdalena Wolczyk, Leonard Schärfen, Bac Viet Le, Wojciech Swieszkowski, Katarzyna Piwocka, Tomasz Skorski, Karla M Neugebauer.

Chronic myeloid leukemia (CML) is treated with Abl1 tyrosine kinase inhibitors (TKIs). Quiescent cancer cells residing in the bone marrow (BM) can survive the treatment and cause CML relapse. We previously found that a subset of alternative splicing (AS) changes detected in CML cells surviving months of therapy are initiated within hours of treatment onset. Here, we investigated how AS in CML cells is modulated by the human BM microenvironment. By incorporating humanized BM niche models in vivo, we uncovered stroma-induced transcriptome adaptation that influences transcriptional regulation, transmembrane transport, lipid metabolism, the tricarboxylic acid cycle, and respiratory electron transport. We identified RNA-binding protein TIAR (T-cell intracellular antigen-related protein) as a key mediator of CML survival under TKI imatinib treatment. Our data show TIAR-dependent coordination of RNA processing with the metabolic program induced by stromal interaction. Quantitative nascent proteome analysis revealed that TIAR silencing affects the synthesis of metabolic enzymes and proteins involved in imatinib-induced erythroid differentiation. Besides, TIAR knockdown increased lipid peroxidation in untreated cells and decreased reduction potential in cells upon imatinib treatment. Taken together, TIAR deficiency reduces CML survival, possibly by inducing ferroptosis. These findings identify TIAR-dependent RNA processing within the BM niche as a previously unrecognized mechanism of CML therapy resistance and a potential therapeutic vulnerability.

DOI: https://doi.org/10.64898/2026.05.29.728710
bioRxiv. 2026 Jul 15. pii: 2026.07.14.738455. [Epub ahead of print]

FLT3-ITD signals for CEBPA and p53 proteolysis by the ubiquitin-proteosome pathway.

Xiaorong Gu, Sudipta Biswas, Zeinab Albadry M Zahran, Songa Bae, Ramesh Balusu, Jaroslaw P Maciejewski, Babal K Jha, Yogen Saunthararajah.

  Internal-tandem-duplication of the receptor tyrosine kinase FLT3 (FLT3-ITD) generates ligand-independent signaling and is highly recurrent in acute myeloid leukemias (AMLs). One way signaling pathways can quickly influence cell fates is by phosphorylating key fate-determining proteins to trigger their proteolysis. We investigated the master transcription factor (MTF) driver of granulo-monocytic lineage-fates, CEBPA, for regulation by this mechanism because we found high CEBPA mRNA but little CEBPA protein in FLT3-ITD versus FLT3-wildtype AML cells, and inhibiting FLT3-ITD signaling with tyrosine kinase inhibitors (TKI) rapidly rescued CEBPA protein. Mass spectrometry analyses of CEBPA and its interactome demonstrated prominent interactions with major ubiquitin-proteosome pathway (UPP) components UHRF1 and USP7. TKI treatments decreased CEBPA and USP7 phosphorylations at serine 21 and serine 18 respectively alongside shifts in CEBPA interactions from degradative ubiquitin-ligase UHRF1 toward protective deubiquitinase USP7. The rescued CEBPA activated granulocytic-differentiation. Supporting that the serine-phosphorylations were 'phospho-degrons', UPP-inhibitors (bortezomib, MG132) increased phosphorylated and total CEBPA and USP7. The MTF regulator of apoptosis p53 is a known USP7 client, therefore, we also evaluated p53 status: TKIs and UPP-inhibitors stabilized USP7 and p53, triggering apoptosis in addition to granulocytic-differentiation specifically in FLT3-ITD but not FLT3-wildtype AML cells. UPP-inhibitors produced these consequences in TKI-resistant FLT3-ITD AML cells also. These data predicted genetic loss-of-function to CEBPA or TP53 is redundant in the FLT3-ITD context, borne out by mutual exclusivity of the mutations in clinical series. In summary, FLT3-ITD signals for CEBPA and p53 proteolysis to block lineage-maturation and apoptosis, positioning UPP-inhibitors as therapeutic candidates acting downstream of TKIs.

Keywords:  CEBPA; FLT3-ITD; USP7; acute myeloid leukemia; chemotherapy-resistance; p53; ubiquitin-proteosome pathway

DOI:  https://doi.org/10.64898/2026.07.14.738455
bioRxiv. 2026 Jul 17. pii: 2026.07.16.736849. [Epub ahead of print]

Targeting cellular senescence alleviates bone marrow aging.

Bowen Yan, Jin Han, Yang Yang, Peiyi Zhang, Jason O Brant, Jianhui Chang, Ha-Neui Kim, Maria Almeida, Prabhjot Kaur, Qingchen Yuan, Marco Demaria, Kalyanee Shirlekar, Jennifer Elisseeff, Guangrong Zheng, Ying Liang, Daohong Zhou, Olga A Guryanova.

Aging of the hematopoietic system impairs hematopoietic stem cell (HSC) function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, pharmacologic clearance of senescent cells with the PROTAC compound 753b simultaneously targeting BCL-xL and BCL-2 reverses key secretory, transcriptional, and functional hallmarks of hematopoietic aging with low toxicity, restoring balanced lineage output. Single-cell RNA sequencing further demonstrates that 753b treatment attenuates aging-associated transcriptional signatures in HSCs, while selectively eliminating senescent, pro-survival niche cells without grossly perturbing niche composition. Functionally, 753b suppresses pro-inflammatory cues from both niche and hematopoietic cells including those emanating from neutrophil progenitors, rebalancing global bone marrow secretory ecosystem across stromal and hematopoietic compartments. Collectively, we identify 753b-induced senescent cell clearance as a powerful strategy to rejuvenate aged hematopoiesis and re-establish homeostatic communication between HSCs and their microenvironment, with implications for mitigating age-related hematologic dysfunction and improving hematologic health in older individuals.

DOI: https://doi.org/10.64898/2026.07.16.736849
Blood Adv. 2026 Jul 30. pii: bloodadvances.2026019760. [Epub ahead of print]

ASSESSMENT OF THE IPSS-M IN CHRONIC MYELOMONOCYTIC LEUKEMIA.

Laura Palomo, Mireia Morgades, Manja Meggendorfer, Marina Díaz-Beyá, Helena Pomares, Jose Francisco Falantes-González, Guillermo Ramil, Mariam Ibañez, Mar Tormo, Felix Lopez-Cadenas, Alejandro Avendaño, Juan Carlos Caballero Berrocal, Teresa Bernal Del Castillo, Jordi Vila, Juan Restrepo, Verónica Roldán-Galiacho, Pilar Galán Alvarez, Estefania Cerezo, Cristina Notario Mc Donnell, Ana Garcia-Feria, Luca Lanino, Torsten Haferlach, Sandra Castaño-Díez, Esther Alonso, Marta Pratcorona, Rosa Collado, Marisa Calabuig, Pamela Acha, Monica Del Rey, Gerardo Aguilar-Monserrate, Carmen Loredo, Matteo Giovanni Della Porta, Marta Cabezón, Neus Ruiz-Xiville, Lurdes Zamora, Blanca Xicoy.

Prognostication in chronic myelomonocytic leukemia (CMML) remains a challenge due to the biological complexity and variable clinical course of the disease. This study aimed to evaluate the prognostic utility of the International Prognostic Scoring System-Molecular (IPSS-M) in CMML and its applicability across the myelodysplastic and myeloproliferative subsets of the disease. We conducted a multicenter, retrospective study including 511 patients diagnosed with CMML. Clinical, cytogenetic, and molecular data were collected at diagnosis, including targeted NGS. Patients were stratified using IPSS-M, CPSS-Mol, and the recently developed iCPSS. IPSS-M effectively stratified patients into risk groups with significantly different overall survival (OS) and cumulative incidence of acute myeloid leukemia (AML) progression. Discrimination was maintained after merging overlapping intermediate risk categories, yielding a four-tier model with a c-index of 0.678 for OS and 0.628 for AML progression. This model retained its prognostic performance in both MD-CMML and MP-CMML subsets, with higher discrimination for OS in the MD-CMML group. When compared with CPSS-Mol and iCPSS, adapted IPSS-M showed comparable prognostic performance to iCPSS and improved discrimination compared with CPSS-Mol. These findings support the applicability of an adapted IPSS-M to CMML, extending its use beyond myelodysplastic syndromes and highlighting its potential utility in guiding clinical decision-making and therapeutic strategies. Moreover, this study also provides an external validation of the iCPSS in an independent and genetically well-characterized CMML cohort, reinforcing its clinical utility.

DOI: https://doi.org/10.1182/bloodadvances.2026019760
Leukemia. 2026 Jul 29.

Adaptor-mediated rewiring of FLT3 signaling engages p38 MAPK to sustain gilteritinib resistance in acute myeloid leukemia.

Long Shen, Jinting Fan, Ning Wang, Zihao Wang, Yang Yang, Chenghua Xu, Siyi Liu, Dong Zhang, Youyang Fang, Bingqian Chu, Tingting Zhang, Wenshuo Liu, Lichun Kang, Zhiwei Zhou, Mingming Niu, Hong Wang.

Resistance to FLT3 inhibitors remains a major limitation in the treatment of FLT3-mutated acute myeloid leukemia (AML). Canonically, ERK is considered the predominant MAPK effector downstream of FLT3 signaling. However, pharmacologic inhibition of MEK/ERK provides limited clinical benefit once resistance develops, suggesting that alternative signaling dependencies may emerge under therapeutic pressure. Using an unbiased kinome-wide CRISPR-Cas9 screen in gilteritinib-resistant AML cells, we identified MAPK14 (encoding p38α), rather than MAPK3/MAPK1 (encoding ERK1/2), as a prominent context-dependent dependency associated with the resistant state. Genetic impairment or pharmacologic inhibition of p38 enhanced gilteritinib sensitivity and synergized with FLT3 inhibition to suppress leukemic growth. Mechanistically, resistant cells exhibited adaptor-mediated rewiring of FLT3 signaling, in which p46-SHC1 supported an FLT3-associated MKK3/6-p38 signaling module despite FLT3 inhibition, thereby sustaining downstream programs including MYC expression. Consistent with its role as a stress-responsive kinase, p38 supports leukemic cell survival under prolonged drug exposure. Together, these findings define a non-canonical MAPK signaling state associated with FLT3 inhibitor resistance, provide a mechanistic explanation for the limited efficacy of MEK/ERK-directed therapies in the resistant setting, and offer a rationale for combination strategies targeting stress-adaptive pathways to improve the durability of FLT3-directed therapy in AML.

DOI: https://doi.org/10.1038/s41375-026-03079-x
Sci Adv. 2026 Jul 31. 12(31): eaeb6444

ZMAT3 alleviates cell death in Fanconi anemia via adaptation of sphingolipid metabolism.

Maeva Loock, Blandine Lucchini, Emmanuelle Latour, Margot Tissandier, Marie Lhomme, Maharajah Ponnaiah, Lucie Hernandez, Loic Maillard, Jean Soulier, Olivier Bluteau, Camille Lobry, Marie-Laure Arcangeli, Wilfried Le Goff, Dominique Bluteau.

Fanconi anemia (FA) is characterized by defective DNA repair and chronic p53 activation, predisposing to acute myeloid leukemia through persistent genomic instability. The molecular adaptations enabling cell survival under chronic stress remain poorly understood. This study investigates the role of ZMAT3, a p53 responsive RNA binding protein overexpressed in FA deficient cells, to elucidate its role in cellular adaptation. Using FA patient fibroblasts and Fancg KO mouse models, we launched transcriptomic profiling, lipidomic, and functional analyses. RNA-seq and lipidomic analyses revealed unexpected alterations in sphingolipid metabolism upon ZMAT3 depletion, linked to ceramide accumulation and downregulation of ASAH1 (acid ceramidase). Functionally, ZMAT3 depletion increased DNA damage and enhanced ferroptosis susceptibility, an iron dependent cell death mechanism. Mechanistically, our results showed that ZMAT3 promotes ASAH1 expression, limits ceramide accumulation and protects cells from ferroptosis induced death which could participate to preleukemic clonal evolution and pointing to areas for further exploration in FA-associated malignancies.

DOI: https://doi.org/10.1126/sciadv.aeb6444
Blood Adv. 2026 Jul 30. pii: bloodadvances.2026019942. [Epub ahead of print]

Real-world investigation of germline predisposition to myelodysplastic syndromes.

Anna Tranberg, Maria Creignou, Teresa Mortera-Blanco, Elsa Bernard, Ann-Charlotte Björklund, Mikaela Hillberg Widfeldt, Indira Barbosa, Matilda Kjellander Kynning, David Cabrerizo Granados, Vanessa Lundin, Johanna S Ungerstedt, Gabriele Todisco, Elli Papaemmanuil, Eva S Hellstrom-Lindberg, Bianca Tesi.

Follow-up of potential germline variants revealed by diagnostic targeted sequencing (TS) for myelodysplastic syndromes (MDS) has been proposed by clinical guidelines. However, their feasibility and clinical yield in routine MDS practice remain uncertain. We evaluated real-world applicability of systematic germline follow-up in an unselected cohort of 716 patients (median age 74 years) evaluated for MDS. Their diagnostic TS data was analyzed to identify variants in CEBPA, DDX41, ETV6, GATA2, and RUNX1 with a variant allele frequency ≥35%. In total, 98 variants were identified in 87 (12.2%) patients. Germline investigation was possible for 62 patients; for the remaining 25 without biobanked material, medical charts were reviewed. We identified pathogenic/likely pathogenic (P/LP) germline variants in 19 patients (2.7%). Most P/LP variants were found in DDX41 (73.7%), followed by 10.5%, 10.5%, and 5.3% in RUNX1, GATA2, and ETV6, for germline conversion rates between 5.4% and 93.3%. Patients with P/LP variants had a median age at diagnosis of 73 years, with marked male predominance (3.75:1). Most patients were diagnosed with MDS-EB1 or MDS-EB2 (68.4%) and had normal cytogenetics (95%). A review of medical charts in younger patients (<50 years) revealed germline predisposition in other genes in additional five patients, revisiting the prevalence of predisposition to 3.4% overall and to 16.7% in those under 50. Our results show that systematic germline follow-up after diagnostic TS succeeds in identifying predisposition in nearly 3% of patients at a typical adult MDS clinic. Germline testing for genes not routinely assessed by diagnostic TS is required in younger patients.

DOI: https://doi.org/10.1182/bloodadvances.2026019942
Lancet Haematol. 2026 Aug;pii: S2352-3026(26)00167-5. [Epub ahead of print]13(8): e533-e544

Low-dose ruxolitinib for graft-versus-host disease prevention in haploidentical haematopoietic stem-cell transplantation: a multicentre, open-label, randomised, controlled, phase 3 trial.

Hengwei Wu, Wenming Shi, Zhuoyue Shi, Yi Luo, Jian Yu, Weijie Cao, Junjie Cao, Xiaojun Xu, Xiaoxia Hu, Ying Lu, Huarui Fu, Lizhen Liu, Xiaoyu Lai, Luxin Yang, Yishan Ye, Congxiao Zhang, Jimin Shi, He Huang, Yanmin Zhao.

BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after haploidentical haematopoietic stem-cell transplantation (HSCT). Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor with established activity in steroid-refractory GVHD, has shown promise for prophylaxis in early studies, but there is little evidence from randomised trials in the haploidentical HSCT setting. We investigated whether, within a backbone of antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate, replacing mycophenolate mofetil with low-dose ruxolitinib could reduce acute GVHD after haploidentical HSCT.
METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial conducted at five centres in China, eligible patients were aged 12-70 years, had haematological malignancies for which allogeneic HSCT was indicated, had a Karnofsky performance status of at least 70 or a Lansky score of at least 70 for patients younger than 16 years, and were undergoing their first myeloablative haploidentical HSCT. Patients were randomly assigned (1:1) to receive antithymocyte globulin, a calcineurin inhibitor, short-course methotrexate, and low-dose ruxolitinib, or standard prophylaxis with antithymocyte globulin, a calcineurin inhibitor, short-course methotrexate, and mycophenolate mofetil. Randomisation was stratified by centre and patient age (<40 years vs ≥40 years) using computer-generated permuted blocks with random block sizes. Oral ruxolitinib was started on day 1 at 5 mg twice daily for patients weighing at least 50 kg and 5 mg once daily for those weighing less than 50 kg, continued up to day 60, and then tapered to day 90 in the absence of grade II-IV acute GVHD. The primary endpoint was the cumulative incidence of grade II-IV acute GVHD by day 100. Efficacy and safety were analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of the assigned prophylaxis, excluding those with major protocol deviations. This trial is registered with ClinicalTrials.gov, NCT04838704, and is complete.
FINDINGS: Between April 1, 2021, and Dec 28, 2023, 215 patients were randomly assigned, of whom 206 were included in the modified intention-to-treat population (103 in the ruxolitinib prophylaxis group and 103 in the standard prophylaxis group). The median recipient age was 40 years (IQR 24-48), 98 (48%) patients were female and 108 (52%) were male, and all participants were Chinese. Among surviving patients, the median follow-up was 26·4 months (IQR 20·0-33·3). By day 100, grade II-IV acute GVHD occurred in seven (cumulative incidence of 6·8% [95% CI 1·9-11·7]) of 103 patients in the ruxolitinib prophylaxis group and 38 (36·9% [27·5-46·3]) of 103 patients in the standard prophylaxis group (subdistribution hazard ratio 0·15, 95% CI 0·07-0·34; p<0·0001). The most common grade 3-4 adverse events in the ruxolitinib prophylaxis group and the standard prophylaxis group were thrombocytopenia (17 [17%] vs 11 [11%]), neutropenia (14 [14%] vs 9 [9%]), anaemia (12 [12%] vs 9 [9%]), and cystitis (7 [7%] vs 10 [10%]). Serious adverse events occurred in 31 (30%) patients in the ruxolitinib prophylaxis group and 36 (35%) patients in the standard prophylaxis group. No fatal adverse events occurred in the ruxolitinib prophylaxis group. Three deaths occurred in the standard prophylaxis group: pulmonary infection (n=1), sepsis, bacteraemia, or fungaemia (n=1) and transplant-associated thrombotic microangiopathy (n=1). No deaths were considered related to the assigned study drug.
INTERPRETATION: Low-dose ruxolitinib, used in place of mycophenolate mofetil within a backbone of prophylactic antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate, reduced grade II-IV acute GVHD by day 100 after haploidentical HSCT and had manageable toxicity. These findings support further evaluation of targeted JAK1/2 inhibition as part of GVHD prophylaxis.
FUNDING: National Natural Science Foundation of China.

DOI: https://doi.org/10.1016/S2352-3026(26)00167-5
Nature. 2026 Jul 29.

Mitochondrial metabolism and epigenetic crosstalk drive SASP.

Hélène Martini, Jodie Birch, Francisco D M Marques, Stella Victorelli, Anthony B Lagnado, Nicholas Pirius, Ana Catarina Franco, Gung Lee, Yeaeun Han, Jennifer L Rowsey, Wazim Mohammed Ismail, Amelia Mazzone, Tianna M Espe, Taro Hitosugi, Ya Li, Alexander M Washington, Aaron Havas, Rabi Murad, Xue Lei, Rebecca A Porritt, Oliver D K Maddocks, Jair Machado Espindola-Netto, Dominik Saul, Sundeep Khosla, Diana Jurk, Enis Kostallari, Alexandre Gaspar-Maia, Peter D Adams, João F Passos.

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP)1. Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme2,3. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes. Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.

DOI: https://doi.org/10.1038/s41586-026-10791-2
Br J Haematol. 2026 Jul 26.

Donor age as a dual-risk factor for donor safety and recipient survival in allogeneic haematopoietic stem cell transplantation.

Satoshi Nishiwaki, Yoshiko Atsuta, Ryu Yanagisawa, Hideki Nakasone, Takashi Nagayama, Fumiya Wada, Naoyuki Uchida, Noriko Doki, Takahiro Fukuda, Masatsugu Tanaka, Tetsuya Nishida, Yuta Hasegawa, Noboru Asada, Masashi Sawa, Jun Ishikawa, Toshiro Kawakita, Tetsuya Eto, Yoshinobu Kanda, Moeko Hino, Kazuhiko Ikeda, Junya Kanda, Ken Tabuchi, Koichi Miyamura, Koji Kato, Yasuo Morishima, Shingo Yano, Yoshihisa Kodera.

  Donor selection in allogeneic haematopoietic stem cell transplantation (allo-HSCT) requires balancing donor safety and recipient survival. We aimed to identify dual-association donor factors (DADFs)-donor characteristics associated with both increased serious adverse events (SAEs) and inferior patient survival-using umbilical cord blood (UCB) as a donor-safety benchmark. This nationwide retrospective cohort study analysed Japanese registry data (2013-2022) including 22 892 donors and 29 559 recipients. Logistic regression identified donor SAE risk factors, while patient outcomes were evaluated using inverse probability of treatment weighting (IPTW)-adjusted Cox models with UCB as reference. Propensity score matching (PSM) compared UCB with older donor haploidentical transplantation using post-transplant cyclophosphamide (OD-PTCy-Haplo). Among donors, 93 (0.41%) experienced an SAE. Older donor age and female sex were independent risk factors for SAE. In IPTW-adjusted analyses, allo-HSCT from older haploidentical donors was associated with inferior overall survival (OS) and relapse-free survival (RFS) compared with UCB. In PSM analyses of elderly high-risk recipients, OD-PTCy-Haplo resulted in significantly worse OS and RFS than UCB. Older donor age emerged as a donor characteristic associated with increased donor SAE risk and inferior patient survival, particularly in haploidentical transplantation. UCB may offer a more favourable balance between donor safety and patient outcomes in selected high-risk settings.

Keywords:  allogeneic haematopoietic stem cell transplantation; older donor age; patient outcomes; severe adverse event

DOI:  https://doi.org/10.1111/bjh.70707