bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–06–07
27 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Ziftomenib with venetoclax and azacitidine in relapsed/refractory NPM1-mutated acute myeloid leukemia.
  2. ELN-DAVID Recommendations for NGS-based FLT3-ITD MRD Testing in Patients with Acute Myeloid Leukemia.
  3. Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.
  4. Therapeutic Targeting of IL-17A-Driven PTGS2/NLRP3 Inflammasome Activation in Juvenile Myelomonocytic Leukemia.
  5. Niche-level immune evasion in TP53 mutant AML residual disease revealed by spatial proteomics.
  6. Donor cell-derived haematological neoplasms after allogeneic haematopoietic cell transplantation: recommendations from the EBMT Practice Harmonisation and Guidelines Committee.
  7. Dynamic genetic and nongenetic RAS pathway activation drives resistance to FLT3 and BCL2 inhibitor therapy.
  8. CMML is in the eye of the be-WHO-lder: interrogating the newly proposed entity of oligomonocytic CMML: MDS or CMML?
  9. Selinexor Plus Ruxolitinib in JAK Inhibitor-Naïve Myelofibrosis: Phase 3 SENTRY Trial.
  10. The KDM-family inhibitor JIB-04 sensitizes AML cells to venetoclax by inducing a ferroptosis-like phenotype.
  11. Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.
  12. Targeting the METTL1/m⁷G axis as a therapeutic strategy in myeloid leukemia.
  13. All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia.
  14. HMA+VEN triplet regimens for the initial treatment of AML in adults (PRO).
  15. Inhibition of MLLT1 limits growth of KMT2A::AFF1 leukaemias without killing healthy haematopoietic stem cells.
  16. p97 Inhibition Synergistically Enhances Hypomethylating Therapy Through Targeting of PLK1 in Acute Myeloid Leukemia.
  17. Outcomes of allogeneic hematopoietic stem cell transplantation in patients with blast phase myelofibrosis: molecular signature and intensive chemotherapy matter.
  18. Hematologic Responses Achieved with Luspatercept in Higher-Risk Myelodysplastic Syndromes.
  19. Selection of human hematopoietic stem cells bearing the intended functional edit by transient AND-gate reporters.
  20. TP53 deficiency in AML induces resistance to T-cell engagers through an immunosuppressive secretome.
  21. Type I interferon-activated NK cells control polycythemia vera in vivo.
  22. HLA matching in contemporary haematopoietic cell transplantation: Recommendations from the EBMT Practice Harmonisation and Guidelines Committee.
  23. AKT inhibitor capivasertib reverses EVI1-driven resistance to venetoclax in acute myeloid leukaemia.
  24. Association of hypomethylating agents + venetoclax in the real-life treatment of Myeloproliferative Neoplasms in blastic phase.
  25. Cell autonomous inflammation in VEXAS is mediated by cGAS-STING.
  26. High-avidity cathepsin-G-specific CAR-T cells for the treatment of acute myeloid leukemia.
  27. Stage-Specific Degradation of Cyclin D3 Orchestrates Myelopoiesis and Restrains Myeloproliferative Neoplasms Development.
  1. Blood. 2026 Jun 02. pii: blood.2026034043. [Epub ahead of print]
    Ziftomenib with venetoclax and azacitidine in relapsed/refractory NPM1-mutated acute myeloid leukemia.
    Eunice S Wang, Harry P Erba, Amer M Zeidan, Gail J Roboz, Jessica K Altman, Anjali S Advani, Tara L Lin, Stephen A Strickland, Mark B Juckett, Keith W Pratz, James K Mangan, Christine M McMahon, Leonard Clarkson Alsfeld, Suresh Kumar Balasubramanian, Guru Subramanian Guru Murthy, Marcello Rotta, Neil Palmisiano, James McCloskey, Antoine N Saliba, Mohamad Khawandanah, Yazan F Madanat, Kiran Naqvi, Ayman H Qasrawi, Gary J Schiller, Talha Badar, Ivana Gojo, George Yaghmour, Diaa Osman, Hongling Zhang, Ying Tian, Harris S Soifer, Marcie Riches, Daniel Corum, Mollie Leoni, Amir T Fathi, Ghayas C Issa.
      Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (<0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.
    DOI:  https://doi.org/10.1182/blood.2026034043
  2. Blood. 2026 Jun 03. pii: blood.2026033569. [Epub ahead of print]
    ELN-DAVID Recommendations for NGS-based FLT3-ITD MRD Testing in Patients with Acute Myeloid Leukemia.
    Christopher S Hourigan, Lisanne Beugelink, Jad Othman, Gege Gui, Adam Ivey, Richard James Dillon, Christian Thiede, Mark J Levis, Laura W Dillon, Andrew H Wei, Ing Soo Tiong, Sun Loo, Konstanze Döhner, Isabell Arnhardt, Artur Kowalik, Nicola Potter, Dennis Dong Hwan Kim, Claude Preudhomme, Nicolas Duployez, Michael Heuser, Peter Jm Valk.
      FLT3-ITD measurable residual disease (MRD) testing for patients in remission from acute myeloid leukemia (AML) is now recommended by the recently updated clinical standard of care guidelines. This companion technical note provides important laboratory and clinical recommendations regarding such testing.
    DOI:  https://doi.org/10.1182/blood.2026033569
  3. Leukemia. 2026 Jun 02.
    Sphingosine-1-phosphate receptor modulators resensitize FLT3-ITD acute myeloid leukemia cells with NRAS mutations to FLT3 inhibitors.
    Aditi Chatterjee, Moaath K Mustafa Ali, Christopher M Bailey, Yuchen Liu, Donald Small, Catherine C Smith, Elie Traer, Yin Wang, Giovannino Silvestri, Maria R Baer.
      FLT3 inhibitor efficacy in AML with FLT3-ITD is short-lived, frequently due to new mutations, most commonly in NRAS. Sphingosine kinase 1 (SPHK1), which phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), is upregulated and localized to the plasma membrane in RAS-mutated cells. We studied S1P and FLT3 co-targeting to overcome FLT3 inhibitor resistance in NRAS-mutated FLT3-ITD AML cells. NRAS-mutated FLT3-ITD AML cell lines and patient blasts were treated with FLT3 inhibitors and/or S1P receptor (S1PR) modulators. FLT3 inhibitor sensitivity was assessed by immunoblotting, cytotoxicity, apoptosis and colony formation. Co-treatment was also assessed in vivo in an orthotopic mouse model. Downstream RAS and SPHK1 effectors were measured by immunoblotting and qRT-PCR. The S1PR modulators fingolimod (FTY720) and mocravimod (KRP-203) resensitized FLT3-ITD-expressing MOLM-14 and MV4-11 human AML cells with G12D, G12S, Q61K or Q61H, but not G12C, and patient blasts with G13D, G13V or G12D NRAS mutations to FLT3 inhibitors. Moreover, FTY720 co-treatment resensitized G12D NRAS-mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70 S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS-mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy.
    DOI:  https://doi.org/10.1038/s41375-026-02982-7
  4. Blood. 2026 Jun 02. pii: blood.2025032588. [Epub ahead of print]
    Therapeutic Targeting of IL-17A-Driven PTGS2/NLRP3 Inflammasome Activation in Juvenile Myelomonocytic Leukemia.
    Santhosh Kumar Pasupuleti, Baskar Ramdas, Kanaka Sai Ram Padam, Rahul Kanumuri, Lakshmi Reddy Palam, Ramesh Kumar, Tzu-Chieh Ho, Alex G Lee, Wade Clapp, Cheng-Kui Qu, Elliot Stieglitz, Kai Yang, Reuben Kapur.
      Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myelodysplastic syndrome or myeloproliferative disorder for which hematopoietic stem cell transplantation remains the only curative option; however, outcomes are particularly poor in patients harboring PTPN11 (encodes SHP2 phosphatase) mutations. Using a Shp2E76K/+ JMML mouse model, we identify a pathogenic IL-17A/PTGS2/NLRP3 signaling axis that drives bone marrow inflammation, suppresses antitumor immunity, and promotes leukemic progression. Shp2E76K/+ mice exhibited profound immune dysregulation, characterized by expansion of regulatory T cells (Tregs), increased T-cell exhaustion, and impaired cytotoxic function with reduced CD4⁺ and CD8⁺ T-cell frequencies. Mechanistically, mutant macrophages upregulated IL-17A, triggering NLRP3 inflammasome activation, PTGS2 induction, caspase-1 cleavage, and IL-1β maturation, thereby amplifying inflammatory signaling within the marrow niche. Therapeutically, IL-17A neutralization suppressed inflammasome activity, while combined inhibition of NLRP3 and PTGS2 restored cytotoxic T-cell function, reduced systemic and marrow inflammation, reversed myeloproliferation, and significantly prolonged survival in Shp2E76K/+ mice. Importantly, ex vivo treatment of primary JMML patient samples with dual NLRP3/PTGS2 inhibition combined with MEK blockade significantly reduced leukemic progenitor colony formation, supporting translational relevance. In patient-derived xenograft models of PTPN11-mutant JMML, dual NLRP3/PTGS2 inhibition combined with MEK blockade most effectively reduced leukemic burden, decreased human CD45⁺ engraftment, and depleted leukemic CD34⁺CD38⁺ progenitors and GMPs while restoring MEP populations, resulting in significantly improved overall survival. Together, these findings establish IL-17A/PTGS2/NLRP3 signaling as a central driver of immune suppression and myeloid expansion in PTPN11-mutant JMML and highlight combinatorial anti-inflammatory targeting as a promising therapeutic strategy for this high-risk disease.
    DOI:  https://doi.org/10.1182/blood.2025032588
  5. bioRxiv. 2026 May 19. pii: 2026.05.15.725421. [Epub ahead of print]
    Niche-level immune evasion in TP53 mutant AML residual disease revealed by spatial proteomics.
    Hideaki Mizuno, Yuki Nishida, Andrea Bedoy, Edward Ayoub, Yoonkyu Lee, Akshay Basi, Koji Sasaki, Guillermo Garcia-Manero, Jared Burks, Rashmi Kanagal-Shamanna, Michael Andreeff.
      Measurable (or minimal) residual disease (MRD) predicts relapse in patients with acute myeloid leukemia (AML). However, the biological and spatial characteristics of the AML bone marrow (BM) microenvironment (BMME) in which MRD cells survive remain largely unexplored; in particular, little is known of the BMME in TP53 mutant ( TP53 mut ) AML. Here, we applied sequential immunofluorescence to whole BM biopsy specimens obtained from patients with TP53 wild-type ( TP53 WT ) AML and TP53 mut AML at diagnosis and in morphological complete remission (CR) to generate a comprehensive spatial map of the hematopoietic and BMME components. We identified TP53 mut leukemia cells based on high p53 expression and delineated their spatial organization relative to stromal and immune niches. Biopsy-based cell composition analysis revealed marked B-cell depletion and an increased abundance of regulatory T-cells (Tregs) in TP53 mut BM at CR. Unlike TP53 WT BM, TP53 mut BM at CR exhibited persistent TP53 mut erythroid and immature leukemia cell clusters, spatially segregated from T-cell clusters, in perisinusoidal niches, suggesting niche-level immune evasion. Spatial profiling further revealed that Tregs characterized by FOXP3 upregulation were enriched near TP53 mut MRD cells, indicating a locally enhanced immunosuppressive activity. Single-cell RNA sequencing-based cell-cell communication analysis identified erythroid-T-cell interactions mediated by the GDF15-CD48 axis as a potential mechanism of T-cell suppression, suggesting that the erythroid differentiation of TP53 mut AML cells enhances local immunosuppression. Collectively, our results show a spatially organized immunosuppressive BMME in TP53 mut AML and highlight the potential of spatial proteomics to identify actionable MRD niches in leukemias.
    Key points: TP53 mutant erythroid and immature leukemia cells form spatial clusters segregated from T-cells in complete remission. An erythroblast-centered immunosuppressive niche characterizes TP53 mutant leukemia cells.
    DOI:  https://doi.org/10.64898/2026.05.15.725421
  6. Lancet Haematol. 2026 Jun;pii: S2352-3026(26)00046-3. [Epub ahead of print]13(6): e408-e417
    Donor cell-derived haematological neoplasms after allogeneic haematopoietic cell transplantation: recommendations from the EBMT Practice Harmonisation and Guidelines Committee.
    Carmelo Gurnari, Chris Armstrong, Giorgia Battipaglia, Gonzalo Bentolila, Eolia Brissot, Yves Chalandon, Fernando Barroso Duarte, Joanna Drozd-Sokolowska, Vanueza Funke, Nico Gagelmann, Thierry Guillaume, Robert Hasserjian, Juan Carlos Hernández-Boluda, Devendra Hiwase, Andrés Jerez, Michael Loschi, Marin Medjugorac, Mufaddal T Moonim, Nicola Polverelli, Micaela Quarchioni, Christof Scheid, Katja Sockel, Daniel H Wiseman, Francesco Onida, Kavita Raj, Annalisa Ruggeri, Isabel Sánchez-Ortega, Natalia Aranguiz Garcia, Mario Cazzola, Fabio Ciceri, Tomasz Czerw, Jaroslaw P Maciejewski, Simona Pagliuca, Lisa Pleyer, Patryk Sobieralski, Jurjen Versluis, Maria Teresa Voso, Donal P McLornan, Ibrahim Yakoub-Agha, Marie Robin.
      Donor cell-derived haematological neoplasms (DDHN) are rare disorders and currently do not have standardised diagnostic criteria and therapeutic management. International experts in allogeneic transplantation and haematological malignancies from Europe, the Americas, and Australia worked together on behalf of the EBMT Practice Harmonisation and Guidelines Committee to delineate a pragmatic diagnostic framework and issue guidance for downstream clinical management for DDHN. The team met on Sept 18-19, 2025, in Berlin, Germany, to discuss the definition, molecular insights, treatments, and donor outcomes for DDHN after an intensive review of the literature. In this Review, we present the epidemiology and clinical definitions of DDHN, provide guidance on diagnosis and prevention, address therapeutic considerations, and outline recommendations for donor management.
    DOI:  https://doi.org/10.1016/S2352-3026(26)00046-3
  7. Blood. 2026 Jun 01. pii: blood.2025032466. [Epub ahead of print]
    Dynamic genetic and nongenetic RAS pathway activation drives resistance to FLT3 and BCL2 inhibitor therapy.
    Vanessa E Kennedy, Cheryl A C Peretz, Anushka Walia, Brenda Chyla, Yan Sun, Jason E Hill, Elaine Tran, Andrew D Koh, Timothy T Ferng, Samantha Pintar, Matthew Jones, Bogdan Popescu, Isabelle Lomeli, Farid Chehab, Natalia Murad, August John, Ritu Parna Roy, Adam B Olshen, Christine A Berryhill, Christopher Davis, Steven Patrick Angus, Jose M Rivera, Alicia Meshulam, Elliot Stieglitz, Sunil Kumar Joshi, Elie Traer, Monique Dail, Habib Hamidi, Jessica K Altman, Naval G Daver, Mark J Levis, James McCloskey, Alexander E Perl, Catherine C Smith.
      Bulk sequencing of relapsed tumors reveals mutations associated with resistance to cancer therapy but is insufficient to fully assess all causes of relapse. Due to inherent tumor heterogeneity, on-treatment tumor evolution may select for genetically distinct clones or shifts in malignant transcriptional states not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of a clinical trial cohort of acute myeloid leukemia (AML) patients treated on the Phase 1b clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Gilt) to characterize immunophenotypic, transcriptional, and genetic clonal evolution driving resistance. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, resistance was associated with RAS activation via multiple mechanisms including selection for RAS mutant clones, non-mutational upregulation of RAS transcriptional programs and a shift to RAS-associated monocytic AML differentiation. In an in vitro model of monocytic differentiation associated with non-mutational RAS transcriptional activation, we demonstrated that RAS pathway inhibition re-sensitized to Ven/Gilt. These data illustrate that convergent resistance pathways in patients can be activated via diverse genetic and non-genetic mechanisms. These results underscore that RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to AML monocytic differentiation and highlight RAS pathway inhibition as a viable clinical strategy to combat resistance. CT# NCT03625505.
    DOI:  https://doi.org/10.1182/blood.2025032466
  8. Blood Neoplasia. 2026 Aug;3(3): 100224
    CMML is in the eye of the be-WHO-lder: interrogating the newly proposed entity of oligomonocytic CMML: MDS or CMML?
    Rami S Komrokji, Zena Komrokji, Najla H Al Ali, Zhuoer Xie, Onyee Chan, Andrew T Kuykendall, Alison R Walker, Seongseok Yun, Sam B Reynolds, Rory Shallis, Jeffrey E Lancet, David A Sallman, Eric Padron.
      The World Health Organization and international consensus 2022 classifications have proposed lowering the absolute monocyte count threshold to ≥ 0.5 × 109/L for the diagnosis of chronic myelomonocytic leukemia (CMML). This was based on reports describing patients with oligomonocytic CMML (O-CMML) (0.5 × 109/L to 1.0 × 109/L) as a CMML variant. We identified patients among the myelodysplastic syndrome (MDS) database with O-CMML who meet the new criteria for CMML and compared them to MDS and CMML (≥1.0 × 109/L). Among 1861 patients with MDS, 468 (25%) were O-CMML meeting new CMML criteria. The genomic landscape of O-CMML was more comparable to MDS. Classical CMML somatic mutations (TET-2, ASXL-1 and SRSF2) frequencies were closer to MDS. Proliferative CMML (P-CMML) mutations were less common. DNMT3A and TP53 mutations were more commonly observed in MDS and O-CMML compared to CMML. SF3B1 SM was observed in 29% of O-CMML compared to 16% in MDS, 8% dysplastic CMML (D-CMML) and 5% P-CMML (P < .005). Thirteen patients (2.8%) progressed from O-CMML to CMML. The rate of acute myeloid leukemia transformation was less than MDS and P-CMML. The hazard ratio for overall survival was 1.2 (95% confidence interval [CI], 1.03-1.4; P = .018) for O-CMML, 1.3 (95% CI, 1.07-1.58; P = .008) for D-CMML and 1.87 for P-CMML (95% CI, 1.57-2.4; P = .005) compared to MDS after adjusting for molecular international prognostic scoring system. Although O-CMML may be a unique entity, the current classification does not enrich CMML-like variants by all clinical measures. A comprehensive analysis of clinical, molecular and immunophenotype is needed for better classification.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100224
  9. J Clin Oncol. 2026 Jun 02. 101200JCO2601080
    Selinexor Plus Ruxolitinib in JAK Inhibitor-Naïve Myelofibrosis: Phase 3 SENTRY Trial.
    SENTRY Trial Investigators
       PURPOSE: Ruxolitinib improves splenomegaly and symptoms in myelofibrosis but lacks reliable clonal burden reduction. Selinexor, an oral inhibitor of exportin 1, has demonstrated activity in myelofibrosis. We evaluated selinexor plus ruxolitinib versus ruxolitinib alone in JAK inhibitor-naïve myelofibrosis.
    PATIENTS AND METHODS: In this double-blind, phase 3 trial, patients were randomized (2:1) to receive selinexor plus ruxolitinib or placebo plus ruxolitinib. Co-primary endpoints were spleen volume reduction ≥35% (SVR35) and absolute mean change in total symptom score (AbsTSS; excluding fatigue) from baseline to Week 24.
    RESULTS: 353 patients were randomized. At Week 24, SVR35 was achieved in 49.8% of the selinexor plus ruxolitinib group versus 28.0% of the placebo plus ruxolitinib group (difference, 21.8 percentage points; odds ratio, 2.58; 95% CI, 1.60 to 4.17; P<0.0001). Differences were evident by Week 12 and through Week 36. The AbsTSS co-primary endpoint was not met; however, symptom scores improved from baseline in both groups (-9.9 selinexor plus ruxolitinib, -10.9 placebo plus ruxolitinib), with no significant between-group difference.At median follow-up of ∼12 months, the overall survival (OS) hazard ratio was 0.43 (95% CI, 0.19 to 1.00; nominal P=0.022).Grade ≥3 adverse events occurred in 70.1% and 50.0% of patients in the selinexor plus ruxolitinib or placebo plus ruxolitinib groups, respectively, most commonly anemia, thrombocytopenia, and neutropenia. Nausea was more frequent with selinexor but predominantly low-grade and early.
    CONCLUSIONS: In patients with JAK inhibitor-naïve myelofibrosis, selinexor plus ruxolitinib met its co-primary endpoint of improved SVR35 but did not meet the AbsTSS co-primary endpoint, compared with placebo plus ruxolitinib. An early OS difference was observed. The safety profile was consistent with known adverse event profiles of the individual agents.
    TRIAL REGISTRATION NUMBER: ClinicalTrials.Gov: NCT04562389; EudraCT: 2020-003883-19.
    Keywords:  Antineoplastic Combined Chemotherapy Protocols; Myelofibrosis; Ruxolitinib; Selinexor; Spleen
    DOI:  https://doi.org/10.1200/JCO-26-01080
  10. Blood Neoplasia. 2026 Aug;3(3): 100236
    The KDM-family inhibitor JIB-04 sensitizes AML cells to venetoclax by inducing a ferroptosis-like phenotype.
    Katharina Wohlan, Dandan Fan, Anna G Guzman, Alexis Quezada, Hyunji Park, Elmira Khabusheva, Farzane Sivandzade, Matthew Wither, Amber Alcorn, Tamara Thevarajah, Steven M Kornblau, Courtney D DiNardo, Jianzhong Su, Margaret A Goodell, Rachel E Rau.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy with various molecular and cytogenetic subtypes. Treatment options for older adult patients are limited due to high toxicity of conventional chemotherapy. The B-cell leukemia/lymphoma 2 inhibitor venetoclax is effective in combination with hypomethylating agents or low-dose cytarabine, but ∼30% of patients do not respond to the initial combination treatment. Thus, alternative combinations are needed to sensitize AML cells to venetoclax and overcome resistance mechanisms. Here, we report that targeting histone lysine-specific demethylases induces a ferroptosis-like phenotype driven by oxidative stress in various AML subtypes. In both patient samples and cell lines, JIB-04 increases the level of reactive oxygen species, ferrous iron, and lipid peroxidation, all signs of ferroptosis. The combination of JIB-04 and venetoclax proved to be highly synergistic. Blocking the JIB-04-induced phenotype by using the antioxidant N-acetyl-l-cysteine reverses the synergistic killing. At the molecular level, the ferroptosis inducers HMOX1, SAT1, and PTGS2 were found to be upregulated by JIB-04. Collectively, these findings identify JIB-04 as a potential new ferroptosis inducer in AML and highlight the potential of oxidative stress induction as a valuable strategy in combination with venetoclax to treat AML.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100236
  11. Nat Commun. 2026 May 30.
    Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.
    Geethu Emily Thomas, Veronique Voisin, Kazem Nouri, Rose Hurren, Karen Kai-Lin Fang, Ali Chegini, Marcela Gronda, Yongran Yan, Neil MacLean, Yulia Jitkova, Dakai Ling, Mary Ma, Xiao Ming Wang, Andrea Arruda, Vito Spadavecchio, Mark D Minden, Li Zhang, Jong Bok Lee, Aaron D Schimmer.
      Eukaryotic cells have separate genomes in the nucleus and mitochondria. Mitochondrial DNA is transcribed bi-directionally to generate mitochondrial RNA (mtRNA) and dsRNA as a by-product of this transcription. We demonstrate that mtRNA transcription and degradation are increased in AML (Acute Myeloid Leukemia) cells and stem cells resulting in higher rates of mtRNA turnover. We discover that the mitochondrial degradosome, SUV3 and PNPase, is upregulated in AML cells and stem cells and functionally important for degradation of mtRNA and mitochondrial dsRNA (double stranded RNA) in AML. Depleting SUV3 or PNPase impairs mtRNA degradation and promotes the accumulation of dsRNA. dsRNA that accumulates after depleting SUV3 or PNPase, stimulates IFN-I signaling that induces AML differentiation, decreases stemness and increases sensitivity to immune-mediating cytotoxicity. Thus, this work highlights mitochondrial RNA regulation in AML and identifies a mechanism by which mtRNA turnover influences AML differentiation, stem cell function, and immune sensitization.
    DOI:  https://doi.org/10.1038/s41467-026-73558-3
  12. Blood. 2026 Mar 12. pii: blood.2025030336. [Epub ahead of print]
    Targeting the METTL1/m⁷G axis as a therapeutic strategy in myeloid leukemia.
    Lili Ren, Honghai Zhang, Olga Bobileva, Francesco Nai, Hongjie Bi, Anthony Chan, Genevieve E Baker, Lei Dong, David Guarin, Weidong Hu, Wei Li, Irena Leite, Xueer Wang, Xiaoxu Zhang, Meilin Xue, Haixia Wang, Hanjun Qin, Xiwei Wu, Lucy Y Ghoda, Lin Xu, Bin Zhang, Ling Li, Mark Wunderlich, James C Mulloy, Courtney L Jones, Seán E O'Leary, Hongzhi Li, Steven T Rosen, Chun-Wei David Chen, Nora Heisterkamp, J Jefferson P Perry, Yunsun Nam, Jianjun Chen, Amedeo Caflisch, Xiaobo Li, Rui Su.
      N7-methylguanosine (m7G), a prevalent modification in tRNAs, is primarily catalyzed by the methyltransferase METTL1. While growing evidence supports a role for METTL1 in various tumors, its therapeutic potential and precise function in leukemia stem cell (LSC) homeostasis remain largely unexplored. Here, we identify METTL1 as a key regulator of LSC self-renewal and homing within bone marrow (BM) microenvironment through catalyzing m7G formation on a specific tRNA, tRNAPheGAA, thereby driving leukemogenesis. Mechanistically, METTL1 loss significantly reduces m7G abundance and steady-state levels of tRNAPheGAA, leading to translation suppression and degradation of transcripts enriched with tRNAPheGAA-related codons, such as tyrosine-protein kinase HCK. Decreased HCK expression disrupts CXCR4 signaling, impairing LSC self-renewal and BM homing. Therapeutically, we characterize a small-molecule METTL1 inhibitor (M1i; NSC137443), through high throughput screening. Pharmacological inhibition of METTL1 demonstrates potent anti-tumor efficacy by reduction of tRNA m7G levels and disrupting the tRNAPheGAA/HCK/CXCR4 cascade. Notably, targeting METTL1 significantly reduces LSC frequency, delays leukemogenesis, and prolongs survival in multiple acute myeloid leukemia models. Our findings establish a previously unrecognized role for METTL1 and its target tRNAPheGAA in LSC homeostasis and provide compelling proof-of-concept evidence that METTL1 is a druggable epitranscriptomic target for anti-leukemia therapy.
    DOI:  https://doi.org/10.1182/blood.2025030336
  13. N Engl J Med. 2026 Jun 04. 394(21): 2107-2116
    All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia.
    Gail J Roboz, Amer M Zeidan, Gabriel N Mannis, Pau Montesinos, Montserrat Arnan, Michael R Savona, Olatoyosi Odenike, James K McCloskey, Harshad V Amin, Amir T Fathi, Teresa Bernal Del Castillo, Gabriela Rodríguez-Macías, Jane L Liesveld, Annie P Im, Jan Cerny, Teresa C Gentile, Aram Oganesian, Danna Chan, Yubing Wan, Margit Dijkstra, Harold N Keer, Elizabeth A Griffiths, Courtney D DiNardo.
       BACKGROUND: For patients with acute myeloid leukemia (AML) who are 75 years of age or older or who are ineligible for intensive induction chemotherapy, azacitidine or decitabine plus venetoclax is the standard of care, but parenteral administration imposes a burden on patients and providers. Oral decitabine-cedazuridine, approved in Europe for AML, has pharmacokinetic properties equivalent to those of intravenous decitabine but provides limited survival benefit as monotherapy.
    METHODS: In this phase 1-2, open-label, multicenter, nonrandomized trial, we assigned patients with newly diagnosed AML who were 75 years of age or older or who were ineligible for intensive chemotherapy to receive oral decitabine-cedazuridine plus oral venetoclax. To mitigate myelosuppression observed in phase 1, schedule adjustments were encouraged in phase 2b after bone marrow blast clearance. The primary end points were the venetoclax area under the curve from 0 to 24 hours and maximum observed concentration with or without decitabine-cedazuridine (measures of drug interaction) on days 5 and 15 of cycle 2 (phase 1-2a) and complete response (phase 2a-b).
    RESULTS: A total of 189 patients were enrolled (30 patients in phase 1, 58 patients in phase 2a, and 101 patients in phase 2b). No drug-drug interactions were observed between decitabine-cedazuridine and venetoclax. In the pivotal phase 2b, the percentage of patients with a complete response was 47% (95% confidence interval [CI], 36 to 57), the percentage with a complete response or complete response with incomplete hematologic recovery was 63% (95% CI, 53 to 73), and median overall survival was 15.5 months (95% CI, 7.6 to could not be estimated). Common adverse events of grade 3 or higher in phase 2b were anemia (in 30% of the patients), neutropenia (in 26%), and febrile neutropenia (in 25%). Mortality was 3% at 30 days and 10% at 60 days.
    CONCLUSIONS: Among patients with newly diagnosed AML who were ineligible for intensive chemotherapy, all-oral decitabine-cedazuridine plus venetoclax caused no drug interactions and resulted in a complete response in nearly half the patients, with myelosuppressive effects. (Funded by Taiho Oncology; ASCERTAIN-V ClinicalTrials.gov number, NCT04657081.).
    DOI:  https://doi.org/10.1056/NEJMoa2510223
  14. Blood Adv. 2026 Jun 04. pii: bloodadvances.2025018557. [Epub ahead of print]
    HMA+VEN triplet regimens for the initial treatment of AML in adults (PRO).
    Courtney D DiNardo, Curtis A Lachowiez.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025018557
  15. Exp Hematol. 2026 Jun 03. pii: S0301-472X(26)00091-3. [Epub ahead of print] 105458
    Inhibition of MLLT1 limits growth of KMT2A::AFF1 leukaemias without killing healthy haematopoietic stem cells.
    Shivani Rajhansa, Nicholas T Crump, Hwei Minn Khoo, Ana Dopico-Fernandez, Yavor Bozhilov, Paul E Brennan, Oleg Fedorov, Cassandra Adams, Gillian Farnie, Thomas A Milne, Adam C Wilkinson.
      A major challenge in cancer therapeutics has been the identification of targets that are selectively toxic to cancer cells while displaying limited effects on healthy counterparts. Toxicities related to blood production from haematopoietic stem and progenitor cells (HSPCs) can be particularly problematic and can result in patient morbidity and mortality. MLLT1 has been identified as a key potential target in acute myeloid leukaemia. Here we evaluated the sensitivity of an MLLT1 inhibitor, SGC-iMLLT, on a panel of leukaemia cell lines and on healthy haematopoietic stem and progenitor cells (HSPCs). We found that SGC-iMLLT downregulated MLLT1 target genes and strongly inhibited KMT2A::AFF1-driven leukaemia growth in vitro and in vivo. By contrast, SGC-iMLLT did not alter in vitro colony forming potential of human HSPCs or affect long-term in vivo function of mouse HSPCs. These results suggest that SGC-iMLLT may have a promising therapeutic window in the treatment of KMT2A::AFF1-driven leukaemias, and that further clinical development is warranted. TeaserAbstract (1): A major challenge in cancer therapeutics has been the identification of targets that are selectively toxic to cancer cells while displaying limited effects on healthy counterparts. We evaluated a novel MLLT1 inhibitor, SGC-iMLLT, on a panel of leukaemia cell lines and on healthy haematopoietic stem and progenitor cells (HSPCs). SGC-iMLLT strongly inhibited MLL-AF4-driven leukaemia growth in vitro and in vivo, did not alter in vitro colony forming potential of human HSPCs or affect long-term in vivo function of mouse HSPCs. SGC-iMLLT may have a promising therapeutic window in the treatment of MLL-AF4-driven leukaemias.
    Keywords:  KMT2A::AFF1; MLL:AF4; MLLT1; acute lymphoblastic leukaemia; haematopoietic stem cell; leukaemia
    DOI:  https://doi.org/10.1016/j.exphem.2026.105458
  16. Cancer Res Commun. 2026 Jun 05.
    p97 Inhibition Synergistically Enhances Hypomethylating Therapy Through Targeting of PLK1 in Acute Myeloid Leukemia.
    Steffan T Nawrocki, Ning Wang, Claudia M Espitia, Harley Wu, Claudia Villa Celi, Julian Olea, Paniz Zarand, Homa Dadrastoussi, Hittu Matta, Sruthi Sureshkumar, Madison E Gamble, Natalie L Hakim, David Drum, Jack Angeles, Kaijin Wu, Jiang F Zhong, Xuelian Chen, Alex Duong, Jennifer S Carew, Kevin R Kelly.
      Acute myeloid leukemia (AML) remains defined by therapeutic resistance, adverse genetic heterogeneity, and poor long-term survival, underscoring the need for mechanistically informed regimens that exploit core stress-adaptation liabilities. Polo-like kinase 1 (PLK1) is a central regulator of replication recovery and mitotic progression, yet direct PLK1 inhibitors have been limited by tolerability and incomplete target suppression. Here, we define a clinically actionable strategy that functionally targets PLK1 by combining inhibition of the AAA+ ATPase p97/valosin-containing protein (VCP) with the hypomethylating agent decitabine (DAC). Using AML cell lines, primary patient specimens, and an orthotopic in vivo model, we show that the clinically relevant p97 inhibitor CB-5339 induces proteotoxic and replication stress, activates the unfolded protein response, and triggers apoptosis. Formal synergy analyses demonstrate that CB-5339 and DAC cooperate across molecular subtypes, including FLT3-ITD+, KMT2A-rearranged, and TP53-mutant AML, to reduce cell viability at pharmacologically relevant concentrations. Transcriptomic, biochemical, and genetic studies identify synergistic suppression of PLK1 as a central consequence of combination treatment, converting stress-dependent PLK1 reliance into a therapeutic vulnerability. Consistent with this mechanism, PLK1 knockdown phenocopies the antileukemic effects of the combination and enhances sensitivity to both agents. In vivo, CB-5339/DAC is well tolerated, significantly prolongs survival, reduces leukemic burden, and suppresses PLK1 in bone marrow blasts. Together, these data establish p97 inhibition as a rational means to exploit replication and proteotoxic stress in AML and provide strong rationale for clinical evaluation of CB-5339 plus DAC in high-risk disease.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-26-0035
  17. Clin Exp Med. 2026 May 30.
    Outcomes of allogeneic hematopoietic stem cell transplantation in patients with blast phase myelofibrosis: molecular signature and intensive chemotherapy matter.
    Francesca Valsecchi, Maria Chiara Finazzi, Silvia Salmoiraghi, Chiara Pavoni, Anna Grassi, Alessandra Algarotti, Marta Bellini, Marco Frigeni, Annalisa Condorelli, Benedetta Rambaldi, Giuliana Rizzuto, Gianluca Cavallaro, Clara Belotti, Martina Milani, Orietta Spinelli, Federico Lussana, Alessandro Rambaldi.
      Patients with blast-phase (BP) myeloproliferative neoplasms have dismal outcomes, but allogeneic hematopoietic stem cell transplantation (alloHSCT) may offer a potential cure. However, the optimal pre-transplant blast-reduction therapy remains to be determined. We retrospectively analyzed outcomes in a molecularly annotated cohort of 24 patients with BP myelofibrosis (MF) who underwent alloHSCT between 2008 and 2023. Before conditioning, 20 patients received intensive induction chemotherapy, 1 received decitabine plus venetoclax, and 3 proceeded directly to transplant. At transplantation, 13 patients (54%) were in complete remission (CR), defined as bone marrow blast < 5%, or CR with incomplete count recovery (CRi), while 11 (46%) had active disease. The median follow-up was 2.9 years (range 0.02-15.5). The 3-year overall survival (OS) was 62%, progression-free survival (PFS) was 49%, relapse incidence was 38%, and non-relapse mortality was 12%. There was a trend toward better OS and PFS in patients transplanted in CR/CRi compared with those with active disease (OS 68% vs. 55%, HR 0.42, p = 0.16; PFS 61% vs. 36%, HR 0.49, p = 0.21). Mutations in TP53 and EZH2 were associated with significantly inferior PFS (HR 6.28, p = 0.008 for TP53 and HR 3.8, p = 0.04 for EZH2).Compared with a historical cohort of 50 patients transplanted during the same period for chronic-phase MF, outcomes were similar (3-year OS: 62% vs. 58%; p = 0.6181). In conclusion, our results suggest that achieving remission before alloHSCT in BP-MF is associated with favorable outcomes. The adverse impact of TP53 or EZH2 mutations supports early post-transplant strategies to prevent relapse.
    DOI:  https://doi.org/10.1007/s10238-026-02191-7
  18. Blood Adv. 2026 Jun 04. pii: bloodadvances.2025019244. [Epub ahead of print]
    Hematologic Responses Achieved with Luspatercept in Higher-Risk Myelodysplastic Syndromes.
    Daniel Leonard, David A Sallman, Kelly Pugh, Christopher Bell, Najila H Al Ali, Uma Borate, Rami S Komrokji, Andrew M Brunner.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025019244
  19. Nat Biotechnol. 2026 Jun 01.
    Selection of human hematopoietic stem cells bearing the intended functional edit by transient AND-gate reporters.
    Daniele Canarutto, Martina Fiumara, Vigneshwaran Venkatesan, Chiara Gaddoni, Kohei Shiroshita, Angelica Varesi, Luisa Albano, Gabriele Pelosi, Alfredo Silva, Claudia Firrito, Giulia Schiroli, Deborah Cipria, Stefano Beretta, Angelo Amabile, Anna Villa, Erika Zonari, Bernhard Gentner, Angelo Lombardo, Pietro Genovese, Samuele Ferrari, Luigi Naldini.
      Targeted genomic integration of gene-sized cassettes into hematopoietic stem and progenitor cells (HSPCs) for genetic disease treatment is constrained by the low efficiency of homology-directed repair (HDR) and frequent unintended genetic changes at the editing site. Here, to overcome these challenges, we introduce selection by means of artificial transactivators (SMArT), which transiently implements AND reporter gates to achieve templated integration of a functional cassette at the target site. HDR-edited HSPCs were enriched to 80-100% purity through transient selector expression, whereas cells carrying undesired and potentially genotoxic on-target edits were preferentially depleted. Xenotransplantation of SMArT-enriched HSPCs in immunodeficient mice resulted in fully HDR-edited human grafts with the selector no longer detectable. SMArT strategies were implemented through clinically compliant manufacturing and selectors. They support both safe harbor integration and gene correction, can preserve physiological transcriptional regulation and are portable across loci also with polyfunctional editors. Overall, SMArT strategies may broaden the therapeutic applicability of gene-sized editing while reducing its genotoxic burden.
    DOI:  https://doi.org/10.1038/s41587-026-03142-z
  20. Leukemia. 2026 Jun 01.
    TP53 deficiency in AML induces resistance to T-cell engagers through an immunosuppressive secretome.
    Lis Winter, Lea Pawlowsky, Amelie Muth, Anne-Sophie Neumann, Kieron White, Maryam Kazerani, Daniel Nixdorf, Bettina Brauchle, Lisa Rohrbacher, Gerulf Hänel, Agnese Petrera, Eva Briem, Gordon V Hoffmann, Thomas Janert, Emanuele Carlini, Adrian Gottschlich, Karsten Spiekermann, Tobias Straub, Roman Kischel, Sebastian Kobold, Michael Andreeff, Veit L Buecklein, Marion Subklewe.
      Bispecific T-cell engagers (BiTE® molecules) have transformed the treatment of B-cell malignancies, yet clinical activity in AML has been modest. Resistance is driven in part by the genetic heterogeneity of AML, most notably TP53 mutations, present in 10-15% of de novo and up to 25% of therapy-related AML. Thus, we hypothesized that TP53 aberrations in AML contribute to cell-intrinsic and extrinsic resistance against T-cell-based immunotherapy. Cytotoxicity against TP53-deleted (DEL) primary AML cells and TP53-knockdown (KD) AML cell lines was reduced in co-cultures with T cells stimulated with the BiTE molecule AMG 330 (CD3×CD33). In addition, T-cell proliferation and proinflammatory cytokine secretion was impaired in co-cultures with TP53 KD cells. Transwell assays identified the secretome of TP53 KD AML cells as a key contributor to the immunosuppressive effects. Proteomic analysis revealed TGF-β1 in TP53 KD co-cultures as a mediator of T-cell suppression. RNA sequencing of T cells co-cultured with TP53 KD cells uncovered a transcriptional shift toward a senescent cell cycle profile. Our data collectively identify the immunosuppressive secretome of TP53-deficient AML as a key barrier to T-cell-engaging immunotherapies, underscoring an unmet clinical need for strategies able to restore T-cell function in TP53 KD AML.
    DOI:  https://doi.org/10.1038/s41375-026-02991-6
  21. Blood. 2026 Jun 02. pii: blood.2026033951. [Epub ahead of print]
    Type I interferon-activated NK cells control polycythemia vera in vivo.
    Johanna Lossa, Tina M Schnöder, Zora Ronge, Nelly Haasch, Katrin Hodapp, Federico Marini, Najla Abassi, Matthias M Gaida, Shin-Jye Lee, Alina Henrich, Michaela N Höhne-Wiechmann, Carlos Thull Mogollón, Kristian Schütze, Matthias Klein, Tobias Bopp, Hansjörg Schild, Daniel Sasca, Carl Claudius Crodel, Florian H Heidel, Steffen Koschmieder, Hans Christian Probst, Markus P Radsak, Sabine Muth.
      Polycythemia vera (PV) is a clonal hematopoietic stem cell (HSC) disorder resulting in overproduction of erythrocytes. While Interferon-a (IFN-a) has shown therapeutic efficacy in PV and other myeloproliferative neoplasms (MPN), its precise mechanism of action remains poorly understood. In this study, we identify natural killer (NK) cells as primary immune effectors responsive to IFN-a treatment in PV essential for disease control in vivo. Using a transgenic mouse model of PV, we demonstrate that IFN-a induces the expansion of CD27+ NK cells in the bone marrow. In patients with PV or ET undergoing IFN-a therapy, the frequency of CD56bright NK cells is increased and correlates with the molecular response. Depletion of NK cells abrogated the therapeutic effects of IFN-a. In vitro experiments demonstrate that NK cells preferentially killed Jak2VF mutant hematopoietic stem and progenitor cells (HSPCs) in a TNF-a dependent manner and independent of IFN-g or NKG2D. Notably, PV mice depleted of NK cells or lacking type-I interferon (IFN) receptor on NK cells showed accelerated disease progression in the absence of exogenous IFN-a. This suggests that direct sensing of basal levels of type-I IFNs by NK cells is essential for attenuating disease progression, emphasizing a critical role for NK cells in immune surveillance of MPN. These findings offer new insights into type-I IFN-mediated immune modulation in MPN and highlight the potential of NK cell activation to improve therapeutic outcomes.
    DOI:  https://doi.org/10.1182/blood.2026033951
  22. Bone Marrow Transplant. 2026 Jun 02.
    HLA matching in contemporary haematopoietic cell transplantation: Recommendations from the EBMT Practice Harmonisation and Guidelines Committee.
    Esteban Arrieta-Bolaños, Alberto Cardoso Martins Lima, Marco Andreani, Dianne De Santis, Florent Malard, Neema P Mayor, Rohtesh S Mehta, Roland Meisel, Simona Pagliuca, Effie Petersdorf, Simona Piemontese, Nicoletta Sacchi, Nicole Santoro, Jaime Sanz, Johannes Schetelig, Stephen R Spellman, Francesco Onida, Isabel Sánchez-Ortega, Mohamad Mohty, Ibrahim Yakoub-Agha, Katharina Fleischhauer, Annalisa Ruggeri.
      HLA compatibility has been a cornerstone for safe and successful allogeneic haematopoietic cell transplantation (HCT), with human leukocyte antigen (HLA)-mismatched transplants consistently associated with inferior survival. However, recent advances in typing technologies, supportive care, and novel graft-versus-host disease (GvHD) prophylaxes have prompted the revisiting of HLA mismatch relevance in contemporary HCT. Within the framework of the 3rd Workshops of the Practice Harmonization & Guidelines Committee, the EBMT convened a group of experts in histocompatibility & immunogenetics, HCT immunobiology, and clinical HCT, to review the current state of the art and develop a set of consensus-based recommendations on the role of HLA in current HCT. The topics included technological aspects of HLA typing, the role of HLA mismatches in donor selection, and the detection and management of anti-HLA antibodies in HLA-mismatched transplantation. Moreover, the role of HLA matching relative to other non-HLA factors and in the context of novel GvHD prophylaxes, non-malignant disease, and pediatric populations was defined. Finally, the relevance of special models for HLA matching and of post-HCT monitoring of HLA-loss in malignant disease relapse was reviewed. The present document summarizes the expert consensus on these topics, to provide evidence-based recommendations for clinical decision-making.
    DOI:  https://doi.org/10.1038/s41409-026-02922-0
  23. Br J Haematol. 2026 Jun 04.
    AKT inhibitor capivasertib reverses EVI1-driven resistance to venetoclax in acute myeloid leukaemia.
    Jiayin Zhou, Xiangjie Kui, Dan Huang, Xuehong Zhang, Yuchao Hao, Fang Xie, Jiacheng Lou, Jinsong Yan.
      Acute myeloid leukaemia (AML) with MDS1 and EVI1 complex locus (MECOM) rearrangement is recognized by the World Health Organization as a distinct entity characterized by poor prognosis and aggressive disease progression. This rearrangement evokes aberrant ecotropic viral integration site 1 (EVI1) overexpression, which enhances leukaemic stem cell self-renewal and drives chemoresistance. However, the mechanisms by which EVI1 contributes to venetoclax resistance remain unclear. In this study, patients with AML were stratified into the EVI1-high and EVI1-low groups based on transcript levels. The EVI1-high subgroup exhibited significantly inferior clinical outcomes and reduced complete remission rates following chemotherapy or venetoclax-based regimens. Meanwhile, we demonstrated that elevated EVI1 expression confers resistance to venetoclax by stabilizing myeloid cell leukaemia 1 (MCL-1) through activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signalling pathway in vitro. Mechanistically, elevated EVI1 levels were associated with increased phosphorylation of MCL-1 at threonine 163 (T163pMCL-1), thereby stabilizing MCL-1 by attenuating its ubiquitin-proteasome-mediated degradation. Importantly, cotreatment with venetoclax and the clinically available AKT inhibitor capivasertib effectively restored sensitivity in both cell lines and patient-derived primary AML samples with high EVI1 expression. Overall, our findings reveal a novel molecular mechanism underlying EVI1-mediated venetoclax resistance through PI3K/AKT-driven MCL-1 stabilization and suggest a combination strategy involving AKT inhibition as a promising approach for overcoming therapeutic resistance in this high-risk AML subset.
    Keywords:   EVI1 ; MCL‐1; MECOM rearrangement; PI3K/AKT signalling; acute myeloid leukaemia; capivasertib; venetoclax resistance
    DOI:  https://doi.org/10.1111/bjh.70530
  24. Leuk Res. 2026 May 20. pii: S0145-2126(26)00099-8. [Epub ahead of print]167 108255
    Association of hypomethylating agents + venetoclax in the real-life treatment of Myeloproliferative Neoplasms in blastic phase.
    Roberto Latagliata, Novella Pugliese, Dorela Lame, Gianluca Cristiano, Giulia De Luca, Alda Strazimiri, Fabrizio Cavalca, Lorenzo Rizzo, Simone Zoletto, Vincenzo Federico, Daniele Cattaneo, Monica Crugnola, Annalisa Biagi, Pasquale Niscola, Raffaele Palmieri, Olga Mulas, Beatrice Esposito Vangone, Michelina Santopietro, Antonella Bruzzese, Mario Tiribelli, Ambra Di Veroli, Fabio Stagno, Lucia Ciuffreda, Alessandra Iurlo, Nicola Di Renzo, Gianni Binotto, Prassede Salutari, Marta Riva, Massimiliano Bonifacio, Elena Maria Elli, Antonio Curti, Antonella Poloni.
       BACKGROUND: Patients (pts) with Myeloproliferative Neoplasms evolved in blastic phase (MPN-BP) have a dismal overall survival (OS). Very few data on the association of hypomethylating agents (HMA) and venetoclax (VEN) are available at present in homogeneous cohort of MPN-BP pts.
    METHODS: Data of 61 pts with MPN-BP treated frontline with HMA + VEN in 21 hematologic Centers in Italy outside clinical trials from 11/2018 to 8/2024 were retrospectively collected and analysed.
    RESULTS: Pts were treated for a median of 4 courses (IQR 2-8). Overall, 56 pts (91.8%) had at least one hematologic toxicity of grade 3-4: in particular, severe neutropenia (PMN < 0.5 × 109/l) was reported in 50 pts (81.9%). Thirty-two pts (52.4%) had at least one infective episode during the treatment: pulmonary infections were reported in 13 pts (21.3%). Overall Response Rate (ORR) was 60.6%, with a median response duration of 9.4 months (95%CI 4.3-18.3): in particular, 26 patients (42.6%) achieved ALR-C/Ci, with a median response duration of 18.3 months (95%CI 1.2-35.3). Median OS of the whole cohort was 10.5 months (95%CI 7.7-13.3). Pts with any type of response had a significantly longer OS compared to pts with progressive/stable disease [13.6 (95%CI 10.3-21.9) versus 7.1 (95%CI 4.4-11.7) months, respectively (p < 0.001)].
    CONCLUSIONS: Our real-life data confirm that HMA + VEN combination could have a role in MPN-BP: however, response duration is still very short, with a persistently poor median OS. As a consequence, addition of other targeted therapies should be explored.
    Keywords:  Blastic phase; Hypomethylating agents; Myeloproliferative Neoplasms; Venetoclax
    DOI:  https://doi.org/10.1016/j.leukres.2026.108255
  25. bioRxiv. 2026 May 29. pii: 2026.05.26.727520. [Epub ahead of print]
    Cell autonomous inflammation in VEXAS is mediated by cGAS-STING.
    Samuel J Magaziner, Jason C Collins, Brecca Miller, Patrick Zheng, Amy K Wang, Jerome Hadjadj, Juan Carlos Baladrán, Maria Sirenko, Maya English, James Bertlin, Rebecca Murray, Peter H Whitney, Tania J González-Robles, Deborah Rivera, Yan Wang, Duy T Tran, Zulfeqhar A Syed, Valentina Baena, Timothee Lionnet, Kelly V Ruggles, Iannis Aifantis, Dan A Landau, Achim Werner, David B Beck.
      VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a severe adult-onset inflammatory disease caused by somatic mutations that reduce cytoplasmic activity of UBA1, the primary initiating enzyme for ubiquitylation. How this hypomorphic state drives cell-intrinsic immune activation in mature myeloid cells is unknown. Using unbiased multi-omic, biochemical, and cell biological analyses of model systems and patient-derived cells, we show that loss of cytoplasmic UBA1 activity convergently disrupts endoplasmic reticulum- associated degradation (ERAD) and mitochondrial homeostasis. ERAD failure arises from preferential under-charging of ERAD E2 enzymes, explaining hallmark VEXAS features, including ER-derived vacuoles and unfolded protein response activation, and promotes accumulation of the ERAD substrate STING. Simultaneously, mitochondrial dysfunction drives cytosolic leakage of mitochondrial DNA, inducing cGAS-dependent STING signaling and inflammatory cytokine production. STING inhibition or reversal of mitochondrial DNA leakage resolves multi-cytokine inflammation in VEXAS models and patient myeloid cells, establishing the cGAS-STING pathway as a therapeutically actionable vulnerability.
    DOI:  https://doi.org/10.64898/2026.05.26.727520
  26. Blood. 2026 Mar 12. pii: blood.2025030577. [Epub ahead of print]
    High-avidity cathepsin-G-specific CAR-T cells for the treatment of acute myeloid leukemia.
    Gianpietro Dotti, Tara Walhart, Marta Biondi, Simone Stucchi, Guangming Li, Ourania Tsahouridis, Peishun Shou, Kyogo Suzuki, Elizabeth G Hunt, Andrew Kennedy, Jessica Thaxton, Tracy Withers, Laura Herring, Courtney G Elliott, Sally Anne Hunsucker, Marta Serafini, Leah Flick, Eben Isaac Lichtman, Mark G Woodcock, LIshan Su, Zhiyuan Yang, Guangyan Xiong, Ziyou Cui, Pei Wang, Cheng Liu, Barbara Savoldo, Paul M Armistead, Feifei Song.
      Chimeric antigen receptor (CAR) T cells specific for myeloid-associated antigens expressed on the cell surface of acute myeloid leukemia (AML) can cause depletion of normal myeloid progenitor cells. We developed a CAR specific for a human Leucocyte Histocompatibility Antigen (HLA)-A*02:01-restricted peptide of the myeloid-restricted cathepsin-G protein. Cathepsin-G-specific CAR (CG1.CAR) T cells were further engineered to increase their functional avidity. Specifically, we developed CG1.CAR-T cells co-expressing the lymphocyte-specific protein tyrosine kinase (LCK) and duplicated CD3ζ chain, which allows the functional recognition of the CG1 peptide as low as 0.025 mM. Optimized CG1.CAR T cells displayed antileukemia effects in vitro and in vivo in AML patient-derived-xenotransplant (PDX) mouse models and did not cause hematopoietic toxicity in colony assays and humanized mice. Mechanistically, LCK overexpression in CG1.CAR-T cells caused transcriptional modifications characterized by the overexpression of mitochondrial-encoded electron transport chain components that were correlated with increased mitochondrial mass and improved respiratory capacity. Based on these data, CG1.CAR-T cells hold clinical potential for the treatment of AML.
    DOI:  https://doi.org/10.1182/blood.2025030577
  27. Cancer Res. 2026 Jun 01.
    Stage-Specific Degradation of Cyclin D3 Orchestrates Myelopoiesis and Restrains Myeloproliferative Neoplasms Development.
    Bartosz Mucha, Vincenzo Tarallo, Ata Abbas, Melina Hall, Shuyuan Zhang, Marganit Farago, Polly J Phillips-Mason, Harrison Lindley, Mark Cameron, Chen Zhao, Amar B Desai, J Alan Diehl.
      Accumulation of D cyclins during the G1 phase of the cell cycle is a key regulatory step that derepresses the transcriptional program required for DNA replication, facilitating S-phase entry. Among the three D cyclins, cyclin D3 predominates in hematopoietic cells. Accordingly, cyclin D3 mutations are implicated in lymphoid malignancies. Here, we provided evidence demonstrating a critical role for cyclin D3 in myelopoiesis and further demonstrated the stage specific degradation of cyclin D3 dictates normal myelopoiesis. In a knock-in mouse model expressing a degradation-resistant cyclin D3 variant (D3T283A), sustained cyclin D3 protein levels enhanced granulocyte-monocyte differentiation and altered megakaryocyte-erythrocyte outputs, consistent with trends toward microcytic erythrocytes and increased platelet production. This was accompanied by extramedullary hematopoiesis. Splenic hematopoietic stem and progenitor cells (HSPCs) from D3T283A mice exhibited increased self-renewal and a competitive repopulation advantage in irradiated immunocompromised recipients. Prolonged D3T283A expression drove highly penetrant myeloproliferative neoplasm (MPN) development, significantly reducing survival. In contrast, mice with a comparable stabilizing mutation in cyclin D2 (D2T280A), another D cyclin abundant in immune cells, showed no immunophenotypic changes. D3T283A led to upregulation of FOXM1 and PRMT5 dependent transcriptomic programs that played different roles in shaping the immunophenotype, and targeting FOXM1 and PRMT5 suppressed myeloproliferation. Together, these findings highlight a distinct and pivotal role for cyclin D3 in myelopoiesis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4990
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