bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–07–12
23 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Menin-dependent megakaryocyte proliferation and fibrosis in myeloproliferative neoplasms.
  2. Tagraxofusp, Azacitidine, and Venetoclax in Blastic Plasmacytoid Dendritic Cell Neoplasm.
  3. USP22 is a novel vulnerability regulating MEIS1 protein abundance and gene transcription in KMT2Ar acute leukemia.
  4. Decreased TXNRD1 is associated with resistance to tagraxofusp in blastic plasmacytoid dendritic cell neoplasms, as seen in phase II.
  5. Venetoclax in combination with cytarabine with or without idarubicin or azacitidine in children, adolescents, and young adults with relapsed or refractory acute myeloid leukaemia (VENAML): a multicentre, phase 1 expansion study.
  6. Integrating novel therapeutic strategies in myeloproliferative neoplasms: Driving disease-directed progress.
  7. Splicing-associated network PAK1-CLK1/4-SRRM1 is a vulnerability to overcome chemoresistance in human and mouse acute myeloid leukemia.
  8. Genetic screening of triple negative thrombocytosis patients identifies germline MPL compound mutations and SH2B3/LNK truncating mutations.
  9. Germline landscape stratification defines distinct molecular and prognostic groups in therapy related myeloid neoplasms.
  10. Leukaemic stem cell burden enhances prognostic precision in the non-adverse European LeukemiaNet risk group of acute myeloid leukaemia.
  11. Advanced fibrosis, TP53 variants and acute/pure erythroid leukaemia: Diagnostic harbingers of ERCC6L2-related bone marrow failure syndrome?
  12. Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues.
  13. Chromatin landscape and epigenetic heterogeneity of acute myeloid leukaemia.
  14. Non-genotoxic transplantation and in vivo selection through epitope editing.
  15. Immortal time bias limits the conclusion that post-transplant hypomethylating agent maintenance improves outcomes in myelodysplastic syndromes.
  16. Splenic radiotherapy before allogeneic transplantation for myelofibrosis.
  17. Inflammatory signatures in the spectrum of myeloid diseases.
  18. The H3K4 methyltransferase KMT2D is an essential cofactor for GATA1 at erythroid gene enhancers.
  19. Outcomes of Germline Testing for Children with Hematologic Malignancies Undergoing Hematopoietic Cell Transplantation.
  20. Characteristics of clonal cytopenia of undetermined significance in the presence of ZRSR2 mutations.
  21. Gut Microbiota Drives Aging-related Erythropoiesis Impairment via Phenylacetic Acid-induced Histone Phenylacetylation.
  22. Intracellular iron homeostasis-regulated epigenetic reprogramming contributes to -7/del(7q) leukemia.
  23. NCCN Guidelines® Insights: Myeloproliferative Neoplasms, Version 2.2026.
  1. Cancer Cell. 2026 Jul 09. pii: S1535-6108(26)00295-3. [Epub ahead of print]
    Menin-dependent megakaryocyte proliferation and fibrosis in myeloproliferative neoplasms.
    Jeremy Wen, Anitria Cotton, Rashid Mehmood, Man Mohan, Trent Hall, Amber L Broadhurst, Kevin Zhang, Yunusa Olufadi, Guolian Kang, Bridget Marcellino, John Mascarenhas, Ronald Hoffman, Laura J Janke, Sandeep Gurbuxani, Gerard M McGeehan, John D Crispino.
      Menin inhibition, an approved therapy for KMT2A-rearranged and NPM1 mutant acute leukemia, is accompanied by decreased platelet counts in 15-20% of heavily pre-treated patients. While studying the mechanism underlying this effect, we discovered that menin inhibition reduced the numbers of megakaryocyte progenitors in human CD34+ cultures and in mice. Because megakaryocytes are key drivers of myeloproliferative neoplasms (MPNs), we investigated the extent to which menin inhibition ameliorates MPN phenotypes. We found that the menin inhibitor revumenib has potent anti-tumor activity, synergizes with ruxolitinib, and shows only subtle effects on healthy mice. Moreover, revumenib suppressed megakaryopoiesis of primary MPN patient specimens in vitro and in vivo. Importantly, genetic knockout of MEN1 and its target MEF2C phenocopied the action of revumenib, confirming an on-target effect of the drug. Together, we reveal menin as a dependency in proliferative megakaryocytes and support further evaluation of menin inhibition as a potential therapy for MPNs.
    Keywords:  megakaryocyte; menin; myeloproliferative neoplasms; revumenib
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.008
  2. Blood. 2026 Jul 07. pii: blood.2026033906. [Epub ahead of print]
    Tagraxofusp, Azacitidine, and Venetoclax in Blastic Plasmacytoid Dendritic Cell Neoplasm.
    Andrew A Lane, Marlise R Luskin, Julia H Keating, Nicole R LeBoeuf, Jacqueline S Garcia, Shai Shimony, Rebecca Leonard, Adon Goodpaster, Theresa Nguyen, Ilene Galinsky, Ashleigh Eberly Puleo, Naval G Daver, Nitin Jain, Guillermo Garcia-Manero, Hagop M Kantarjian, Marina Konopleva, Anthony S Stein, Naveen Pemmaraju.
      Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an orphan, aggressive hematologic malignancy characterized by high CD123 expression. Tagraxofusp (TAG), a CD123-directed toxin, is the only approved therapy. Prior studies demonstrated BPDCN dependence on BCL2, sensitivity to venetoclax (VEN), and reversal of TAG resistance with azacitidine (AZA). We conducted a phase 2 study evaluating combination therapy with TAG, AZA, and VEN in patients with BPDCN (NCT03113643). Patients with previously untreated (1L) or relapsed/refractory (R/R) BPDCN received 28-day cycles of AZA (75 mg/m² days 1-7), VEN (400 mg days 1-21), and TAG (12 µg/kg days 4-6). Eligibility followed TAG guidelines to mitigate risk of capillary leak syndrome (CLS). Twenty-seven patients were enrolled (16 1L, 11 R/R), with median age of 70 years (range 21-81). Composite complete remission (CR/CRi/CRc) rates were 88% in 1L and 64% in R/R cohorts. Median duration of response was not reached in 1L and was 7.2 months in R/R patients. CLS occurred in 15% of patients; most were grade 2. In the 1L cohort, median overall and progression-free survival were not reached; the 2-year overall survival was 65% and 2-year progression-free survival was 53%. Median overall survival in R/R patients was 8.4 months. A high proportion of patients proceeded to allogeneic stem cell transplantation in remission (63% 1L, including 10 of 11 patients age 75 or younger; and 55% R/R). TAG-AZA-VEN is highly active in both untreated and relapsed BPDCN with a predictable and manageable safety profile, supporting its use as a new therapeutic option.
    DOI:  https://doi.org/10.1182/blood.2026033906
  3. Blood. 2026 Jul 08. pii: blood.2025031845. [Epub ahead of print]
    USP22 is a novel vulnerability regulating MEIS1 protein abundance and gene transcription in KMT2Ar acute leukemia.
    Sarah Bröchtel, Constanze Schneider, Marius Müller, Christina Villinger, Thomas Plenge, Manoj K Gupta, Luca Immanuel Kesel, Sebastian Scheich, Sebastian Wolf, Ali Yavuz Cakir, Björn Häupl, Florian Buettner, Stefan Knapp, Hubert Serve, Kimberly Stegmaier, Florian Perner, Thomas Oellerich, Anjali Cremer.
      Patients with acute leukemias harboring translocations involving gene lysine methyltransferase 2A (KMT2A) have a poor prognosis due to chemotherapy resistance with rapid relapse following standard treatments. The resulting KMT2A fusion proteins dysregulate gene expression, leading to an upregulation of leukemogenic transcription factors such as HOXA9 and MEIS1, which drives leukemic transformation. Although Menin inhibitors are proving to be promising new therapeutics for patients with KMT2A-rearranged (KMT2Ar) acute leukemia, resistance mechanisms have already been described and new therapeutic approaches for this patient subgroup must be identified. Here, a genome-wide CRISPR/Cas9 screen in a KMT2Ar B-cell acute lymphoblastic leukemia (ALL) cell line identified the deubiquitinase USP22 as a novel regulator of MEIS1 protein stability. USP22 is a member of the Spt-Ada-Gcn5 acetyltransferase (SAGA) multiprotein complex, which has crucial functions in shaping the chromatin landscape and modulating transcription. Genetic depletion of USP22 impaired cellular growth and proliferation in KMT2Ar acute leukemia models. Chromatin immunoprecipitation revealed cooperative binding between USP22 and MEIS1 at critical oncogenic target genes suggesting that USP22 safeguards leukemogenic transcription by protecting MEIS1 from proteasomal degradation. Genetic or chemical inhibition of USP22 led to polyubiquitination of MEIS1 resulting in proteasomal degradation and downregulation of the expression of target genes. Our study identifies USP22 as a novel regulator of MEIS1 protein stability, that could potentially be exploited as a therapeutic target in the future in KMT2Ar leukemias.
    DOI:  https://doi.org/10.1182/blood.2025031845
  4. Leukemia. 2026 Jul 06.
    Decreased TXNRD1 is associated with resistance to tagraxofusp in blastic plasmacytoid dendritic cell neoplasms, as seen in phase II.
    Hannah C Beird, Sankaranarayanan Kannan, Jingjing Liu, Janice Chen, Arturo Olguin, Poonam Desai, Tianyu Cai, Lina Han, Jennifer L Cotton, Sandeep Singh, Saurabh Kumar Gupta, Latasha Little, Marcos R Estecio, Xingzhi Song, Hussein A Abbas, Jianhua Zhang, Curtis Gumbs, Christopher Brooks, Hagop Kantarjian, Michael Andreeff, Marina Konopleva, P Andrew Futreal, Naveen Pemmaraju.
      Tagraxofusp is a CD123-targeted therapy comprised of a recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin payload. It is the first approved treatment specifically for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). To identify biomarkers of response, bone marrow samples from 12 BPDCN patients who were treated with tagraxofusp in the pivotal phase II trial (NCT02113982) were profiled longitudinally using a gene panel and single-cell RNA sequencing. Residual tumor cells following tagraxofusp expressed lower levels of TXNRD1 that would reduce the efficacy of tagraxofusp. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp. Responders had either wild-type or missense TET2 mutations, while transient and non-responders had at least one truncating TET2 mutation. Examples of these mutations within the catalytic domain of TET2 were constructed and transduced into cells. Missense and truncating mutants displayed reduced sensitivities to hypomethylating agents and prolonged S-phase stasis. These results suggest that the levels of TXNRD1 interact with intrinsic TET2 truncating mutations within the bone marrow to modulate patient response to tagraxofusp.
    DOI:  https://doi.org/10.1038/s41375-026-03022-0
  5. Lancet Haematol. 2026 Jul 08. pii: S2352-3026(26)00136-5. [Epub ahead of print]
    Venetoclax in combination with cytarabine with or without idarubicin or azacitidine in children, adolescents, and young adults with relapsed or refractory acute myeloid leukaemia (VENAML): a multicentre, phase 1 expansion study.
    Katelyn P Daniels, Stanley B Pounds, Huiyun Wu, Lei Wang, Thomas B Alexander, Amit Budhraja, Joshua Wolf, Tamara Westover, Paul E Mead, Cyrus M Mehr, Soumyasri Das Gupta, Norman J Lacayo, Hiroto Inaba, Matthew Rees, Ching-Hon Pui, Joseph T Opferman, Jeffery M Klco, Jeffrey E Rubnitz, Seth E Karol.
       BACKGROUND: The prognosis for paediatric patients with relapsed or refractory acute myeloid leukaemia remains poor. Although encouraging, published paediatric data on venetoclax combined with intensive chemotherapy are scarce. We aimed to refine efficacy and toxicity estimates from the previously published dose-escalation phase of this study.
    METHODS: This multicentre, phase 1 study included two phases, an initial dose-escalation phase to identify the primary endpoint of recommended phase 2 dose (RP2D; previously reported), followed by an expansion cohort phase, the results of which are reported here. Paediatric patients (aged 2-24 years) with relapsed or refractory acute myeloid leukaemia from three US research hospitals were included. Patients had at least 5% blasts in the bone marrow by morphology or at least 1% blasts by flow cytometry. Treatment varied across cohorts. Patients received oral venetoclax 360 mg/m2 (maximum 600 mg) daily for 27 days after a 50% dose reduction on day 1 and intravenous cytarabine 1000 mg/m2 per dose every 12 h for eight doses on days 8-11 (cohort A), with intravenous idarubicin (12 mg/m2 on day 8; cohort B) and dexrazoxane or intravenous azacitidine (75 mg/m2 on days 1-7; cohort C). Here, we report results for all patients treated at the RP2D, including patients treated in the expansion cohort phase (cohort A and B) and patients in cohort C added by protocol amendment (Oct 13, 2020). This final report describes the key secondary endpoint of the rates of complete response with or without haematological recovery at the RP2D. Analyses were on the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT03194932) and is completed.
    FINDINGS: From July 1, 2017, to July 22, 2022, 61 patients were enrolled and 44 patients were subsequently included and treated at the RP2D (21 [48%] female, 23 [52%] male; 22 [50%] in cohort A, 15 [34%] in cohort B, and seven [16%] in cohort C). The median follow-up was 5·3 years (IQR 4·2-6·3). After 1 cycle, 25 (57% [95% CI 41-72]) patients had a complete response with or without haematological recovery; 19 were negative for measurable residual disease. Common grade 3 or 4 adverse events included febrile neutropenia (23 [52%]), gastrointestinal disorders (14[32%]]) including colitis (four [9%]), and infections (11 [25%]). There were two grade 5 adverse events due to sepsis and multiorgan failure.
    INTERPRETATION: Venetoclax with high-dose cytarabine is active with acceptable safety in paediatric patients with relapsed or refractory AML. These findings support ongoing research of venetoclax with high-dose cytarabine in this population, including the randomised paediatric phase 3 trial (NCT05183035).
    FUNDING: US National Institutes of Health (NIH), American Lebanese Syrian Associated Charities (ALSAC), AbbVie, Gateway for Cancer Research.
    DOI:  https://doi.org/10.1016/S2352-3026(26)00136-5
  6. Br J Haematol. 2026 Jul 09.
    Integrating novel therapeutic strategies in myeloproliferative neoplasms: Driving disease-directed progress.
    Trung Q Ngo, Maria Georgiou, Donal P McLornan, Claire N Harrison.
      Over the past decade, there has been a substantial increase in the diversity and number of therapeutic options for myeloproliferative neoplasms (MPNs). While many remain within the clinical trial arena, the clinician and patient community have seen more approvals reaching the clinic and a rethink on how best we should be approaching these disorders is required. In parallel, there needs to be a paradigm shift in end-point considerations within MPN clinical trial design, with a growing emphasis on longer term disease stability and modification, molecular responses, histomorphological modification, reductions in complications (e.g. thrombotic complications or disease transformation) and improved survival alongside the conventional goals such as haematological responses and symptom and spleen improvements where relevant. Given the heterogeneity of these disorders, with often marked intrapatient variability, greater consideration must be given to optimised sequencing strategies and rational combination approaches and, importantly, an emphasis on patient-specific trajectories. In this review, we appraise the contemporary therapeutic armamentarium across the MPN spectrum and explore how these advances may best facilitate increasing personalised approaches in an evolving and complex treatment landscape.
    Keywords:  JAK inhibitor; myeloproliferative neoplasm; novel therapy; transplantation
    DOI:  https://doi.org/10.1111/bjh.70672
  7. Sci Transl Med. 2026 Jul 08. 18(857): eadx3847
    Splicing-associated network PAK1-CLK1/4-SRRM1 is a vulnerability to overcome chemoresistance in human and mouse acute myeloid leukemia.
    Camille Vaganay, Frank Ling, Lois M Kelly, Juliette Charles, Paul-Arthur Meslin, Hélène Pasquer, Rathana Kim, Marie Passet, Matthieu Duchmann, Léa Pelissier-Menjaud, Séverine Lecourt, Angela H Su, Emmanuelle Latour, Christopher F Bassil, Gabriela Alexe, Gael Fortin, Duong Ho Nhat, Cécile Culeux, Carine Legrand, Sofiane Fodil, Tony Huynh, Khansa Saadallah, Azucena Ramos, Bérangère Lombard, Damarys Loew, Christopher D Delaney, Catherine Lonchamp, Morgane Fontaine, Kim Pacchiardi, Anja Kocijancic, Lisa Aziez, Nina Fenouille, Marie Sebert, Lionel Adès, Emmanuel Raffoux, Michael T Hemann, Emmanuelle Clappier, Lina Benajiba, Kimberly Stegmaier, Kris C Wood, Raphaël Itzykson, Antoine Forget, Camille Lobry, Alexandre Puissant.
      Chemotherapy resistance in acute myeloid leukemia (AML) remains a major clinical challenge. Integration of multiomic profiling and in vivo functional genomics revealed splicing dysregulation as a determinant of chemoresistance in AML. We uncovered a network involving the splicing regulator SRRM1 and the CLK1/4 and PAK1 kinase families as vulnerabilities in chemoresistant AML cells. Both kinase families are hyperactivated in chemoresistant cells, promoting SRRM1 phosphorylation and altering its scaffolding function. We also identified a relapse-associated PAK1 variant, c.1429G>T p.(Ala477→Ser), that confers chemotherapy resistance. Combined PAK1 and CLK1/4 inhibition recapitulated the splicing changes induced by SRRM1 loss, preferentially targeting chemoresistant AML and enhancing chemotherapy efficacy in cell lines, primary cells, and mouse models. Last, we pinpointed MAP2K5 as a critical downstream effector because missplicing of exons 17 and 18 of MAP2K5 upon SRRM1 depletion sensitized cells to chemotherapy. Our findings highlight a therapeutic strategy to overcome AML relapse by targeting splicing dysregulation.
    DOI:  https://doi.org/10.1126/scitranslmed.adx3847
  8. Haematologica. 2026 Jul 09.
    Genetic screening of triple negative thrombocytosis patients identifies germline MPL compound mutations and SH2B3/LNK truncating mutations.
    Bruno Cassinat, Louise Lecordier, Sarah Awan-Toor, Denis Clay, Diego Elrio, Emmanuelle Verger, Rafael Daltro De Oliveira, Helene Pasquer, Lina Benajiba, Nelly Bosselut, Ludovic Drouet, Juliette Soret, Thierry Leblanc, Luc Darnige, Lin-Pierre Zhao, Damien Luque Paz, Francoise Boyer, Eric Lippert, Louis Drevon, Stephane Giraudier, Jean-Jacques Kiladjian, Nabih Maslah, Laura Velazquez.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300850
  9. Blood Adv. 2026 Jul 10. pii: bloodadvances.2026020704. [Epub ahead of print]
    Germline landscape stratification defines distinct molecular and prognostic groups in therapy related myeloid neoplasms.
    Oriol Calvete, Julia Mestre, Lorea Chaparro-González, Lucía Ruiz Pérez-Hita, Alba Mesa Tudel, Blanca Xicoy, Lurdes Zamora, Isabel Granada, Mar Mallo, Emili Cid, Estefania Mancici, Claudia Lozano, Laura Palomo, Pamela Acha, Maria Julia Montoro, Koji Sasaki, Courtney D DiNardo, Guillermo Garcia-Manero, Guillermo Montalban-Bravo, Neus Torres Hernandez, Marta Santiago Balsera, José Cervera, Gonzalo Maortua, Raquel de Paz, Martí Mascaró, Alfonso Garcia Da Vila, Sara Garcia-Avila, Juan Jose Rodríguez-Sevilla, Leonor Arenillas, Beatriz Bellosillo, Rashmi Kanagal-Shamanna, Francesc Sole.
      Exposure to chemotherapy and/or radiotherapy increases the risk of therapy-related myeloid neoplasms (t-MN), a heterogeneous group of disorders currently classified by treatment history rather than molecular features. Although germline predisposition has been suggested in approximately 20% of cases, its prevalence and clinical impact remain insufficiently defined. To address this, we analyzed 100 patients with t-MN by integrating clinical characteristics, prior treatment regimens, and genomic profiling. Somatic and germline variants were identified using targeted next-generation sequencing (NGS; n = 33) or whole-exome sequencing (n = 67). Somatic abnormalities, including cytogenetic and/or molecular alterations, were detected in 89.8% of patients. Germline variants were identified in 32.3% of cases, including mutations in cancer predisposition genes (19.8%) and myeloid disease-related genes (14.6%). Patient stratification by germline landscape and gene category defined two prognostic scenarios and three subgroups with distinct clinical outcomes. Patients harboring germline cancer predisposition variants exhibited were enriched for TP53 mutations, complex karyotypes, and had an adverse prognosis. In contrast, patients with germline myeloid-related variants and those without detectable germline variants showed recurrent mutations in TET2, DNMT3A, SF3B1, SRSF2, RUNX1 and ASXL1, were associated with normal karyotypes, and favorable outcomes. These findings underscore the importance of the germline landscape in t-MN pathogenesis and support its incorporation into disease classification and risk stratification. Notably, chemotherapy exposure was associated with complex karyotypes and poor prognosis in patients with germline cancer predisposition variants, highlighting a subgroup that may benefit from targeted surveillance and preventive strategies.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020704
  10. Br J Haematol. 2026 Jul 11.
    Leukaemic stem cell burden enhances prognostic precision in the non-adverse European LeukemiaNet risk group of acute myeloid leukaemia.
    Aafreen Khan, Smeeta Gajendra, Sandeep Rai, Deepshi Thakral, Vivek Kumar Singh, Ashish Datt Upadhyay, Sameer Bakhshi, Rachna Seth, Ranjit Kumar Sahoo, Ritu Gupta.
      Leukaemic stem cells (LSCs) are chemo-resistant leukaemia-initiating clones that drive refractoriness and relapse in acute myeloid leukaemia (AML). The study evaluated the prognostic significance of LSC burden in treatment naïve AML patients. LSCs were quantified using Next-generation flow cytometry; patients were stratified into LSCneg/low and LSChigh groups based on the median LSC percentage, and correlated with post-induction morphological remission and measurable residual disease (MRD) status, and long-term outcomes including relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS). LSCs were detectable in 93.5% patients, with a median frequency of 0.386%. Patients with LSCneg/low (≤0.386%) had higher rates of complete remission (CR) (p = 0.05) and MRD negativity (p = 0.002). Lower LSC burden was associated with improved RFS, EFS and OS (all p < 0.05) suggesting the prognostic relevance of LSC quantitation in AML. In both Cluster of Differentiation 34 positve (CD34+) and CD34 negative (CD34-) AML, low LSC% was associated with superior survival outcomes (p < 0.05). LSC burden is a strong, independent predictor of response and survival in AML, and its integration with European LeukemiaNet risk-stratification and MRD assessment may enhance risk refinement and individualized therapy.
    Keywords:  ELN risk stratification; acute myeloid leukaemia; flow cytometry; leukaemic stem cells; survival outcomes
    DOI:  https://doi.org/10.1111/bjh.70679
  11. Br J Haematol. 2026 Jul 07.
    Advanced fibrosis, TP53 variants and acute/pure erythroid leukaemia: Diagnostic harbingers of ERCC6L2-related bone marrow failure syndrome?
    Sai Sudha Valisekka, Meghan E Lindstrom, Olivia J Michel, Roy L Kao.
      
    DOI:  https://doi.org/10.1111/bjh.70666
  12. Science. 2026 Jul 09. 393(6807): 188-194
    Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues.
    Samuel Ojeda, Meng Wang, Kheewoong Baek, Wallace Bourgeois, Alba Sommerschield, Hong Yue, Rebecca J Metivier, Panos Karagiannis, Talya S Levitz, Yuan Xiong, Katherine A Donovan, Scott A Armstrong, Eric S Fischer.
      Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending cereblon (CRBN)-based molecular glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo-electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of histone H3 lysine 9 acetylation (H3K9Ac), antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.
    DOI:  https://doi.org/10.1126/science.aef5391
  13. Nature. 2026 Jul 08.
    Chromatin landscape and epigenetic heterogeneity of acute myeloid leukaemia.
    Yotaro Ochi, Markus Liew-Littorin, Yasuhito Nannya, Sofia Bengtzen, Benedicte Piauger, Stefan Deneberg, Martin Jädersten, Vladimir Lazarevic, Jörg Cammenga, Anna Robelius, Lovisa Wennström, Emma Ölander, Senji Kasahara, Nobuhiro Hiramoto, Nobuhiro Kanemura, Nobuo Sezaki, Maki Sakurada, Makoto Iwasaki, Junya Kanda, Yasunori Ueda, Satoshi Yoshihara, Tom Erkers, Nona Struyf, Yu Watanabe, Masanori Motomura, Masahiro M Nakagawa, Ryunosuke Saiki, Hidehito Fukushima, Koji Okazaki, Suguru Morimoto, Akinori Yoda, Rurika Okuda, Shintaro Komatsu, Guoxiang Xie, Albin Österroos, Ayana Kon, Lanying Zhao, Yuichi Shiraishi, Takayuki Ishikawa, Satoru Miyano, Kotoe Katayama, Seiya Imoto, Shuichi Matsuda, Akifumi Takaori-Kondo, Hiroyuki Aburatani, Hiroshi I Suzuki, Olli Kallioniemi, Gunnar Juliusson, Martin Höglund, Sören Lehmann, Seishi Ogawa.
      Acute myeloid leukaemia (AML) is an aggressive blood cancer characterized by the unregulated proliferation of immature myeloblasts. Gene mutations have been shown to have a large effect on pathogenesis, inter-tumour heterogeneity and clinical outcomes in AML1-8; however, the role of epigenetic alterations in these respects has been investigated less extensively. Here we use ATAC-seq (assay for transposase-accessible chromatin with sequencing) in a cohort of 1,563 individuals with a recent diagnosis of AML (the 'eCHROMA' cohort) to show that AML can be classified into 16 subgroups on the basis of chromatin accessibility profiles. Multiomics analyses of gene mutations, the transcriptome, DNA methylation and histone marks show that these ATAC subgroups exhibit distinct driver mutations, differentiation states, gene expression, DNA methylation and super-enhancer profiles, and are also associated with clinical outcomes. These findings were validated in independent cohorts. Single-cell ATAC sequencing reveals that all leukaemic cells in each subgroup share a common chromatin accessibility profile, which suggests that subgroup-specific epigenomic fingerprints underlie the ATAC-based classification. Mechanistically, the subgroups have distinct gene-regulatory networks that are driven by the activities of key transcription factors in haematopoiesis, and in which subgroup-specific super-enhancers have a pivotal role. Multiomics single-cell analysis further reveals deregulated trajectories of differentiation coupled with chromatin accessibility and gene expression. Notably, ATAC subgroups have an independent prognostic effect, compared with genomic classification, and are associated with particular drug sensitivities. In summary, ATAC-based chromatin profiling, combined with multiomics data, provides insights into AML pathogenesis beyond genomics and constitutes a valuable resource for AML research.
    DOI:  https://doi.org/10.1038/s41586-026-10703-4
  14. Nature. 2026 Jul 08.
    Non-genotoxic transplantation and in vivo selection through epitope editing.
    Gabriele Casirati, Andrea Cosentino, Marta Freschi, Jing Zeng, Adele Mucci, Sébastien Levesque, Nola Neri, Enrico Drago, Viola Carzaniga, Francesco Romano, Varun Katta, Azusa Matsubara, Yichao Li, Mohammed S Mahmoud, Moisés Chávez-Navarro, Christian Brendel, John P Manis, Shengdar Tsai, Danilo Pellin, Daniel Bauer, Pietro Genovese.
      The short-term and long-term effects of genotoxic pre-transplant conditioning remain barriers to the broader application of haematopoietic stem/progenitor cell (HSPC) transplantation and gene therapies1-4. Although monoclonal antibodies targeting KIT have been proposed as alternatives to chemotherapy or radiotherapy5-7, their pharmacokinetics hinder clinical applications owing to the risk of depleting transplanted HSPCs. Here, to address this issue, we identified amino acid changes in the extracellular domain of KIT that disrupt the binding of two therapeutic monoclonal antibodies8,9, which impair stem cell factor (SCF)-mediated signalling without affecting KIT expression or functionality. We exploited adenine base editing10 or prime editing11 to efficiently introduce these mutations in HSPCs and combined them with the disruption of the BCL11A erythroid enhancer to promote expression of fetal haemoglobin (HbF)12,13, a therapeutic approach for several haemoglobinopathies. This strategy enables in vivo co-selection of gene-engineered cells to reach the threshold required to provide therapeutic benefit in patients affected by sickle cell disease and β-thalassaemia. We show progressive enrichment of KIT plus BCL11A multiplex-edited haematopoiesis under selective pressure with KIT monoclonal antibody, in vitro and in vivo. We report that extended treatment with anti-KIT regimens leads to superior in vivo enrichment while avoiding clonal selection, as assessed by a lentiviral barcoded library. Finally, by overcoming the limitations of monoclonal antibody pharmacokinetics, epitope editing enables novel haematopoietic replacement regimens that are not limited by on-target graft elimination, allowing prolonged immune-based conditioning that maximizes haematopoietic niche clearance without chemo-radiotherapy or monoclonal antibody wash-out.
    DOI:  https://doi.org/10.1038/s41586-026-10737-8
  15. Br J Haematol. 2026 Jul 05.
    Immortal time bias limits the conclusion that post-transplant hypomethylating agent maintenance improves outcomes in myelodysplastic syndromes.
    Naif I AlJohani.
      
    DOI:  https://doi.org/10.1111/bjh.70669
  16. Br J Haematol. 2026 Jul 07.
    Splenic radiotherapy before allogeneic transplantation for myelofibrosis.
    Gerard Gurumurthy, Gemma Barnard, Charles Crawley, Gail Horan, Thankamma Ajithkumar.
      
    Keywords:  haematopoietic stem cell transplantation; myelofibrosis; myeloproliferative disorders; splenic radiotherapy; splenomegaly
    DOI:  https://doi.org/10.1111/bjh.70673
  17. Hemasphere. 2026 Jul;10(7): e70428
    Inflammatory signatures in the spectrum of myeloid diseases.
    Alice Ibbotson, Simon Crouch, Jacqueline Ferrari, Thomas Young, Ann W Morgan, Anna Gallì, Sara Pozzi, Martina Sarchi, Virginia Camilotto, Martina Boldini, Chiara Elena, Luca Malcovati, Sinisa Savic.
      Dysregulated innate immunity contributes to clonal cytopenias and myeloid neoplasms, but its extent across disease stages and clinical relevance remain incompletely defined. We analyzed plasma ASC/NLRP3 double-positive (DP) specks, ASC single-positive (SP) specks, and 45 cytokines in 223 patients with idiopathic cytopenias of undetermined significance (ICUS)/clonal cytopenias of undetermined significance (CCUS), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) and 39 matched non-inflammatory controls using adjusted regression, survival modeling, and paired longitudinal analyses. Inflammasome activation and cytokine perturbations were evident across the disease spectrum. DP-ASC specks were elevated in MDS and CMML, whereas SP-ASC specks were increased across all groups, indicating activation of ASC-containing inflammasomes beyond NLRP3. Cytokines followed a graded ICUS → MDS → CMML pattern, with widespread upregulation of interleukins and chemokines (including IL-7, IL-8, IL-11/CXCL11, and CCL7) alongside suppression of stem and progenitor support factors such as CSF3, FLT3LG, TRAIL, and TWEAK. At baseline, elevated IL-15 and MMP1 predicted progression to acute myeloid Leukaemia, while higher IL-10, CXCL8, and IL-18 were associated with reduced survival; ASC specks were not independently prognostic. Longitudinal increases in selected cytokines distinguished progressors (area under the curve 0.82; 95% CI: 0.49-1.0). Cytokine patterns correlated with mutation categories, with the isolated SF3B1 mutation associated with higher DP-ASC specks. These findings define early and progressive inflammasome engagement and nominate dynamic cytokine panels and the inflammasome-IL-1 axis as actionable biomarkers and therapeutic targets.
    DOI:  https://doi.org/10.1002/hem3.70428
  18. Nat Commun. 2026 Jul 06.
    The H3K4 methyltransferase KMT2D is an essential cofactor for GATA1 at erythroid gene enhancers.
    Jianxiang Zhang, Ye Xin, Li Cheng, Yuan Xing, Yuxin Ouyang, Mengli Zhang, Yubin Chen, Ruopeng Feng, Xiaohui Qiu, Beisi Xu, Yong Cheng, Chunliang Li, Hans-Martin Herz, Mitchell J Weiss, Peng Xu.
      Gene expression during cellular differentiation is coordinated by combinatorial interactions between transcription factors (TFs) and cofactors. Although the TF GATA1 coordinates gene transcription in hematopoiesis, the specific cofactors required for GATA1-driven gene expression are incompletely defined. We identify the H3K4 methyltransferase KMT2D, as a cofactor of GATA1 in erythropoiesis. Loss of KMT2D in human erythroid precursors causes developmental arrest with impaired expression of numerous erythroid genes. Mechanistically, KMT2D colocalizes with GATA1 on more than one thousand erythroid enhancers, and such co-occupancy is associated with stronger transcriptional activity than occupancy by GATA1 alone. Acute depletion of KMT2D in erythroid precursors causes rapid reductions of H3K4me1 and H3K27ac on a subset of GATA1-bound enhancers and impairs their target gene expression. Moreover, acute depletion of GATA1 or KMT2D individually causes downregulation of overlapping gene sets. Our findings demonstrate how a lineage-specific TF cooperates with a ubiquitous epigenetic regulator to drive lineage-specific gene expression.
    DOI:  https://doi.org/10.1038/s41467-026-75253-9
  19. Blood Adv. 2026 Jul 08. pii: bloodadvances.2026020262. [Epub ahead of print]
    Outcomes of Germline Testing for Children with Hematologic Malignancies Undergoing Hematopoietic Cell Transplantation.
    Arti S Pandey, Roya Mostafavi, Emily Ashcraft, Chengzhou Wu, Dinesh Keerthi, Sara Lewis, Rose McGee, Alise Blake, LilyAnne M Grieve, Stacy Hines-Dowell, Lynn Harrison, Ninad Oak, Leslie Taylor, Melissa Perrino, Ali Y Suliman, Jamie L Maciaszek, Lu Wang, Cheng Cheng, Brandon M Triplett, Kim E Nichols.
      Recent studies reveal that a growing proportion of children with hematologic malignancies (HM) harbor germline pathogenic or likely pathogenic variants (hereafter "PV") in cancer predisposing genes (CPG). Identifying these children is critical as the information gained guides leukemia therapy, family testing, and selection of related donors for hematopoietic cell transplantation (HCT). Nevertheless, it remains unclear how often children with HM being considered for HCT undergo genetic evaluation, and whether germline data are used to guide clinical practice. To address this gap, we reviewed the records of 286 children who underwent >1 HCT for HM at our institution between Jan 1, 2017, and Dec. 31, 2023. We examined the timeline of genetic evaluation, prevalence of germline PV, and impact of PV on HCT outcomes. Overall, 227 (79%) children met with a genetic counselor prior to their first HCT, 192 underwent testing, and 142 had results returned before the HCT. Thirty-six patients (19%) harbored a germline CPG PV, among whom 12 (6%) had PV aligning with their HM diagnosis. One of five patients who received an HCT from a PV-positive relative developed donor-derived leukemia. We observed no significant differences in time to neutrophil engraftment, cumulative incidence of relapse, or overall survival between patients with and without PV, although the cohort was heterogeneous with respect to the underlying PV. Given the high prevalence of PV in children with HM, prompt referral to genetics is warranted to ensure timely counseling and germline testing to detect a hereditary predisposition and inform donor selection for HCT.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020262
  20. Haematologica. 2026 Jul 09.
    Characteristics of clonal cytopenia of undetermined significance in the presence of ZRSR2 mutations.
    Mahmoud Yacout, Bahga Katamesh, Yazan Jabban, Rong He, Patricia Greipp, Dragan Jevremovic, Alma Oskarsdottir, Cecilia Arana Yi, Yael Kusne, Nathan Punwani, James Foran, Talha Badar, Hemant Murthy, Aasiya Matin, Tariq Kewan, Mehrdad Hefazi Torghabeh, Antoine N Saliba, Abhishek Mangaonkar, Mithun Shah, Mark Litzow, Mrinal Patnaik, Hassan Alkhateeb, Aref Al-Kali.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2026.300806
  21. Blood. 2026 Jul 10. pii: blood.2026033155. [Epub ahead of print]
    Gut Microbiota Drives Aging-related Erythropoiesis Impairment via Phenylacetic Acid-induced Histone Phenylacetylation.
    Yifei Xie, Xiangrui Qiao, Hao Wu, Yiming Hua, Bolin Li, Ning Ding, Jinglong Pang, Mingmin Zhang, Wen Xi, Kai Deng, Yu Xu, Peining Liu, Xue Shi, Lele Cheng, Xiaozhen Zhuo, Ting Li, Zuyi Yuan, Yue Wu.
      Anemia, the most prevalent hematologic disorder in older adults, imposes a significant burden of cardiovascular events, cognitive decline, and mortality. However, the mechanisms underlying aging-related anemia, especially epigenetic dysregulation in hematopoietic stem and progenitor cells (HSPCs), remain incompletely understood. Although the gut microbiota is critical for hematopoiesis, its specific contribution to aging-related erythropoiesis impairment remains unclear. Here, we reveal that aging markedly activates phenylalanine metabolism and elevates plasma phenylacetic acid (PAA) levels in both humans and mice. We identify Odoribacter splanchnicus (O.splanchnicus) as a key gut symbiont whose abundance is significantly increased in aged mice and which directly drives PAA production from phenylalanine via the oxoacid:ferredoxin oxidoreductase (OFOR) superfamily encoded by porA,nifJ, and iorA/iorB. Rifaximin treatment selectively reduces O.splanchnicus and plasma PAA, thereby alleviating aging-related anemia. Mechanistically, PAA promotes a novel post-translational modification (PTMs) termed histone lysine phenylacetylation (Kpa) through the acetyltransferases HBO1. Elevated histone Kpa increases chromatin accessibility at the GATA2 promoter, disrupts the GATA switch, and blocks erythroid differentiation of HSPCs. In vivo, supplementation with sodium phenylacetate (NaPA) exacerbates anemia in microbiota-depleted mice, whereas the HBO1 inhibitor WM-3835 restores erythropoiesis by reversing histone Kpa and normalizing the GATA switch. Furthermore, dietary phenylalanine restriction lowers circulating PAA and effectively ameliorates aging-related anemia in both naturally aged mice and O.splanchnicus-colonized mice. These findings provide the first evidence that gut microbiota-derived PAA plays a critical role in the development of aging-related erythropoiesis impairment and offer multiple translatable strategies for treating this condition.
    DOI:  https://doi.org/10.1182/blood.2026033155
  22. Nat Commun. 2026 Jul 10.
    Intracellular iron homeostasis-regulated epigenetic reprogramming contributes to -7/del(7q) leukemia.
    Jianan Zheng, Yiman Peng, Xintong Deng, Lanxin Zhang, Zhongwang Wang, Xuelan Chen, He Li, Yanxin Li, Qi Zhang, Liuxian Zheng, Ziyi Qi, Lan Wang, Min Lu, Wenguo Cui, Li Wang, Yu Wu, Weili Zhao, Ting Niu, Chong Chen, Yu Liu.
      Chromosome copy number variations are poorly understood drivers of human malignancies. -7/del(7q) is common in acute myeloid leukemia, confers a poor prognosis, and is thought to harbor several tumor suppressors. Previously, we identified the histone methyltransferase KMT2C as a tumor suppressor in this region. Here, through a differentiation CRISPR screen in hematopoietic stem and progenitor cells, we find that the mitochondrial iron transporter ABCB8 is essential for their differentiation. ABCB8 deficiency accelerates leukemogenesis in vivo and disrupts iron homeostasis, reducing cytoplasmic iron availability and impairing iron-dependent enzymes, including the histone demethylase KDM6A. Consequently, ABCB8 loss elevates H3K27me3 levels, repressing differentiation genes in an iron- and KDM6A-dependent manner. Notably, ABCB8 and KMT2C, neighboring genes on 7q, cooperatively regulate H3K27me3 to suppress leukemogenesis. Our findings reveal ABCB8 as a tumor suppressor in -7/del(7q) acute myeloid leukemia and uncover an epigenetic collaboration between neighboring tumor suppressors, driven by iron-mediated chromatin remodeling.
    DOI:  https://doi.org/10.1038/s41467-026-75292-2
  23. J Natl Compr Canc Netw. 2026 Jul;pii: e260034. [Epub ahead of print]24(7):
    NCCN Guidelines® Insights: Myeloproliferative Neoplasms, Version 2.2026.
    Aaron T Gerds, Jason Gotlib, Peter Abdelmessieh, Haris Ali, Mariana Castells, Brian J Chernak, Manuel R Espinoza-Gutarra, Ruth Fein Revell, Steven Green, Krishna Gundabolu, Elizabeth Hexner, Tania Jain, Catriona H Jamieson, Irum Khan, Andrew T Kuykendall, Yazan F Madanat, Lucia Masarova, Brandon McMahon, Sanjay R Mohan, Kalyan V Nadiminti, Stephen Oh, Jeanne Palmer, Ami B Patel, Anand A Patel, Nikolai Podoltsev, Lindsay Rein, Rachel Salit, Mary Sehl, Moshe Talpaz, Martha Wadleigh, Sarah A Wall, Mary Anne Bergman, Cindy Hochstetler.
      The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are a group of heterogenous hematologic malignancies characterized by the proliferation of blood cells and consist of myelofibrosis, polycythemia vera, and essential thrombocythemia. The NCCN Guidelines for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the aim of providing recommendations for the comprehensive care of adults with these diseases. The panel of experts convenes at least once a year to discuss requested changes to the Guidelines and to evaluate emerging data. These Guideline Insights focus on some of the recent updates for myelofibrosis.
    DOI:  https://doi.org/10.6004/jnccn.2026.0034
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