bims-tremyl 2026-08-23 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2026–08–23
thirty-one papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Determinants of survival after failure of frontline venetoclax plus hypomethylating agent therapy in 356 patients with newly diagnosed acute myeloid leukemia.
Dual MYC and GSPT1 Protein Degrader for MYC-Driven Hematologic Malignancies.
Venetoclax combined with high-dose cytarabine and mitoxantrone for relapsed or refractory acute myeloid leukemia: outcomes and risk stratification.
Human CEBPA -N AML exhibits enhanced engraftment and a C/EBP α -p30-driven leukemic stem cell program.
Real-world outcomes of venetoclax plus hypomethylating agents in unfit acute myeloid leukaemia: Results of the GIMEMA AML2320 trial.
Treatment sequence with gilteritinib and allogeneic haematopoietic stem cell transplantation in relapsed/refractory FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukaemia patients: A multicentre real-world study.
NRAS knockdown reverses monocytic cell state and resensitizes resistant FLT3-AML cells to gilteritinib.
Subtype-specific outcome after allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis: a registry study of the European competence network on mastocytosis.
Distinct clinical and genetic characteristics of myelodysplastic syndrome in younger patients.
Immunotherapeutic targeting of calreticulin mutant myeloproliferative neoplasms.
De novo JAK2-mutated acute myeloid leukaemia: Clinical outcomes and molecular features.
Oncogenic DHX15 mutation enhances mitochondrial metabolism and sustains leukemia stemness.
Mutant TP53 allelic states in human hematopoietic stem and progenitor cells.
ATRA resistance conferred by a clustered subset of hotspot PML::RARA mutations enhancing basal repression rather than precluding transactivation.
Modeling KRAS mutations in KMT2A::MLLT3 acute myeloid leukemia promotes leukemic progression and transcriptional rewiring.
A novel role for transcription factor NFE2 in redox regulation and chemotherapy resistance in acute myeloid leukemia.
Treatment of older adults with newly diagnosed FLT3-mutated AML: focus on lower-intensity triplet regimens.
Impact of cytoreductive therapy in myeloproliferative neoplasm-associated splanchnic vein thrombosis.
STING agonists in combination with epigenetic drugs potentiate ZNFX1-driven inflammatory necroptosis in TP53 -mutated AML.
Myeloproliferative Neoplasms.
FLT3-ITD signals for CEBPA and p53 proteolysis by the ubiquitin-proteosome pathway.
PKM2 modulation regulates leukemia cell survival.
Use of selective serotonin reuptake inhibitors and risk of myeloid malignancy: A nationwide Danish case-control study.
Enhanced prognosis of acute myeloid leukaemia patients with dmCEBPAbZIP -inf mutations: Insights from a multicentre Chinese cohort study.
Sapablursen for Erythrocytosis Control in Patients with Polycythemia Vera.
Leveraging paired germline and somatic analysis to improve the classification of DDX41 variants.
CD55 promotes hematopoietic stem and progenitor cell survival in a mouse model of immune-mediated aplastic anaemia.
The Inv(16) Oncogene CBFB::MYH11 is Required for the Survival of Leukemia Cells in the Blood and Spleen, but not the Bone Marrow.
Cladribine-based salvage therapy in relapsed/refractory AML: A multicenter retrospective study.
An Italian cartography of VEXAS-related thrombosis.
Deep molecular remission and encouraging survival without transplantation: V-CAG for arsenic-resistant relapsed APL.

Blood Cancer J. 2026 Aug 17. pii: 138. [Epub ahead of print]16(1):

Determinants of survival after failure of frontline venetoclax plus hypomethylating agent therapy in 356 patients with newly diagnosed acute myeloid leukemia.

Mahnoor Fatima, Sudhesh Kumar, Momna Warraich, Kristen McCullough, Aref Al-Kali, Hassan B Alkhateeb, Kebede H Begna, Abhishek Mangaonkar, Antoine N Saliba, Mark R Litzow, William Hogan, Mithun V Shah, Mrinal M Patnaik, Animesh Pardanani, Talha Badar, James Foran, Jeanne Palmer, Cecilia Arana Yi, Ayalew Tefferi, Naseema Gangat.

DOI: https://doi.org/10.1038/s41408-026-01612-w
Blood. 2026 Aug 17. pii: blood.2025030170. [Epub ahead of print]

Dual MYC and GSPT1 Protein Degrader for MYC-Driven Hematologic Malignancies.

Yuki Nishida, Valeria Impedovo, Edward Ayoub, Natalia Baran, Darah A Scruggs, Hideaki Mizuno, Shayaun Khazaei, Lauren B Ostermann, Kazuharu Kamachi, Liang Zhang, Jo Ishizawa, Sandeep Singh, Andrea D Bedoy, Po Yee Mak, Bing Z Carter, Eiji Sugihara, Tetsuya Takimoto, Youzhi Tong, Honghua Yan, Dong Chen, Ji Huang, Hsu-Feng Chu, Liang Tong, Zamal Ahmed, Sarita Namjoshi, John Tainer, Mihai Gagea, Thomas Huynh, Abhishek Maiti, Koji Sasaki, Branko Cuglievan, Steffen Boettcher, Torsten Haferlach, Stefano Tiziani, Liandong Ma, Michael Andreeff.

Direct targeting of the oncoprotein MYC has not yet been successful. We here report a novel dual protein degrader, GT19630, which binds directly to MYC and G1 to S phase transition protein 1 (GSPT1). GT19630 disrupts a novel feedforward loop of MYC and GSPT1, where MYC promotes transcription of GSPT1, and GSPT1 senses the stop codon of MYC to properly terminate its translation. The agent induces integrated stress response and abrogates oxidative phosphorylation through inhibition of the TCA cycle, resulting in apoptosis. GT19630 has superior activity compared to GSPT1- targeting molecular glues. GT19630 induces profound anti-proliferative effects and apoptosis at low nanomolar concentrations in a multitude of leukemia and lymphoma cell lines and primary samples, including those with TP53 mutations. GT19630 is highly active in vivo in models of therapy-resistant hematologic malignancies, including Burkitt's lymphoma, acute myeloid leukemia (AML) and multiple myeloma. CD34+ AML blasts overexpress MYC protein compared to normal hematopoietic stem/progenitor cells (HSPCs) and GT19630 induces greater cytotoxicity in AML cells compared to normal HSPCs. Further, GT19630 restores sensitivity to venetoclax and profoundly prolongs survival in vivo in venetoclax-resistant AML. GT19630 was well tolerated in humanized Crbn mice. In conclusion, our data support the development of the MYC/GSPT1 degrader GT19630 as a therapeutic strategy of MYC-driven hematologic malignancies.

DOI: https://doi.org/10.1182/blood.2025030170
Haematologica. 2026 Aug 20.

Venetoclax combined with high-dose cytarabine and mitoxantrone for relapsed or refractory acute myeloid leukemia: outcomes and risk stratification.

Andrew F Berdel, Christoph Röllig, Clara Burkhard-Meier, Marco Tembrink, Julia M Unglaub, Tim Sauer, Martina Crysandt, Edgar Jost, Paul Jaeger, Christoph Kiefel, Lars Fransecky, Krischan Braitsch, Katharina Götze, Kai Wille, Kerstin Schäfer-Eckart, Klaus Metzeler, Sara Hilber, Julian Ronnacker, Marcel Kemper, Nardos Hölscher, Klaus Wethmar, Thomas Schroeder, Sylvia Herold, David Poitz, Björn Steffen, Andreas Rank, Mathias Hänel, Jan Moritz Middeke, Martin Kaufmann, Andreas Burchert, Johannes Schetelig, Uwe Platzbecker, Christian Thiede, Matthias Stelljes, Georg Lenz, Hubert Serve, Claudia Baldus, Martin Bornhäuser, Carsten Müller-Tidow, Jan-Henrik Mikesch, Lukas Frenzel, Maher Hanoun, Leo Ruhnke, Christoph Schliemann.

Relapsed or refractory acute myeloid leukemia (R/R AML) remains a therapeutic challenge, with standard high‑dose cytarabine-based salvage regimens achieving complete remission (CR) rates of around 50%. In the phase 1/2 RELAX trial, adding venetoclax (VEN) to high‑dose cytarabine and mitoxantrone (HAM) was considered safe and resulted in CR or CR with incomplete hematologic recovery (CRi) in 75% of patients. Here, we performed a multicenter real‑world analysis of 128 R/R AML patients treated with HAM plus VEN (VEN 400 mg days 1-14, cytarabine 1000 mg/m² IV twice daily days 3-5, mitoxantrone 10 mg/m² IV days 5-7) between March 2023 and June 2025. The median age was 60 years (range, 20-74). Patients had a median of 1 prior therapy (range, 1-5), 38% had prior allogeneic hematopoietic cell transplantation (HCT), and 25% VEN exposure. Overall, 69% achieved CR/CRi; response rates were higher in patients with one prior therapy line (78%) and VEN-naïve patients (76%). Sixty-eight percent proceeded to HCT. After a median follow-up of 11.5 months, estimated 1‑year RFS and OS rates were 59% and 58%, respectively. In a prognostic classifier derived from pooled real-world and RELAX trial data (183 patients), TP53 mutation, complex karyotype, ≥2 prior therapy lines, and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 predicted inferior outcomes. Patients without these features had a 1-year OS of 73%. HAM plus VEN retains high efficacy and encouraging survival outcomes in a real-world setting, supporting its use as an effective salvage and bridge-to-transplant strategy.

DOI: https://doi.org/10.3324/haematol.2026.301102
bioRxiv. 2026 Aug 04. pii: 2026.08.03.742558. [Epub ahead of print]

Human CEBPA -N AML exhibits enhanced engraftment and a C/EBP α -p30-driven leukemic stem cell program.

Philomina Sona Peramangalam, Mayuresh Konde, Onur Karakaslar, Sebastian Wolf, Shikan Zheng, Akmal Salimov, Sridevi Surapally, Marieke Griffioen, Tongjun Gu, Sridhar Rao, Daniel G Tenen, Thomas Oellerich, Erik van den Akker, Martin Carroll, Caner Saygin, John A Pulikkan.

Leukemic stem cells (LSCs) play a central role in disease progression, therapeutic resistance, and relapse in acute myeloid leukemia (AML). However, the identification and characterization of LSCs remain challenging because of their low abundance and their close phenotypic resemblance to normal hematopoietic stem and progenitor cells. Although patient-derived xenograft (PDX) models have provided important insights into AML biology and LSC heterogeneity, the relative engraftment potential of distinct CEBPA mutation subtypes and the immunophenotypic identity of LSCs in CEBPA N-terminal mutant AML ( CEBPA - N -AML) remain poorly defined. To address these questions, we compared the engraftment characteristics of primary human CEBPA-mutated AML samples representing the major mutational subtypes using the highly permissive NSGS xenograft model. Primary CEBPA -N-AML samples exhibited markedly greater engraftment efficiency and leukemogenic potential than other CEBPA -mutated AML subtypes. Furthermore, we identified a CD366⁺CD73⁺CD123⁺CD117⁺CD371⁺CD247⁺ cell population that is highly enriched for functional LSCs in CEBPA-N -AML, demonstrating enhanced clonogenic activity, leukemia-initiating capacity, and long-term self-renewal. Collectively, our findings demonstrate that the leukemogenic potential of CEBPA -mutated AML is strongly influenced by mutation subtype, with CEBPA-N -AML exhibiting superior leukemia-propagating capacity in vivo. We further define a novel immunophenotypic LSC signature specific to CEBPA-N -AML, providing new insights into LSC heterogeneity in CEBPA -mutated AML and establishing a foundation for the development of LSC-directed therapeutic strategies.

DOI: https://doi.org/10.64898/2026.08.03.742558
Br J Haematol. 2026 Aug 17.

Real-world outcomes of venetoclax plus hypomethylating agents in unfit acute myeloid leukaemia: Results of the GIMEMA AML2320 trial.

Raffaele Palmieri, Alfonso Piciocchi, Stefano Soddu, Marco Frigeni, Erika Borlenghi, Nicola Fracchiolla, Maria Paola Martelli, Ernesta Audisio, Alessandro Cignetti, Giacomo Gianfaldoni, Calogero Vetro, Nicola di Rienzo, Daniela Esposito, Ambra Di Veroli, Carmine Selleri, Federica Gigli, Antonio Curti, Antonino Mulè, Catello Califano, Sara Bigliardi, Massimo Breccia, Claudio Fozza, Monica Bocchia, Albana Lico, Federico Simonetti, Elisabetta Pierdomenico, Monia Marchetti, Ilaria Cerroni, Francesco Buccisano, Maria Ilaria Del Principe, Luca Maurillo, Giovangiacinto Paterno, Paola Fazi, Marco Vignetti, Giuseppe Rossi, Alessandro Rambaldi, Adriano Venditti.

  Venetoclax (VEN) plus hypomethylating agents (HMAs) represents the standard of care for newly diagnosed acute myeloid leukaemia (AML) patients unfit for intensive chemotherapy, but prospective real-world observational data outside randomized clinical trials remain limited. The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) AML2320 is a prospective, multicentre, observational study (NCT04589728) including 193 newly diagnosed unfit AML patients receiving VEN plus azacitidine or decitabine between November 2020 and December 2021. Primary end-point was overall survival (OS); secondary end-points included composite complete remission (cCR), disease-free survival and safety. Median age was 74 years with 42% of patients being ≥75 years. After completing cycle 4, cCR was achieved in 73% of the patients, with 54% responding before cycle 2. After a median follow-up of 23 months, median OS was 13.0 months. cCR achievement within cycle 4 correlated with longer OS (19.1 vs. 9.1 months, p = 0.001). Patients receiving 400 mg VEN without azoles had improved OS compared with those on reduced doses with azoles (18.2 vs. 11.4 months, p = 0.015). An anchored matching-adjusted indirect comparison with the phase III VIALE-A trial (NCT02993523) showed comparable median OS (14.8 months vs. 14.9 months; p = 0.6). The GIMEMA AML2320 trial confirmed the efficacy of VEN/HMAs in a prospective, real-world unfit population. Early remission was associated with improved outcomes.

Keywords:  acute myeloid leukaemia; hypomethylating agents; real‐world evidence; unfit patients; venetoclax

DOI:  https://doi.org/10.1111/bjh.70752
Br J Haematol. 2026 Aug 18.

Treatment sequence with gilteritinib and allogeneic haematopoietic stem cell transplantation in relapsed/refractory FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukaemia patients: A multicentre real-world study.

German Cooperative Transplant Study Group and Study Alliance Leukemia (SAL)

  Patients with relapsed or refractory acute myeloid leukaemia (r/r AML) harbouring FMS-like tyrosine kinase 3 (FLT3) mutations generally have poor prognosis and limited treatment options. The second-generation FLT3 inhibitor gilteritinib provides better disease control compared to standard relapse therapies and was approved based on two randomized trials. We analysed its efficacy and safety in a real-world cohort of r/r AML patients undergoing gilteritinib treatment including allogeneic haematopoietic stem cell transplantation (alloHSCT). Data were collected from all consecutive r/r AML patients with FLT3-internal tandem duplication and/or FLT3-tyrosine kinase domain mutations receiving gilteritinib at 25 centres. Response and survival were analysed using descriptive and correlative statistics. A total of 156 patients were analysed, 55.1% with relapse after previous alloHSCT, and 46.2% with prior FLT3 inhibitor exposure. The overall complete remission/incomplete remission (CR/Cri) rate was 45.3%, with a median overall survival (OS) of 10.0 months. Patients receiving gilteritinib only had a 1-year OS of 34%, while those with consolidating alloHSCT had a 1-year OS of 76%-92%, depending on gilteritinib maintenance post-transplant. Resuming gilteritinib post-transplant led to an 85.7% CR/CRi rate. Our real-world data confirm that gilteritinib is an effective single-agent therapy for r/r AML with FLT3 mutations, with best outcomes when used as a bridge to transplant and post-transplant maintenance.

Keywords:   AML ; FLT3 ; allogeneic haematopoietic stem cell transplantation; gilteritinib; maintenance; relapse; survival

DOI:  https://doi.org/10.1111/bjh.70735
Blood. 2026 Aug 11. pii: blood.2026033305. [Epub ahead of print]

NRAS knockdown reverses monocytic cell state and resensitizes resistant FLT3-AML cells to gilteritinib.

Sunil K Joshi, Hadi Maazi, Janét Pittsenbarger, Belinda B Garana, Andy Kaempf, Ariane Huang, Marina A Gritsenko, Chelsea Hutchinson-Bunch, Karl K Weitz, Rosalie K Chu, Sara J C Gosline, Paul D Piehowski, Ann-Kathrin Eisfeld, Martin P Carroll, Alexander E Perl, Karin D Rodland, Bill H Chang, Alexey S Revenko, Jeffrey W Tyner, Brian J Druker, Elie Traer.

While the FLT3 inhibitor gilteritinib is initially effective in patients with FLT3-mutated acute myeloid leukemia (AML), patients invariably relapse within months of treatment. Gilteritinib resistance is commonly driven by the emergence of NRAS mutations and a shift towards a more monocytic cell state. We hypothesized that directly targeting and depleting NRAS protein would reverse these adaptive differentiation changes and restore therapeutic sensitivity. To test this, we utilized a mutation-agnostic antisense oligonucleotide (ASO) to selectively knock down NRAS expression across gilteritinib-resistant AML cell lines, in vivo cell-line-derived xenografts, and primary patient samples. NRAS ASO successfully resensitized gilteritinib resistant cells with multiple distinct NRAS mutations, displaying superior efficacy compared to downstream MEK inhibition. This therapeutic efficacy was independent of NRAS mutant variant allele frequency, suggesting that wild-type NRAS may also contribute to resistance. Comprehensive multi-omic profiling (transcriptomics, proteomics, phosphoproteomics) revealed that NRAS knockdown consistently reversed monocytic phenotype, shifting cells back toward a more primitive cell state. Monocytic differentiation and NRAS mutations are established drivers of resistance to diverse targeted regimens in AML, including FLT3, IDH, and BCL2 inhibitors, so we also tested venetoclax resistant primary cells with NRAS mutations. Resistant cells were resensitized to venetoclax after NRAS knockdown, suggesting that NRAS knockdown may be more broadly applicable in overcoming monocytic cell state and drug resistance in AML.

DOI: https://doi.org/10.1182/blood.2026033305
Exp Hematol Oncol. 2026 Aug 20. pii: 79. [Epub ahead of print]15(1):

Subtype-specific outcome after allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis: a registry study of the European competence network on mastocytosis.

Stefan Haug, Wolfgang R Sperr, Claudia Wehr, Federico Bonofiglio, Saskia K Klein, Hanneke C Kluin-Nelemans, André B Mulder, Olivier Hermine, Julien Rossignol, Felipe Suarez, Ambroise Marcais, William Shomali, Cecelia Perkins, Deborah Christen, Werner Rabitsch, Emir Hadzijusufovic, Jaroslava Voglová, Madlen Jentzsch, Juliana Schwaab, Johannes Lübke, Mattias Mattsson, Hans Hagglund, Ingunn Dybedal, Daniel Baffoe, Patrizia Bonnadonna, Massimiliano Bonifacio, Ilaria Tanasi, Mariarita Sciumè, Marek Niedoszytko, Aleksandar Gorska, Andrzej Mital, Massimo Triggiani, Roberta Parente, Akif Selim Yavuz, Chiara Elena, Luca Malcovati, Jacqueline Ferrari, Friederike Wortmann, Knut Brockow, Tobias Michael Franz, Michael Makris, Sotirios G Papageorgiou, Christine Breynaert, Toon Ieven, Irena Angelova-Fischer, Alex Stefan, Judit Várkonyi, Vito Sabato, Tanja Daniela Schug, Paul L A van Daele, Anna Belloni Fortina, Francesca Caroppo, Theo Gulen, Marc Heizmann, Karin Hartmann, Axel Rüfer, Michael Doubek, Jens Panse, Jason Gotlib, Michel Arock, Hanneke N G Oude Elberink, Andreas Reiter, Peter Valent, Khalid Shoumariyeh.

  Advanced systemic mastocytosis (AdvSM), comprising aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated hematological neoplasm, is a heterogeneous myeloid neoplasm with poor prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative treatment, yet its benefit across AdvSM subtypes in the era of KIT-targeted tyrosine kinase inhibitors (TKIs) such as midostaurin and avapritinib remains unclear. To identify patient subgroups benefiting from allo-HCT and to define prognostic factors for post-transplant survival, we analyzed 631 AdvSM patients from the European Competence Network on Mastocytosis registry, including 69 who underwent allo-HCT. Treatment effects were assessed using time-dependent Cox regression in a transplant-eligible complete-case cohort (n = 419). In this cohort, allo-HCT showed no overall survival (OS) benefit (hazard ratio [HR] 1.21, 95% CI 0.80-1.84; p = 0.37), whereas TKI response emerged as a strong independent predictor of survival (HR 0.42; p<0.001). Subtype-stratified analysis revealed an allo-HCT benefit exclusively in patients with systemic mastocytosis associated with acute myeloid leukemia (n = 30; HR 0.20; p = 0.020). Among the 69 transplanted patients, median OS was 49.6 months with 2-year and 5-year survival of 63% and 46%, respectively. The International Prognostic Scoring System for Mastocytosis (IPSM) at transplantation independently predicted both OS (HR per category 1.68; p = 0.026) and progression-free survival (HR 1.99; p = 0.003), whereas the Mutation-Adjusted Risk Score and diagnostic subtype did not reach statistical significance. Competing risk analysis demonstrated that higher IPSM captured both relapse-related and transplant-related mortality. These findings suggest that the survival benefit of allo-HCT in AdvSM is driven primarily by control of the associated myeloid neoplasm. Accordingly, allo-HCT should be prioritized in patients with SM-AML, whereas TKI-directed strategies may be preferred in other subtypes, with IPSM at transplantation potentially guiding transplant selection and timing.

Keywords:   KIT D816V; Advanced systemic mastocytosis; Allogeneic stem cell transplantation; IPSM; MARS; Systemic mastocytosis; Tyrosine kinase inhibitors

DOI:  https://doi.org/10.1186/s40164-026-00819-8
Br J Haematol. 2026 Aug 21.

Distinct clinical and genetic characteristics of myelodysplastic syndrome in younger patients.

Hyunkyung Park, Eun-Ji Choi, Young-Uk Cho, Yunsuk Choi, Han-Seung Park, Jung-Hee Lee, Joon Young Hur, Jisu Jeong, Seungah Cha, Yueun Lee, Young-Shin Lee, Young-Ah Kang, Mijin Jeon, Ji Min Woo, Hyeran Kang, Je-Hwan Lee.

  Myelodysplastic neoplasms (formerly myelodysplastic syndromes, MDS) are heterogeneous clonal haematological malignancies that primarily affect the elderly, though a notable proportion of patients are diagnosed at younger ages. We retrospectively analysed 1437 patients diagnosed or treated at Asan Medical Center between 1989 and 2022, comparing clinical and genetic characteristics by age group. Younger patients (≤50 years) demonstrated improved overall survival (OS) and leukaemia-free survival (all p < 0.001), a higher proportion of females, lower platelet levels, reduced bone marrow blasts, decreased mutation burden and lower scores on the International Prognostic Scoring System. In contrast, the response rates to hypomethylating agents did not significantly differ between age groups (p = 0.543); however, SF3B1 mutation predicted favourable therapeutic response. Mutations in ASXL1, DDX41, DNMT3A, RUNX1, SF3B1, SRSF2, TET2, TP53 and ZRSR2 occurred more frequently in older MDS patients, whereas SAMD9 mutations predominated in younger cohort. In patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT), OS did not differ significantly between younger and older patients; only TP53 mutation reliably predicted inferior post-HSCT OS (hazard ratio 3.099, p = 0.003). In analyses limited to younger patients, the presence of DNMT3A, TP53 and U2AF1 mutations was associated with worse OS. These findings suggest that younger patients represent a biologically distinct subset of MDS.

Keywords:  hypomethylating agent; mutation profile; myelodysplastic syndrome; prognosis; younger patients

DOI:  https://doi.org/10.1111/bjh.70770
Leukemia. 2026 Aug 18.

Immunotherapeutic targeting of calreticulin mutant myeloproliferative neoplasms.

Charles Hertz, Nikolaos Spyrou, Ronald Hoffman, Cansu Cimen Bozkus, Nina Bhardwaj, Douglas Tremblay, Marina Kremyanskaya, John Mascarenhas.

Calreticulin (CALR) frameshift mutations drive the majority of JAK2/MPL-wild-type cases of essential thrombocythemia and myelofibrosis, producing a shared novel C-terminus that activates the thrombopoietin receptor and leads to constitutive Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. CALR mutations transform the multifunctional endoplasmic reticulum (ER)-resident protein into an oncogenic driver that aberrantly traffics to the cell surface, activates the thrombopoietin receptor, MPL, and promotes MF megakaryocytic proliferation and hemopoietic stem cell fitness. Clinically, CALR-mutated MPNs affect younger patients, exhibit thrombocytosis and progressive anemia, and, in MF patients, are associated with a superior survival compared with JAK2- or MPL-mutated disease, yet responses to hydroxyurea and ruxolitinib remain inferior. The C-terminal motif shared between CALR mutations is presented extracellularly on major histocompatibility complex (MHC) Class I molecules and in complex with the thrombopoietin receptor enabling targeting with vaccination and antibody based therapeutic platforms, respectively. Mutant CALR peptide vaccines induce T cell responses but have failed to result in hematologic or molecular responses. Mutant CALR-specific monoclonal antibodies, such as Fc-silent antagonists, can block mutant-CALR-MPL signaling, suppress hematopoietic stem and progenitor cells (HSPC) proliferation and megakaryopoiesis, and achieve rapid, durable hematologic remissions with minimal toxicity in early-phase trials. Preclinical antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor T cell (CAR-T) cells also show potent, selective mutant-cell killing. Here we review the basis and ongoing translational and clinical efforts in the development of CALR-targeted immunotherapies that offer a potential shift from symptom management to disease-modifying treatment in this molecularly defined MPN subset.

DOI: https://doi.org/10.1038/s41375-026-03115-w
Br J Haematol. 2026 Aug 17.

De novo JAK2-mutated acute myeloid leukaemia: Clinical outcomes and molecular features.

Luca Guarnera, Emiliano Fabiani, Eleonora Lumia, Paola Ricci, Nicole Lelli, Federico Moretti, Elisa Meddi, Raffaele Palmieri, Enrico Attardi, Luca Maurillo, Adriano Venditti, Maria Teresa Voso.



Keywords:   JAK2 ; acute myeloid leukaemia; secondary leukemogenesis

DOI:  https://doi.org/10.1111/bjh.70746
Leukemia. 2026 Aug 21.

Oncogenic DHX15 mutation enhances mitochondrial metabolism and sustains leukemia stemness.

Qilong Li, Peiqi Xing, Jin Xu, Jifei Li, Liangjie Chen, Xinlu Li, Yinpeng Bai, Gang Li, Ting Xie, Luzhen Wang, Yuan Wang, Guoliang Qing, Huafeng Wang, Liang Shao, Wei Wu, Zhaoqi Liu, Hudan Liu.

The RUNX1::RUNX1T1 translocation, also termed AML1-ETO, is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML) and is associated with variable clinical outcomes. The R222G hotspot mutation, located in the RNA helicase gene DHX15, is enriched and predominantly found in AML with this translocation, but its diagnostic significance and underlying mechanism remain largely unclear. In this study, we show that pediatric AML patients carrying DHX15 mutations exhibit an inferior prognosis. Functional analysis demonstrates that DHX15R222G cooperates with AML1-ETO fusion protein to enhance AML leukemia stem cell (LSC) activity and promote resistance to standard chemotherapy. Mechanistically, AML1-ETO transcriptionally upregulates mitochondrial transcription factor A (TFAM), while DHX15R222G promotes TFAM protein stabilization and nuclear translocation, resulting in robust activation of oxidative phosphorylation (OXPHOS) gene expression and mitochondrial respiration. Inhibition of oxidative phosphorylation by the Complex V inhibitor S-Gboxin exerts strong anti-leukemic effects and efficiently circumvents chemotherapy resistance in AML1-ETO+ DHX15R222G leukemia. These findings underscore the pivotal role of oncogenic DHX15 mutations in regulating AML LSC activity and identify DHX15R222G as a potential genetic biomarker for AML risk stratification. Moreover, this mutation may predict therapeutic vulnerability to OXPHOS inhibition.

DOI: https://doi.org/10.1038/s41375-026-03102-1
Leukemia. 2026 Aug 18.

Mutant TP53 allelic states in human hematopoietic stem and progenitor cells.

Karin Lind, Sayantanee Dutta, Marco Raffaele Cosenza, Thomas Eder, Johannes Foßelteder, Gabriel Pabst, Wolfgang Schöll, Andreas Prokesch, Holger W Auner, Albert Wölfler, Armin Zebisch, Andreas Reinisch, Florian Grebien, Jan O Korbel, Heinz Sill.

DOI: https://doi.org/10.1038/s41375-026-03106-x
Haematologica. 2026 Aug 13.

ATRA resistance conferred by a clustered subset of hotspot PML::RARA mutations enhancing basal repression rather than precluding transactivation.

Glauce M Barbosa, Hao Yuan, Izabella Tambones, Roland H Stote, Hsin Chieh Wu, Hugues De Thé, Albane Le Maire, Marie-Claude Geoffroy.

Most acute promyelocytic leukemia (APL), driven by the PML::RARA fusion, are now cured with targeted therapies combining all-trans retinoic acid (ATRA) and arsenic trioxide. Some patients treated with earlier ATRA/chemotherapy regimen developed resistance associated with mutations that most often preclude PML::RARA ATRA-binding. Here, we characterized a subset of clustered mutations associated with ATRA-resistance, but not predicted to affect ATRA binding. Most mutants indeed retained full ligand responsiveness, but displayed a basal super-repressive phenotype which did not result from an increased affinity for known corepressors such as NCoR and SMRT. Our findings suggest these mutations are gain-of-function associated with enhanced interactions with unidentified RARA partners with repressive ability. Similar to ATRA-resistant PLZF::RARA variants, these observations stress the role of persistent transcriptional repression of some retinoic acid target genes in acquired ATRA-resistance.

DOI: https://doi.org/10.3324/haematol.2025.300279
Leukemia. 2026 Aug 18.

Modeling KRAS mutations in KMT2A::MLLT3 acute myeloid leukemia promotes leukemic progression and transcriptional rewiring.

Nayeli Esparza, Joan Defrêne, Eva Bresson, Anne-Cécile Soufflet, Martha María Juárez-Rodríguez, Veronique Lisi, Alberto Hernández-Sánchez, Lars Bullinger, Vincent-Philippe Lavallée, Brian T Wilhelm, Frédéric Barabé.

DOI: https://doi.org/10.1038/s41375-026-03112-z
Leukemia. 2026 Aug 19.

A novel role for transcription factor NFE2 in redox regulation and chemotherapy resistance in acute myeloid leukemia.

Anne Marie Staehle, Florian Perner, Hans Felix Staehle, Katharina Gellrich, Fiona Preiß, Annika Grafemeyer, Jana Schulze, Jean-Luca Funk, Albert Gründer, Julia Berner, Sander Bekeschus, Christoph Koellerer, Heike L Pahl.

Elevated activity of transcription factor NFE2 is sufficient to cause leukemic transformation in absence of a classical leukemic driver. However, the molecular mechanism promoting NFE2-driven leukemogenesis is not known. Here we report a previously unrecognized role for NFE2 as a key regulator of the oxidative stress response in leukemic cells. Through a comprehensive analysis of NFE2 genomic occupancy and its effect on chromatin accessibility and transcription, we demonstrate that NFE2 regulates glutathione homeostasis as well as the expression of central detoxifying enzymes. NFE2 constituted one of the highest scoring gene dependencies in MLL-AF9-transformed primary leukemic cells under redox stress, substantially more significant than the universally recognized redox regulator NRF2. Consequently, NFE2 knockdown sensitized leukemic cells to GSH depletion, ferroptosis induction, as well as to cytarabine treatment. Deriving an NFE2 RedOx score, we demonstrate that increased NFE2 activity constitutes an independent predictor of inferior outcome in AML patients at diagnosis.

DOI: https://doi.org/10.1038/s41375-026-03095-x
Expert Rev Hematol. 2026 Aug 18.

Treatment of older adults with newly diagnosed FLT3-mutated AML: focus on lower-intensity triplet regimens.

Sankalp Arora, Naval Daver, Farhad Ravandi, Nicholas J Short.

   INTRODUCTION: Treatment options for older adults with FLT3-mutated AML who are unfit for intensive chemotherapy have evolved substantially. The combination of hypomethylating agent (HMA) and venetoclax is the current standard-of-care regimen for these patients, though outcomes remain suboptimal, particularly in FLT3-ITD mutated AML. More recently, encouraging data have emerged supporting the safety and efficacy of frontline HMA + venetoclax + FLT3 inhibitor 'triplet' regimens.
AREAS COVERED: We summarize the available evidence for different frontline treatment approaches in older adults with FLT3-mutated AML. We also discuss key practical considerations for the use of triplet regimens and provide recommendations to optimize drug doses and durations and improve tolerability. Relevant literature search was carried out using PubMed/MEDLINE databases through June 2026.
EXPERT OPINION: The HMA + venetoclax + FLT3 inhibitor triplet regimens, when administered with appropriate dose optimization and supportive care, can be delivered safely, with very high response rates and improved long-term survival in older adults with FLT3-mutated AML, positioning them as a potential new standard-of-care option. However, randomized controlled trial data are still awaited, and their safe administration requires close monitoring, robust supportive care and expertise that is most readily available at specialized academic centers.

Keywords:  FLT3; FLT3 inhibitor; hypomethylating agent; venetoclax

DOI:  https://doi.org/10.1080/17474086.2026.2720126
Blood Adv. 2026 Aug 20. pii: bloodadvances.2026020925. [Epub ahead of print]

Impact of cytoreductive therapy in myeloproliferative neoplasm-associated splanchnic vein thrombosis.

Douglas Tremblay, Amica Kurniati Ko, Pavlina Chrysafi, Joan How, Rebecca L Zon, Damon E Houghton, Atefeh Ghorbanzadeh, Dahniel Sastow, Sai Swetha Alladi, Maria Georgen, Abishta Prabhu, Vrushali Pachpande, Sai Sudha Valisekka, Balkrishna N Jahagirdar, Sargam Kapoor, Andrew Peseski, Radhika Gangaraju, Ruchi Desai, Guoliang Zheng, Shreyash Dalmia, Vinai Chander Bhagirath, Alejandro Godoy, Alessandra Iurlo, Daniele Cattaneo, Paola Guglielmelli, Alessandro M Vannucchi, Valentina Boldrini, Valerio De Stefano, Silvia Betti, Elena Rossi, Walter Ageno, Jonathan Berry, Margherita Maffioli, Mukul Aggarwal, Amiya Ranjan Nayak, Rishi Dhawan, Thita Chiasakul, Kristen Sanfilippo, Gabriela S Hobbs, John O Mascarenhas, Ronald Hoffman, Lisa Baumann Kreuziger, Rushad D Patell, Joan D Beckman, Mandy N Lauw.

Myeloproliferative neoplasm (MPN) patients are at risk of splanchnic vein thromboses (SVT). Prior studies have failed to demonstrate a benefit of hydroxyurea therapy in preventing recurrent thrombosis after SVT, but are limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. To better assess the impact of cytoreductive therapy on thrombosis recurrence, we performed a retrospective cohort study of MPN-SVT patients from the international GASTRO-MPN Consortium, treating cytoreductive therapy as a time-dependent covariate. We identified 757 patients, of which 43% were treated with cytoreductive therapy. During a median follow-up of 7.4 years, 256 patients (34%) had thrombosis recurrence; 145 (19%) had SVT extension/recurrence/TIPS thrombosis, 138 (18%) an thrombosis recurrence outside the splanchnic bed (74% were venous). Additionally, 262 patients (35%) experienced clinically relevant bleeding and 170 (22%) died. After adjusting for age, sex, prior thrombosis, timing of MPN diagnosis relative to SVT, anticoagulation initiation within 30 days of SVT diagnosis, MPN type, JAK2 status, other cancers and cirrhosis, cytoreductive therapy was associated with a decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). This was driven by a lower risk of SVT extension/recurrence (HR 0.62 95%CI 0.42-0.90, p=0.01) but not by extra-splanchnic thrombosis recurrence (HR 0.97 95%CI 0.72-1.30, p=0.82). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=275), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.07, p=0.09) for recurrent thrombosis. These data support the use of cytoreductive therapy in MPN-SVT patients to prevent recurrent thrombosis, particularly SVT extension/recurrence.

DOI: https://doi.org/10.1182/bloodadvances.2026020925
bioRxiv. 2026 Jul 28. pii: 2026.07.27.741029. [Epub ahead of print]

STING agonists in combination with epigenetic drugs potentiate ZNFX1-driven inflammatory necroptosis in TP53 -mutated AML.

Kaushlendra Tripathi, Lora Stojanovic, Zahra Gohari, Mostafa Abdelrheem, Gabriella Santos, Aviva Tyler, Brandon Cooper, Rena G Lapidus, Darren Perkins, Alonso Heredia, Kenneth P Nephew, Stephen B Baylin, Michael J Topper, Maria R Baer, Feyruz V Rassool.

TP53 -mutated acute myeloid leukemia (AML) has dismal outcomes with current treatments and represents a critical unmet need. TP53 -mutated AML is proposed to be susceptible to immunotherapeutic approaches but, to date, there is no established immunotherapy for this sub-group. Expression of stimulator of interferon genes (STING), a key innate immune driver that activates interferon (IFN) signaling, is decreased by epigenetic silencing or mutation in many cancers, including those with TP53 mutations. Here, we report that response to the next-generation synthetic STING agonist C92 is potentiated in AML cell lines and primary cells with TP53- mutated versus wild-type (WT) cells, representing a previously undescribed vulnerability of these leukemia cells to STING small molecule therapies. Moreover, combining treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC), significantly increases STING activation, with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes. Cell death in TP53 KO versus WT AML is specifically dependent on innate immune zinc finger NFX1-type containing 1 (ZNFX1) and Z-DNA-binding protein 1 (ZBP1) driving increased cleavage and activation of Receptor-Interacting-Serine/Threonine-Protein Kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL), suggesting mechanisms of necroptosis. Finally, C92 and DAC combination significantly reduces leukemia burden in humanized AML mouse models, accompanied by increased immune responses, including cytokines and cytotoxic T lymphocytes in the leukemia microenvironment. These results support development of clinical trial strategies combining STING agonists with DNMTis for patients with TP53 -mutated AML.
Summary: TP53-mutated AML potentiates effects of novel next-generation STING agonist C92, with unique allosteric and non-cyclic dinucleotide (non-CD) mechanism of action, inducing increased STING activation and cytokine release STING agonists and DNMTis, synergistically increase STING activation with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes in TP53 -mutated AML STING agonists induce necroptosis via a STING-ZNFX1-ZBP1-necroptosis axis in TP53 -mutated AML. This drug combination reduces leukemia burden, activates immune responses in AML models and supports translation for high-risk AML patients.
Statement of Translational Relevance: This pre-clinical study identifies a novel therapeutic vulnerability in ( TP53 )-mutated acute myeloid leukemia (AML), a poor prognosis subtype with a critical unmet need. Novel next-generation STING agonist C92, with unique allosteric and non-cyclic dinucleotide (non-CD) mechanism of action, induces increased STING activation and cytokine release, compared with WT TP53 in AML cell lines and primary cells, and has superior STING activity with respect to several STING agonists currently in clinical studies. Combining C92 treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) synergistically increases STING activation, with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes, driving ZNFX1-driven inflammatory necroptotic cell death. Utilizing humanized mouse models, C92 in combination with DAC significantly reduces leukemia burden and enhances cytotoxic T-cell responses in the tumor microenvironment, supporting clinical translation for high-risk AML patients.

DOI: https://doi.org/10.64898/2026.07.27.741029
N Engl J Med. 2026 Aug 20. 395(8): 788-802

Myeloproliferative Neoplasms.

Isabelle Plo, William Vainchenker.

Classic myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, and primary myelofibrosis, are chronic, clonal hematopoietic stem-cell disorders. These disorders are driven by gain-of-function mutations in the genes Janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL) that activate cytokine signaling. These mutations arise decades before clinical disease develops and confer a clonal advantage that is further shaped by comutations in epigenetic, splicing, or signaling genes. Inflammation enhances clonal dominance, favoring the development of myelofibrosis and thrombotic complications. Disease evolution may culminate in secondary acute myeloid leukemia, which has a poor prognosis. Current therapies primarily aim to control symptoms, thrombosis, and splenomegaly, but they have limited disease-modifying effects, except for pegylated interferon alfa and JAK2 inhibitors in some patients. Emerging therapies that selectively target mutant CALR and JAK2 V617F using immunotherapy and selective inhibitors could be a breakthrough in the treatment of persons with myeloproliferative neoplasms, with the expectation of achieving durable disease modification and potentially clonal eradication.

DOI: https://doi.org/10.1056/NEJMra2507867
Res Sq. 2026 Jul 30. pii: rs.3.rs-10436387. [Epub ahead of print]

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

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

FLT3-ITD mutations in acute myeloid leukemias (AMLs) cause ligand-independent signaling. One way signaling pathways potently and immediately influence cell fates is by phosphorylating key fate-determining proteins to trigger their proteolysis. We investigated the master transcription factor (MTF) driver of granulo-monocytic lineage-fates, CEBPA, for regulation by this mechanism because we found high CEBPA mRNA but little CEBPA protein in FLT3-ITD versus FLT3 -wildtype AML cells, and inhibiting FLT3-ITD signaling with tyrosine kinase inhibitors (TKI) rapidly rescued CEBPA protein. Mass spectrometry revealed that CEBPA interacts with major ubiquitin-proteasome pathway (UPP) components: the ubiquitin-ligase UHRF1 and the deubiquitinase USP7. TKI treatment decreased the phosphorylation of CEBPA (Ser21) and USP7 (Ser18) alongside shifts in CEBPA interactions from degradative UHRF1 to protective USP7, stabilizing CEBPA and activating differentiation. Similarly, TKIs and UPP inhibitors stabilized the USP7 client p53, triggering apoptosis specifically in FLT3-ITD cells. Notably, UPP inhibitors (such as bortezomib) successfully stabilized CEBPA and p53 even in TKI-resistant FLT3-ITD cells. Because FLT3-ITD signaling functionally suppresses CEBPA and p53, genetic mutations in CEBPA or TP53 were mutually exclusive with FLT3-ITD in clinical series. In summary, FLT3-ITD drives the UPP-mediated destruction of CEBPA and p53, positioning UPP inhibitors as promising therapeutic candidates acting downstream of TKIs.

DOI: https://doi.org/10.21203/rs.3.rs-10436387/v1
Cancer Metab. 2026 Jul 24. pii: 26. [Epub ahead of print]14(1):

PKM2 modulation regulates leukemia cell survival.

Nikolina Vrdoljak, Ekaterina N Parfenova, Alessia Roma, Drake A Mosca, Mark D Minden, Paul A Spagnuolo.

Acute myeloid leukemia (AML) cells exhibit aberrant metabolism defined by a shift away from oxidative phosphorylation and towards anaerobic glycolysis, favouring cell growth. Glycolytic enzymes are altered for this change to occur, including pyruvate kinase (PK), where the tetrameric and high activity M1 isoform (PKM1) is replaced with the predominantly dimeric and low activity M2 isoform (PKM2). Dimeric PKM2 produces less pyruvate and acts as a protein kinase in the nucleus, demonstrating divergent roles in both cell metabolism and as a transcriptional co-activator. In this study, the role of PKM2 in AML was defined, as PKM2 levels were elevated but PK enzymatic activity was reduced in AML cells compared to normal hematopoietic cells. Genetic and pharmacological studies show that decreasing and increasing PKM2 activity resulted in anti-AML effects both in vitro and in vivo. Indeed, these models show that inhibition and activation of PKM2 disrupt the native oligomeric state of the protein, resulting in reduced nuclear PKM2 accumulation and c-Myc expression, ultimately leading to cell death. Together, these results highlight the importance of PKM2 in AML, uncover the mechanisms by which both inhibition and activation cause AML cell death, and identify a novel modulator of PKM2 activity.

DOI: https://doi.org/10.1186/s40170-026-00440-7
Br J Haematol. 2026 Aug 21.

Use of selective serotonin reuptake inhibitors and risk of myeloid malignancy: A nationwide Danish case-control study.

Katrine Mose, Anton Pottegård, Mette Reilev, Christen Lykkegaard Andersen, Blánaid Hicks, Mathilde Egelund Christensen.

  Preclinical and clinical studies suggest that selective serotonin reuptake inhibitors (SSRIs) can stimulate haematopoiesis by promoting proliferation and mobilization of haematopoietic stem and progenitor cells, but whether SSRI use influences myeloid malignancy risk remains unclear. We therefore conducted a nationwide case-control study using Danish healthcare registries, including 22 293 adults with incident myeloid malignancy diagnosed during 2001-2022 and 445 860 cancer-free controls matched 1:20 on age, sex and calendar year. Ever SSRI use was defined as ≥1 filled prescriptions, and long-term use as prescriptions equivalent to >3 years of use. A 6-month lag period was applied to minimize reverse causation. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic regression adjusted for comorbidities, socioeconomic status and other psychotropic medications. SSRI use was not associated with increased myeloid malignancy risk compared with never use (adjusted OR, 0.98 [95% CI, 0.94-1.01] for ever use; 0.92 [95% CI, 0.86-0.97] for long-term use). No associations were observed across sex or age groups. Estimates were similar across myelodysplastic neoplasms, myeloproliferative neoplasms and acute myeloid leukaemia and individual SSRIs. These findings from a large nationwide study provide reassurance that SSRI treatment is not associated with a clinically meaningful increase in myeloid malignancy risk.

Keywords:  Danish registries; myeloid malignancy; nationwide; pharmacoepidemiology; selective serotonin reuptake inhibitors

DOI:  https://doi.org/10.1111/bjh.70779
Br J Haematol. 2026 Aug 21.

Enhanced prognosis of acute myeloid leukaemia patients with dmCEBPAbZIP -inf mutations: Insights from a multicentre Chinese cohort study.

Guanghui Chang, Pengcheng Shi, Liping Dou, Jinhai Ren, Hongyu Zhang, Qian Jiang, Hao Jiang, Lanping Xu, Xiaohui Zhang, Xiaojun Huang, Suning Chen, Feifei Tang.

  The 2022 European LeukemiaNet (ELN) recommendation redefined favourable-risk CCAAT/enhancer binding protein alpha (CEBPA)-mutated acute myeloid leukaemia (AML) by in-frame C-terminal basic leucine zipper domain (bZIP) mutations rather than double CEBPA mutations. We analysed 411 CEBPA-mutated AML patients from six Chinese centres, classified as single-mutant CEBPAbZIP-other (smCEBPAbZIP-other; n = 38), smCEBPAbZIP-inf (n = 39), double-mutant CEBPAother (dmCEBPAother; n = 37) and dmCEBPAbZIP-inf (n = 297). DmCEBPAbZIP-inf patients were younger, had more de novo AML and showed distinct co-mutation profiles, with more GATA binding protein 2 (GATA2) and fewer nucleophosmin 1 (NPM1)/DNA methyltransferase 3 alpha (DNMT3A) mutations. Additionally, dmCEBPAbZIP-inf patients had a higher composite complete remission (CRc) rate (94.6% vs. 84.2%-89.2%, p = 0.025) and better survival than the other three groups (3-year overall survival [OS]: 80.0% vs. 57.4%-70.6%, p < 0.001; 3-year disease-free survival [DFS]: 74.5% vs. 45.4%-67.9%, p = 0.002). Multivariable Cox regression analysis showed that dmCEBPAbZIP-inf and smCEBPAbZIP-inf had comparable survival, whereas dmCEBPAbZIP-inf had better survival than smCEBPAbZIP-other and dmCEBPAother. However, among intensively treated patients, dmCEBPAbZIP-inf was associated with superior survival compared with smCEBPAbZIP-inf (OS, hazard ratio [HR] = 1.542, p = 0.017; DFS, HR = 1.618, p = 0.014) and other two CEBPA groups in multivariable models. Among dmCEBPAbZIP-inf patients, intensive chemotherapy (HR = 0.51, p = 0.012), adverse karyotype (HR = 1.52, p = 0.037), age ≥50 years (HR = 1.74, p = 0.044), neuroblastoma RAS viral oncogene homolog (NRAS) (HR = 1.64, p = 0.014) and colony-stimulating factor 3 receptor (CSF3R) mutation (HR = 1.78, p = 0.049) were independent factors for OS. No significant difference in survival was observed between patients with CEBPAbZIP-indel and CEBPbZIP-ms mutations. In conclusion, the dmCEBPAbZIP-inf subgroup displayed unique co-mutation gene spectra and had better prognoses among the intensive treated cohort.

Keywords:   CEBPA ; acute myeloid leukaemia; bZIP in‐frame; co‐mutation

DOI:  https://doi.org/10.1111/bjh.70786
Blood. 2026 Aug 18. pii: blood.2026033792. [Epub ahead of print]

Sapablursen for Erythrocytosis Control in Patients with Polycythemia Vera.

Jeanne M Palmer, Jonathan How, Prithviraj Bose, Pankit Vachhani, Adam J Mead, Jonathan Sillar, Aaron T Gerds, Angela G Fleischman, Caitlin M O'Neill, Ross Ian Baker, Ronald Hoffman, Shiangtung Jung, Jon L Ruckle, Keyvan Yousefi, Sanjay Bhanot, Terrance D Barrett, Ruben A Mesa.

Polycythemia vera is characterized by erythrocytosis and increased risk of thrombosis. Sapablursen is an antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6), increases hepcidin production, and reduces iron availability for erythropoiesis. IMPRSSION; an ongoing phase 2a, randomized, open-label study includes patients meeting 2016 WHO criteria for polycythemia vera, requiring ≥3 phlebotomies within 6 months of screening and ≥1 phlebotomy within the last 12 weeks. Cohort A (120 or 80 mg) and Cohort B (40 mg) received sapablursen subcutaneously once every 4 weeks (Q4W). The primary efficacy endpoint was the reduction in phlebotomy frequency from baseline to weeks 17-37 in patients who received ≥1 dose. Forty-nine patients received ≥1 sapablursen dose (median age 61 years; 82% male). The baseline mean±SD weekly phlebotomy rate was 0.15±0.07 in Cohort A; 0.17±0.07 in Cohort B and was reduced by -0.10 (95%CI, -0.13, -0.07; n=32;p<0.0001) in Cohort A; -0.10 (95%CI, -0.14, -0.06; n=17;p=0.0001) in Cohort B. Sapablursen reduced the median (IQR) number of phlebotomies from 5.0 (3.0-6.0,Cohort A; 3.5-6.5,Cohort B) at baseline (26-weeks) to 0 (0-1.0) in the efficacy evaluation window (20-weeks) in Cohort A and 1.5 (0-2.5) in Cohort B. Most adverse events were mild or moderate; anemia and fatigue were most common. The mean change in MPN-SAF-TSS at week 37 was -6.21 points (95%CI: -10.56, -1.85, p=0.0052) in Cohort A; -2.71 points in Cohort B (95% CI: -8.33, 2.91, p=0.34). Sapablursen reduced phlebotomy need, improved symptoms, and was safe and well-tolerated in patients with polycythemia vera. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov: NCT05143957).

DOI: https://doi.org/10.1182/blood.2026033792
Br J Haematol. 2026 Aug 20.

Leveraging paired germline and somatic analysis to improve the classification of DDX41 variants.

Maajid Mohi Ud Din Malik.

DOI: https://doi.org/10.1111/bjh.70789
Blood Adv. 2026 Aug 20. pii: bloodadvances.2025018656. [Epub ahead of print]

CD55 promotes hematopoietic stem and progenitor cell survival in a mouse model of immune-mediated aplastic anaemia.

Foteini Kalampalika, Raul Sanchez-Lanzas, Amanda Jimenez-Pompa, Abigail Hateley, Miguel Ganuza.

Idiopathic aplastic anaemia (AA) is a life-threatening autoimmune bone marrow (BM) failure syndrome characterized by a hypocellular BM and peripheral pancytopenia. While dysregulation of the complement system has been implicated in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, its role in AA remains poorly understood. Notably, autoantibodies are frequently detected in AA patients and have the potential to activate the complement cascade. Using an immune-mediated murine model of AA, we found that allogeneic transplantation of splenocytes induced BM failure accompanied by activation of the complement system, as evidenced by elevated plasma levels of complement components C3 and C5. To functionally dissect the contributions of direct cytotoxic T-cell effects versus indirect mechanisms such as complement activation, we co-transplanted hematopoietic stem and progenitor cells (HSPCs) congenic to the donor splenocytes into allogeneic recipient mice. In this context, HSPCs deficient in the complement inhibitor Cd55 were negatively selected, indicating increased susceptibility to complement-mediated attack in vivo. Importantly, pharmacological inhibition of the complement cascade rescued the selective disadvantage of Cd55-deficient HSPCs in AA mice, demonstrating that complement activation imposes a negative selective pressure on HSPCs in this model. Together, these findings support a functional role for the complement pathway in the pathogenesis of immune-mediated AA. Further studies are warranted to evaluate the therapeutic potential of combining complement inhibition with standard immunosuppressive therapy in patients with AA.

DOI: https://doi.org/10.1182/bloodadvances.2025018656
Oncogene. 2026 Aug 17.

The Inv(16) Oncogene CBFB::MYH11 is Required for the Survival of Leukemia Cells in the Blood and Spleen, but not the Bone Marrow.

Sipra Panda, Yiqian Wang, Venkatasai Rahul Dogiparthi, Michelle Becker, Arjun Dhir, Calvin Lam, Cecilia Rivas, Lemlem Alemu, Lisa Garrett, Peng Xiao, Samantha A Swenson, Kyle J Hewitt, R Katherine Hyde.

Inversion of chromosome 16 [inv(16)] generates the fusion gene CBFB::MYH11 (CM) and is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML). Expression of CM is required for leukemia initiation. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption that CM is also required after leukemic transformation. However, a role for CM in leukemia maintenance has yet to be shown experimentally. To address this, we used an inducible CM knockdown (KD) mouse model and found that decreased CM eliminated leukemia cells from the peripheral blood and spleen, but not the bone marrow, despite all populations exhibiting significantly decreased CM mRNA and protein. The surviving CM KD cells in the bone marrow showed decreased apoptosis and proliferation, and increased expression of autophagy related genes. Surprisingly, with prolonged KD of CM, ~40% of mice re-established disease despite maintaining decreased CM. Our work indicates that CM is required for leukemia survival in the spleen and peripheral blood, but in the bone marrow CM KD leukemia cells can survive and re-establish disease independent of the fusion protein. These findings imply that targeting CM alone has potential to reduce leukemic burden but not cure the disease.

DOI: https://doi.org/10.1038/s41388-026-03956-w
Leuk Res. 2026 Aug 12. pii: S0145-2126(26)00143-8. [Epub ahead of print]169 108299

Cladribine-based salvage therapy in relapsed/refractory AML: A multicenter retrospective study.

Israeli Acute Leukemia Group (IALG)

  Treatment options after venetoclax-hypomethylating agent (Ven-HMA) failure in acute myeloid leukemia (AML) remain limited, with a median overall survival of 2-3 months. Cladribine targets biologically distinct leukemia stem cells, including monocytic populations implicated in venetoclax resistance. We conducted a multicenter retrospective study across six Israeli academic centers to evaluate cladribine-based salvage therapy, predominantly cladribine, low-dose cytarabine, and venetoclax (CAV), in 31 patients with relapsed/refractory AML. Median age was 70 years (range 21-81); 87% had prior venetoclax exposure, 61% had undergone prior allogeneic transplantation, and 55% were classified as ELN-2022 adverse risk. After a single treatment course, the composite complete remission rate (CRc) was 45% and the overall response rate was 52%. Median overall survival was 5 months, with a 1-year survival of 30%. Patients achieving CRc had significantly longer survival (16.2 vs. 2.9 months; p < 0.0001). Twelve patients (39%) were bridged to cellular therapy, with a median survival of 12.6 months. Toxicity was predominantly hematological; invasive fungal infection occurred in 23% and was associated with fluconazole rather than mold active prophylaxis. The 30-day mortality was 19%. Cladribine-based salvage demonstrates clinically meaningful activity after Ven-HMA failure and can bridge patients to cellular therapy.

Keywords:  Acute myeloid leukemia; Cladribine; Multicenter; Real-world; Relapsed/refractory; Salvage therapy

DOI:  https://doi.org/10.1016/j.leukres.2026.108299
Hemasphere. 2026 Aug;10(8): e70451

An Italian cartography of VEXAS-related thrombosis.

Giorgia Ranucci, Maria Rosaria Pascale, Vittorio Forte, Elisa Diral, Corrado Campochiaro, Jacqueline Ferrari, Mariachiara Cuccaro, Chiara Cattaneo, Francesca Crisafulli, Lucia Cardillo, Valeria Renola, Elisa Meddi, Marianna Velocci, Elisa Casciani, Francesca Romano, Pellegrino Musto, Serafina Barbato, Giorgia Battipaglia, Marco Frigeni, Erika Morsia, Arianna Savi, Cristina Papayannidis, Elena Crisà, Laura Cicconi, Isabella Capodanno, Alfonso Fiumarella, Antonio Pierini, Massimo Breccia, Giovanni Orsolini, Giulia Rivoli, Sara Bindoli, Davide Firinu, Antonio Vitale, Bruno Fattizzo, Monica Bocchia, Luca Cantarini, Chiara Pinton, Gabriele Todisco, Nicola Toschi, Paola Triggianese, Adriano Venditti, Maria Teresa Voso, Carmelo Gurnari.

Thrombotic events (TEs) occur in up to 40% of patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic (VEXAS) syndrome, but data on its clinical-genomics features and anticoagulation strategies are limited. To gain more insight into this, we conducted a two-step study evaluating the prevalence and outcome of TE in VEXAS. First, among 1086 patients followed for TEs, 198 were men aged >40 years with unprovoked thrombosis and no known thrombophilia; 21 also had at least one VEXAS-compatible feature and underwent UBA1 exon 3 testing. No UBA1 mutation was detected in these 21 patients. Next, we leveraged our Italian VEXAS network, and we accrued 87 molecularly confirmed Italian VEXAS cases (median age 70 years). Any history of TE was documented in 43/87 patients (49%), deep vein thrombosis being the most common (71%). Because follow-up varied, incident thrombosis was analyzed using a time-to-first-event framework from molecular VEXAS diagnosis, with death without prior TE treated as a competing event. Among 49 patients without prior/concomitant TE, five developed incident post-diagnosis TE; the 24-month cumulative incidence was 18.3%. Thrombophilia testing revealed a 15% co-occurrence, including heterozygous Factor V Leiden, Factor II G20210A, and anti-cardiolipin antibodies. Treatments comprised direct oral anticoagulants (DOACs) (51%), low molecular weight heparin (LMWH) (28%), Fondaparinux (14%), and vitamin K antagonists (AVKs) (7%). Notably, 27% experienced multiple TEs, of which 22% occurring despite anticoagulation during disease flares. Our findings provide an updated cartography of VEXAS-related TE, suggesting early screening for thrombophilia in these patients to inform both personalized anticoagulation and disease-control strategies.

DOI: https://doi.org/10.1002/hem3.70451
Br J Haematol. 2026 Aug 16.

Deep molecular remission and encouraging survival without transplantation: V-CAG for arsenic-resistant relapsed APL.

Ya-Lan Zhou, Ting Shi, Chuan-Ying Geng, Le-Fu Huang, Yuan Jian, Yun Leng, Yin Wu, Hong-Hu Zhu.



Keywords:  PML mutation; acute promyelocytic leukaemia; arsenic resistance; complete molecular remission; venetoclax

DOI:  https://doi.org/10.1111/bjh.70767