bims-tremyl 2025-07-20 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–07–20
35 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Utility of IDH1/2 mutations as biomarkers for detection of measurable residual disease in acute myeloid leukemia.
Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization.
Epigenetic dysregulation in acute myeloid leukemia.
Olutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome.
Multi-selective RAS(ON) Inhibition Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 and BCL2 Inhibitors in Acute Myeloid Leukemia.
Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy.
Superior GVHD-Free, Relapse-Free Survival for Haploidentical Transplant With PTCy Than Matched Unrelated Donor for AML Patients Transplanted in Second Complete Remission: A Study From the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
Enasidenib as treatment for AML with IDH2 mutation: multicenter real-life study of the early-access program in Spain.
Targeting bone marrow mesenchymal stromal cells-derived IL-6 to overcome acute myeloid leukemia chemoresistance.
Older matched sibling donor versus young haplo-identical donor for elderly patients with acute myeloid leukemia.
Clonal hematopoiesis driven by Dnmt3a mutations promotes metabolic disease development.
MYD88 mutations in clonal hematopoiesis promote inflammation and hematopoietic stem cell expansion.
Long-term follow-up and combined Phase 2 results of eprenetapopt and azacitidine in patients with TP53 mutant MDS/AML.
Ontogeny-specific induction of the KMT2A::AFF1-fusion drives development of a distinct CD24 positive pre-leukemic state.
The acute myeloid leukemia microenvironment impairs neutrophil maturation and function through NFκB signaling.
Differentiation, ageing and leukaemia alter the metabolic profile of human bone marrow haematopoietic stem and progenitor cells.
Multitargeted Reduction of Inflammation and Atherosclerosis in Tet2 -deficient CHIP via XPO1 Inhibition and Atf3 restoration.
Humanized mouse models in MDS.
2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia.
Evolution of clonal hematopoiesis on and off lenalidomide maintenance for multiple myeloma.
Comparative single-cell lineage bias in human and murine hematopoietic stem cells.
DNA demethylation-mediated downregulation of MNX1 in acute myeloid leukemia.
PRC2-mediated apoptosis evasion is a therapeutic target of MDS/AML harboring inv(3)/t(3;3) and monosomy 7.
Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia.
Phase 1 first-in-human dose-expansion study of the oral SF3B1 modulator H3B‑8800 in lower-risk myelodysplastic syndrome.
Aberrant splicing of CHEK1 is a driver of megakaryocytic dysplasia in U2AF1S34F mutant myelodysplastic neoplasms.
---RGI-2001 for the Prophylaxis of Acute Graft-Versus-Host Disease Following Allogeneic HCT.
Surface downmodulation of TIM3 safeguards healthy cells but not acute myeloid leukemia from CAR T-cell therapy.
ASXL1 truncating mutations drive leukemic resistance to T cell attack.
Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib.
Effects of Calreticulin Mutations on HLA Class I Expression in Myeloproliferative Neoplasms.
CRISPR-based therapeutic genome editing for inherited blood disorders.
Longitudinal single cell RNA-sequencing reveals evolution of micro- and macro-states in chronic myeloid leukemia.
Insights into the clinical, platelet and genetic landscape of inherited thrombocytopenia with malignancy risk.
Neutrophils drive vascular occlusion, tumour necrosis and metastasis.

Blood Adv. 2025 Jul 17. pii: bloodadvances.2025016726. [Epub ahead of print]

Utility of IDH1/2 mutations as biomarkers for detection of measurable residual disease in acute myeloid leukemia.

Emma L Boertjes, Christian M Vonk, François G Kavelaars, Marie Engvall, Sofia Nordin, Lisanne Beugelink, Melissa Rijken, Jolinda Konijnenburg, Jurjen Versluis, Bob Löwenberg, Peter J M Valk.

Molecular measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) patients has been established for only a few specific markers, i.e. mutant NPM1 and FLT3-ITD. Mutations in IDH1/2 are present in approximately 20% of AML patients. However, validation of mutant IDH1/2 MRD has been hampered by cohort size as well as the availability of highly sensitive and specific MRD detection assays. Here, we comprehensively investigate the impact of persisting IDH1/2 mutations in complete remission (CR) after intensive chemotherapy in a cohort of 163 newly diagnosed IDH-mutant AML patients enrolled in HOVON-SAKK clinical trials using a next-generation sequencing (NGS)-based approach, targeting all hotspot mutations in IDH1 (R132) and IDH2 (R140, R172). The high sensitivity (10-4) as well as the levels of persisting IDH1/2 mutations detected by the NGS-based approach were confirmed by an independent rolling circle amplification (superRCA) assay. We demonstrate that relapse risk was significantly increased in AML patients with measurable persisting IDH2 mutations (p=0.027, SHR:2.34), but not in patients with persisting mutant IDH1 (p=0.591, SHR:0.80). Moreover, the association of persistence of mutant IDH2 and increased risk of relapse was most pronounced in mutant IDH2 AML patients without concomitant NPM1 mutations or FLT3-ITD (p=0.011, SHR:5.29). Thus, mutant IDH2 appears a potentially useful novel molecular MRD marker with prognostic significance in AML.

DOI: https://doi.org/10.1182/bloodadvances.2025016726
Leukemia. 2025 Jul 16.

Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization.

Eric J Vick, Aishlin Hassan, Kwangmin Choi, Joshua Bennett, Tomoya Muto, Courtnee A Clough, Ashley E Culver-Cochran, Kathleen Hueneman, Lyndsey C Bolanos, Mark Wunderlich, Xiaohu Zhang, Crystal McKnight, Michele Ceribelli, David Holland, Carleen Klumpp-Thomas, Kenneth D Greis, Craig J Thomas, Daniel T Starczynowski.

IRAK4 is a therapeutic target in myeloid malignancies, but current IRAK4 inhibitors show only modest clinical efficacy in acute myeloid leukemia, highlighting the need for combination strategies. To identify drugs with synergistic potential alongside IRAK4 inhibitors, we conducted a high-throughput screen of 2803 investigational and approved drugs in isogenic IRAK4-deficient and wild-type human AML cells. The top hit from this screen was the Cereblon E3 ligase modulator (CELMoD) CC-885. Validation in vitro and in vivo confirmed that CC-885 and related CELMoDs synergize with IRAK4 inhibitors to suppress leukemic cells. Among CC-885 substrates, GSPT1 loss showed the most pronounced effects in IRAK4-inhibited leukemic cells. Transcriptional and proteomic analyses revealed that CC-885 treatment led to c-Myc suppression in IRAK4-deficient leukemic cells. GSPT1 loss reduces translation efficiency, particularly for proteins with short half-lives, such as c-Myc. Accelerated c-Myc protein loss was confirmed following GSPT1 degradation in leukemic cells, with decreased protein stability observed following inhibition of IRAK4. These effects were validated in AML patient cells, supporting the potential of IRAK4 inhibitors to modulate c-Myc activity and enhance combinatorial therapies. This study demonstrates that IRAK4 is a therapeutic target in AML, and that combination therapies, such as with certain GSPT1-targeting CELMoDs, will be necessary to achieve maximal clinical responses.

DOI: https://doi.org/10.1038/s41375-025-02695-3
Semin Hematol. 2025 Jun 19. pii: S0037-1963(25)00028-9. [Epub ahead of print]

Epigenetic dysregulation in acute myeloid leukemia.

Jens Schrezenmeier, B J P Huntly.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy defined by the clonal expansion of undifferentiated myeloid blasts with a block in differentiation and aberrant self-renewal. While recurrent genomic mutations are well-documented in AML, epigenetic dysregulation has emerged as an equally pivotal driver of leukemogenesis, a notion corroborated by the frequent recurrence of mutations in epigenetic regulators. Leukemic cells exhibit pervasive epigenetic alterations-including abnormal DNA methylation patterns, dysregulated histone modification, disrupted chromatin architecture and RNA-based regulatory mechanisms -which collectively rewire gene expression programs. These changes silence key differentiation genes and sustain self-renewal pathways, enforcing the developmental arrest and hyper-proliferation that are the hallmarks of AML. Importantly, epigenetic aberrations in AML are not merely downstream consequences of genetic lesions but actively contribute to the malignant phenotype. Somatic mutations frequently target epigenetic regulators (for example, DNA methyltransferases or histone modifiers), and these lesions cooperate with other genetic alterations to initiate and maintain the leukemic clone. Together, these insights highlight epigenetic dysregulation as a central mechanism in AML pathogenesis.

DOI: https://doi.org/10.1053/j.seminhematol.2025.06.003
Blood Adv. 2025 Jul 16. pii: bloodadvances.2025016718. [Epub ahead of print]

Olutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome.

Jorge E Cortes, Jay Yang, Gail J Roboz, Shira Naomi Dinner, Eunice S Wang, Andrew H Wei, Hua Tian, Francois di Trapani, Maria R Baer, William B Donnellan, Justin M Watts.

Olutasidenib, a potent, selective, oral small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is FDA-approved for mIDH1 relapsed/refractory (R/R) acute myeloid leukemia based on results from the pivotal AML cohort of a multi-arm phase 1/2 trial that also enrolled patients with MDS (NCT02719574). We report pooled data evaluating olutasidenib as monotherapy or combined with azacitidine in R/R and treatment-naïve (TN) higher-risk MDS harboring mIDH1. Endpoints included safety, overall response rate (ORR), complete remission (CR) rate, time-to-response (TTR), duration of response (DOR), overall survival (OS), and transfusion-independence. Twenty-two patients (median age 74 years, 59% male) with IPSS-R intermediate- to very high-risk MDS (n=6 monotherapy [4 R/R, 2 TN]; n=16 combination [11 R/R, 5 TN]) were analyzed. The most frequent AEs were fatigue and cytopenias. Differentiation syndrome occurred in 3 patients (14%); 1(5%) grade 3 severity. QT prolongation occurred in 1 patient receiving combination therapy. ORR was 59% (CR: 27%, 6/22; marrow CR: 32%, 7/22) in intent-to-treat (n=22, ITT) and 68% (CR: 32%, 6/19; marrow CR: 37%, 7/19) in response-evaluable (n=19) patients. ORR (ITT population) was 33% (2/6) for monotherapy (3/6 patients received £half the recommended dose) and 69% (11/16) for combination therapy. Median TTR was 2 months (range 1-13), median DOR 14.6 months (95% CI, 5.8-32.8), and median OS 27.2 months (95% CI, 6.9-37). 62% and 67% of patients who were transfusion-dependent at baseline achieved 56-day RBC and platelet transfusion independence, respectively. Olutasidenib with or without azacitidine demonstrated encouraging clinical activity and tolerability in patients with higher-risk mIDH1 MDS. NCT02719574.

DOI: https://doi.org/10.1182/bloodadvances.2025016718
bioRxiv. 2025 Jun 14. pii: 2025.06.10.658786. [Epub ahead of print]

Multi-selective RAS(ON) Inhibition Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3 and BCL2 Inhibitors in Acute Myeloid Leukemia.

Bogdan Popescu, Matthew F Jones, Madison Piao, Elaine Tran, Andrew Koh, Isabelle Lomeli, Cheryl A C Peretz, Natalia Murad, Sydney Abelson, Carolina Morales, Jose M Rivera, Yana Pikman, Michael L Cheng, Aaron C Logan, Elliot Stieglitz, Catherine C Smith.

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

DOI: https://doi.org/10.1101/2025.06.10.658786
Nat Genet. 2025 Jul 15.

Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy.

Jie Liu, Duc Tran, Liying Xue, Brian J Wiley, Caitlyn Vlasschaert, Caroline J Watson, Hamish A J MacGregor, Xiaoyu Zong, Irenaeus C C Chan, Indraniel Das, Md Mesbah Uddin, Abhishek Niroula, Gabriel Griffin, Benjamin L Ebert, Taralynn Mack, Yash Pershad, Brian Sharber, Michael Berger, Ahmet Zehir, Ryan Ptashkin, Ross L Levine, Elli Papaemmanuil, Vijai Joseph, Teng Gao, Yelena Kemel, Diana Mandelker, Konrad H Stopsack, Paul D P Pharoah, Semanti Mukherjee, Li Ding, Yin Cao, Matthew J Walter, Jamie R Blundell, Nilanjan Chatterjee, Kenneth Offit, Lucy A Godley, Daniel C Link, Zsofia K Stadler, Alexander G Bick, Pradeep Natarajan, Kelly L Bolton.

With age, clonal expansions occur pervasively across normal tissues yet only in rare instances lead to cancer, despite being driven by well-established cancer drivers. Characterization of the factors that influence clonal progression is needed to inform interventional approaches. Germline genetic variation influences cancer risk and shapes tumor mutational profile, but its influence on the mutational landscape of normal tissues is not well known. Here we studied the impact of germline genetic variation on clonal hematopoiesis (CH) in 731,835 individuals. We identified 22 new CH-predisposition genes, most of which predispose to CH driven by specific mutational events. CH-predisposition genes contribute to unique somatic landscapes, reflecting the influence of germline genetic backdrop on gene-specific CH fitness. Correspondingly, somatic-germline interactions influence the risk of CH progression to hematologic malignancies. These results demonstrate that germline genetic variation influences somatic evolution in the blood, findings that likely extend to other tissues.

DOI: https://doi.org/10.1038/s41588-025-02250-x
Am J Hematol. 2025 Jul 12.

Superior GVHD-Free, Relapse-Free Survival for Haploidentical Transplant With PTCy Than Matched Unrelated Donor for AML Patients Transplanted in Second Complete Remission: A Study From the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Yishan Ye, Myriam Labopin, Ibrahim Yakoub-Agha, Gérard Socié, Didier Blaise, Tobias Gedde-Dahl, Igor Wolfgang Blau, Anna Maria Raiola, Jennifer Byrne, Etienne Daguindau, Hélène Labussière-Wallet, Anne Huynh, Ali Bazarbachi, Arnon Nagler, Eolia Brissot, Lin Li, Yi Luo, Jimin Shi, Mohamad Mohty, He Huang, Fabio Ciceri.

  Donor preference for acute myeloid leukemia (AML) patients transplanted in second complete remission (CR2) remains unclear, and hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) from a haploidentical donor (HAPLO) merits attention. Data of 3878 adult AML patients receiving a first allo-HCT in CR2 from the European Society of Blood and Marrow Transplantation registry between 2010 and 2022 were analyzed. Univariate analyses and Cox regression models were used. Results of HCTs from 803 HAPLO PTCy, 1271 matched sibling donor (MSD), and 1804 matched unrelated donor (MUD) were analyzed. A higher proportion (80.7%) of patients with European LeukemiaNet (ELN2022) intermediate-/adverse-risk cytogenetics received an allo-HCT from HAPLO PTCy than from either MUD (79.6%) or MSD (70.2%). On multivariate analysis, HAPLO PTCy grafts (hazard ratio [HR] = 0.65, 95% confidence interval [CI] 0.51-0.82; p < 0.001) were associated with a lower relapse incidence (RI) compared with MSD HCTs, although non-relapse mortality was higher (HR = 1.77, 95% CI 1.34-2.34; p < 0.001). No difference was observed with respect to leukemia-free survival and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) for HAPLO PTCy compared to MSD grafts. Notably, HAPLO PTCy HCT was associated with significantly lower RI (HR = 0.64, 95% CI 0.48-0.82; p < 0.001), chronic GVHD (cGVHD) (HR = 0.64, 95% CI 0.51-0.81; p < 0.001) and extensive cGVHD (HR = 0.47, 95% CI 0.34-0.66; p < 0.001) incidences compared to MUD HCTs. Collectively, HAPLO PTCy HCT was associated with superior GRFS (HR = 0.81, 95% CI 0.68-0.95; p = 0.013) than MUD HCT. For AML patients in CR2, HAPLO PTCy HCT is associated with lower RI and cGVHD, leading to superior GRFS compared with MUD HCTs.

Keywords:  acute myeloid leukemia; haploidentical hematopoietic cell transplantation; post transplant cyclophosphamide; second complete remission

DOI:  https://doi.org/10.1002/ajh.70008
Ann Hematol. 2025 Jul 12.

Enasidenib as treatment for AML with IDH2 mutation: multicenter real-life study of the early-access program in Spain.

Carlos Jiménez-Vicente, Paola Beneit, Isabel Cano-Ferri, Brayan Merchán, Montserrat Arnan, Antoni García Guiñón, Cristina Martínez-Bilbao, Ana Alfonso, Pilar Martínez-Sánchez, Juan Manuel Alonso-Domínguez, Oriana López-Godino, Sandra Castaño-Díez, Inés Zugasti, Jordi Esteve, Marina Díaz-Beyá, Adolfo de la Fuente.

Enasidenib is an oral IDH2 inhibitor that reduces the production of the oncometabolite 2-hydroxyglutarate, differentiating IDH2 mutated leukemic cells with initial promising results for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. We performed a retrospective study in Spain evaluating enasidenib in patients diagnosed with IDH2-mutated myeloid neoplasms (AML, MDS, myeloid sarcoma and chronic myelomonocytic leukemia (CMML). Twenty-three patients were included, with 20 having a refractory/relapsed (R/R) disease status. The median age was 73 years, and the majority patients were classified as adverse risk by the European LeukemiaNet 2022 criteria. The most frequent mutation was IDH2 R140 (69.6%), while 30.4% had R172 mutation. Enasidenib was administered as a single agent in 18 patients, in combination with azacitidine in four patients, and with low-dose cytarabine in another one. The median number of cycles administered was four, with an overall response rate (ORR) of 39.1% and a morphological complete remission (CR) rate of 26.1%. Median overall survival (OS) was 8.3 months. Patients who achieved a complete response had a better outcome than the rest of the patients in terms of OS (19.8 months (95%CI: 15.7-NR) vs. 4.2 (95%CI: 1.5-NR), p = 0.01). Drug-related events included leukocytosis in five patients (21.7%), hyperbilirubinemia in six patients (26.1%) and differentiation syndrome (DS) in four patients (17.4%), including one grade 3 DS and one death related to this latter adverse event (AE), similar to previous findings. Although enasidenib failed to demonstrate a clear overall survival advantage in phase 3 trials, the extended responses and long-term survivors observed herein underscore its therapeutic potential. Ultimately, our data support enasidenib's role as a targeted therapy for IDH2-mutated AML, indicating that expanded access to this agent is warranted to optimize outcomes in these challenging patient populations, especially for R/R AML patients.

DOI: https://doi.org/10.1007/s00277-025-06464-1
Blood Adv. 2025 Jul 16. pii: bloodadvances.2024015496. [Epub ahead of print]

Targeting bone marrow mesenchymal stromal cells-derived IL-6 to overcome acute myeloid leukemia chemoresistance.

Diyu Hou, Danni Cai, Wei Dai, Xinai Liao, Maoqing Tan, Xiaoming Zheng, Liuhuan Wang, Jingru Liu, Jin Wang, Xiaoting Wang, Qiang Fu, Huifang Huang.

In acute myeloid leukemia (AML), elevated IL-6 levels in the bone marrow (BM) are linked to poor prognosis. However, the mechanisms driving this elevation and its role in chemoresistance remain unclear. Using the Prrx1-Cre system, we selectively deleted Il6 in BM mesenchymal stromal cells (MSCs) and established an AML mouse model. Our results show that MSCs are a major source of IL-6 in AML BM. Importantly, Il6 deletion in MSCs reduced oxidative phosphorylation (OXPHOS) activity in AML cells, slowed disease progression, and enhanced the chemosensitivity to cytarabine (Ara-C). Similarly, the OXPHOS inhibitor IACS-010759 improved chemosensitivity in AML mice. Exogenous recombinant IL-6 reversed the chemosensitivity gains from Il6 deletion, confirming its role in chemoresistance. We further demonstrated that Il6 absence in MSCs inhibits mitochondria transfer to AML cells, dampening OXPHOS and enhancing Ara-C efficacy. In summary, our study underscores the critical role of Il6 from MSCs in AML progression and chemoresistance. Targeting IL-6 in MSCs may offer a promising therapeutic strategy for AML. NCT06486350.

DOI: https://doi.org/10.1182/bloodadvances.2024015496
Blood Adv. 2025 Jul 16. pii: bloodadvances.2024015582. [Epub ahead of print]

Older matched sibling donor versus young haplo-identical donor for elderly patients with acute myeloid leukemia.

Xavier Poire, Myriam Labopin, Emmanuelle Polge, Didier Blaise, Patrice Chevallier, Johan A Maertens, Nicolaus Kröger, Caroline Besley, Stephanie Nguyen, Cristina Castilla-Llorente, Gérard Socié, Edouard Forcade, Anne Huynh, Igor Wolfgang Blau, Arnon Nagler, Jaime Sanz, Simona Piemontese, Mohamad Mohty, Fabio Ciceri.

Selection of a suitable donor for allogeneic hematopoietic stem cell transplantation (allo-HCT) has mainly relied on human leukocyte antigen matching, and to date, a matched sibling donor (MSD) remains the first choice. However, patients with acute myeloid leukemia (AML) are older and therefore, have older siblings. Haplo-identical donors (HID) are easily available, and offspring are younger than siblings. As donor age has been associated with worse outcomes, a younger HID might be a better choice than an older MSD for older AML transplanted in first complete remission (CR1). We selected from the EBMT registry database, patients with AML, aged ≥60 years and transplanted in CR1, either from MSD aged ≥50 years or HID £ 40 years. All HID received post-transplant cyclophosphamide as graft-versus-host disease (GvHD) prophylaxis and MSD receiving in vivo T-cell depletion were included. A total of 1247 patients were identified, including 721 MSD and 526 HID. In univariate analysis, HID was associated with lower relapse incidence (p=0.01), higher non-relapse mortality (NRM) (p=0.01) and higher incidence of grade II-IV acute GvHD (p=0.01). The 2-year probability of overall survival (OS), leukemia-free survival (LFS) and GvHD-free and relapse-free survival (GRFS) were 62.5%, 56% and 47%, respectively, without any significant difference between groups. In multivariate analysis, we confirmed that HID was associated with less relapse but more NRM, which translated into similar OS, LFS and GRFS. Based on this retrospective study, young HID led to less relapse but higher NRM than older MSD after allo-HCT in an older AML population in CR1.

DOI: https://doi.org/10.1182/bloodadvances.2024015582
bioRxiv. 2025 May 08. pii: 2025.05.02.651715. [Epub ahead of print]

Clonal hematopoiesis driven by Dnmt3a mutations promotes metabolic disease development.

Bowen Yan, Qingchen Yuan, Prabhjot Kaur, Annalisse R Mckee, Daniil E Shabashvili, Olga A Guryanova.

Clonal hematopoiesis (CH) is associated with an increased risk of non-hematologic chronic diseases including metabolic disorders, yet the causality remains poorly defined. DNMT3A is the most frequently altered gene in CH, commonly through monoallelic loss-of-function (LOF) and Arg882His (RH) hotspot mutations. Here we demonstrate in a mouse model that CH driven by Dnmt3a RH and especially LOF promotes obesity, diabetes, and chronic liver disease, further exacerbated by high-fat diet (HFD).

DOI: https://doi.org/10.1101/2025.05.02.651715
bioRxiv. 2025 Jun 25. pii: 2025.06.19.660202. [Epub ahead of print]

MYD88 mutations in clonal hematopoiesis promote inflammation and hematopoietic stem cell expansion.

Jennifer Yeung, Sophia Y Philbrook, Emma Uible, Lynn Lee, Kwangmin Choi, Puneet Agarwal, Courtnee A Clough, Pravin Patel, Kathryn A Wikenheiser-Brokamp, Kathleen Hueneman, Hans Christian Reinhardt, Tzyy-Jye Doong, Arletta Lozanski, Gerard Lozanski, Tamanna Haque, Erin Hertlein, John C Byrd, Daniel T Starczynowski.

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by expansion of mutant hematopoietic stem and progenitor cells (HSPCs) and an increased risk of chronic diseases and cancers. While mutations in DNMT3A , TET2 , and ASXL1 are common in CHIP, the contribution of less frequent gene mutations is not well understood. Here, we report MYD88 mutations, including lymphoma-associated and novel variants in blood cells of the general population and newly diagnosed solid cancer patients. MYD88 CHIP mutations in HSPCs activate NF-κB, indicating a gain-of-function activity. Modeling MYD88 CHIP in mice, Myd88 L252P (equivalent of human L265P) expression resulted in a competitive fitness advantage of HSPCs. Myd88 L252P HSPCs exhibit a myeloid cell bias and inflammation, leading to hematologic disease. Single-cell RNA sequencing indicated that Myd88 L252P expands distinct hematopoietic and immune cell clusters and activates immune-related pathways in HSPCs. An IRAK1/4 inhibitor suppressed MYD88-dependent NF-κB activation and reversed Myd88 L252P cell expansion. Overall, MYD88 mutations contribute to CHIP by inducing innate immune pathways in HSPCs and inflammatory disease.

DOI: https://doi.org/10.1101/2025.06.19.660202
Hemasphere. 2025 Jul;9(7): e70164

Long-term follow-up and combined Phase 2 results of eprenetapopt and azacitidine in patients with TP53 mutant MDS/AML.

David A Sallman, Rami S Komrokji, Amy E Dezern, Marie Sebert, Guillermo Garcia-Manero, Ramy Rahmé, Eric S Winer, Jacqueline Lehmann-Che, Gail J Roboz, Isabelle Madelaine, Mikkael A Sekeres, Pierre Peterlin, Onyee Chan, Odile Beyne-Rauzy, Andrew Kuykendall, Christian Recher, Amy McLemore, Aspasia Stamatoullas, Ling Zhang, Lise Willems, Qianxing Mo, Emmanuel Raffoux, Lisa Nardelli, Céline Berthon, Najla H Al Ali, Bruno Quesnel, Eric Padron, Hagop M Kantarjian, Alan F List, Lionel Ades, Jeffrey E Lancet, Pierre Fenaux, Thomas Cluzeau.

TP53 gene mutations (mTP53) represent a distinct molecular cohort with poor outcomes. Eprenetapopt (APR-246) is a novel, first-in-class small molecule that reactivates p53 and targets cellular redox balance, ultimately inducing apoptosis and ferroptosis in mTP53 cancer cells. This is a multicenter, international collaboration of the US myelodysplastic syndromes/neoplasms (MDS) clinical research symposium and the Groupe Francophone des Myelodysplasies (GFM) of hypomethylating agents-naïve mTP53 higher risk MDS and oligoblastic acute myeloid leukemia (AML; ≤30% blasts; NCT03072043/NCT03588078). Patients received eprenetapopt 4500 mg iv (Days 1-4) + azacitidine 75 mg/m2 sc/iv × 7 days in 28-day cycles. The primary objective was the complete remission (CR) rate by International Working Group (IWG) 2006 criteria. In total, 100 patients were enrolled with a median age of 68 years (34-87; 47% male). Febrile neutropenia occurred in 37% of patients. Thirty- and 60-day mortality was 1% and 7%, respectively. By intention-to-treat, overall response rate by IWG was 69% with 41% CR. The median duration of CR was 10.2 months (95% CI 8.7-11.8). With a median follow-up of 52 months, median overall survival (OS) was 11.8 months (95% CI 9.4-14.3). Although allogeneic hematopoietic cell transplantation (allo-HCT) was borderline predictive of OS in the overall cohort by landmark analysis (14.7 vs. 14.4 months; P = 0.046), OS was significantly improved in allo-HCT patients based on CR/TP53 next-generation sequencing (NGS) negativity (P = 0.00085; 2-year OS of 54%). In this international, combined analysis of Phase 2 eprenetapopt + azacitidine patients, the combination was well-tolerated with synergistic response rates in mTP53 MDS/AML. Quality of response and NGS negativity strongly predicted OS, particularly in the setting of allo-HCT, validating NGS clearance as a critical biomarker of allo-HCT outcomes in mTP53 patients.

DOI: https://doi.org/10.1002/hem3.70164
Leukemia. 2025 Jul 11.

Ontogeny-specific induction of the KMT2A::AFF1-fusion drives development of a distinct CD24 positive pre-leukemic state.

Ariana S Calderón, Roshanak Ghazanfari, Zahra Masoumi, Shabnam Kharazi, Sara Palo, Stefan Lang, Kristijonas Žemaitis, Mohamed Eldeeb, Agatheeswaran Subramaniam, Shamit Soneji, Ronald W Stam, David Bryder, Charlotta Böiers.

Infant Acute Lymphoblastic Leukemia (ALL) driven by the KMT2A::AFF1 onco-fusion is an aggressive, poor prognosis disease with few co-operative mutations. The fusion originates in utero, yet the embryonic initiating steps of disease development remain poorly understood. Here, we present a novel murine KMT2A::AFF1 model, that provides key insights into KMT2A::AFF1 pre-leukemia, relevant to human disease. The model enables precise oncogene induction, and upon targeting hematopoietic stem and progenitor cells (HSPCs) a selective negative impact on proliferation of hematopoietic stem cells (HSCs) was observed, regardless of developmental state during induction. However, a unique CD24+PreProB subset expanded exclusively within the KMT2A::AFF1 embryonic context. This population was absent when targeting lymphoid progenitors, highlighting the importance of the cell of origin for leukemic development. The CD24+PreProB subset displayed key features of pre-leukemic stem cells, including lineage plasticity and aberrant engraftment ability. In line with their pre-malignant phenotype, single-cell transcriptomics revealed a signature consistent with stemness, and notable, up-regulation of Hmga2, a regulator of self-renewal. The signature was critically transferable to human KMT2A::AFF1 patients. Furthermore, given that CD24 is a potential therapeutic target, our findings uncover a distinct embryonic pre-leukemic state with direct relevance to human disease.

DOI: https://doi.org/10.1038/s41375-025-02665-9
Blood. 2025 Jul 15. pii: blood.2024028199. [Epub ahead of print]

The acute myeloid leukemia microenvironment impairs neutrophil maturation and function through NFκB signaling.

Paran Goel, Sajesan Aryal, Alana M Franceski, Valeriya Kuznetsova, Amanda Fernandes De Oliveira Costa, Francesca Luca, Ashley N Connelly, Daniel W Phillips, Caroline C Ennis, Brittany M Curtiss, Sourajeet Karfa, Brittany L Crown, Christina R Larson, Estelle Carminita, Virginia Camacho, Doug Welsch, Changde Cheng, Asumi Yokota, Isidoro Cobo, Hideyo Hirai, Rui Lu, Ravi Bhatia, Pran K Datta, Paul Brent Ferrell, Robert S Welner.

Acute myeloid leukemia (AML), an aggressive hematological malignancy, is driven by oncogenic mutations in stem and progenitor cells that give rise to AML blasts. While these mutations are well-characterized, their impact on healthy hematopoiesis-those blood cells exposed to AML but not mutated-has not been well-characterized. As the marrow is the major site for granulopoiesis, neutrophils are heavily influenced by AML pathobiology. Indeed, most AML patients report neutropenia, rendering them susceptible to infections. However, since AML studies use peripheral blood mononuclear cells devoid of neutrophils, the characterization of neutrophil dysfunction remains poorly understood. To investigate AML-exposed neutrophils, a pre-clinical AML mouse model was used where primary leukemic cells were transplanted into non-irradiated neutrophil reporter (Ly6G-tdTomato; Catchup) hosts. Neutrophils could not completely mature, suggesting impaired granulopoiesis. Single-cell transcriptomics of AML-exposed neutrophils revealed higher inflammation signatures and expression of CD14, an inflammatory marker. To address the factors contributing to this biology, an ex vivo cytokine screen was performed on marrow neutrophils and identified that NFκB signaling drove CD14 expression. AML-exposed neutrophils displayed widespread chromatin remodeling, and de novo motif discovery predicted increased binding sites for CCAAT-enhancer-binding proteins (C/EBPs) and Interferon regulatory factors (IRFs). Moreover, AML-exposed neutrophils inhibited T-cell proliferation, highlighting their immune-suppressive capability. Finally, similar biology of immature, inflammatory neutrophils was found in AML patients, again indicating dysregulated granulopoiesis. Collectively, these data show that AML-associated inflammation alters neutrophil granulopoiesis, impairs neutrophil function, and drives immunosuppression, thus contributing to patient susceptibility to infection.

DOI: https://doi.org/10.1182/blood.2024028199
Nat Cell Biol. 2025 Jul 15.

Differentiation, ageing and leukaemia alter the metabolic profile of human bone marrow haematopoietic stem and progenitor cells.

Maria-Eleni Lalioti, Mari Carmen Romero-Mulero, Noémie Karabacz, Julian Mess, Helen Demollin, Jasmin Rettkowski, Konrad Schuldes, Michael Mitterer, Carolin Wadle, Khalid Shoumariyeh, Mirijam Egg, Carlos Alfonso-Gonzalez, Karin Jäcklein, Katharina Schönberger, Nikolaos Karantzelis, Gregor Reisig, Philipp Aktories, Isabella M Mayer, Ioanna Tsoukala, Alexander Schäffer, Irene Tirado-Gonzalez, Aurélien Dugourd, Lukas M Braun, Beatriz Silva-Rego, Michael-Jason Jones, Katrin Kierdorf, Julio Saez-Rodriguez, Kilian Reising, Sebastian Gottfried Walter, Hind Medyouf, Valérie Hilgers, Gabriel Ghiaur, Robert Zeiser, Darja Karpova, Simon Renders, Sascha Gravius, Joerg Buescher, Nina Cabezas-Wallscheid.

Metabolic cues are crucial for regulating haematopoietic stem and progenitor cells (HSPCs). However, the metabolic profile of human HSPCs remains poorly understood due to the limited number of cells and the scarcity of bone marrow samples. Here we present the integrated metabolome, lipidome and transcriptome of human adult HSPCs (lineage-, CD34+, CD38-) upon differentiation, ageing and acute myeloid leukaemia. The combination of low-input targeted metabolomics with our newly optimized low-input untargeted lipidomics workflow allows us to detect up to 193 metabolites and lipids from a starting material of 3,000 and 5,000 HSPCs, respectively. Among other findings, we observe elevated levels of the essential nutrient choline in HSPCs compared with downstream progenitors, which decline upon ageing and further decrease in acute myeloid leukaemia. Functionally, we show that choline supplementation fuels lipid production in HSPCs and enhances stemness. Overall, our study provides a comprehensive resource identifying metabolic changes that can be utilized to promote and enhance human stem cell function.

DOI: https://doi.org/10.1038/s41556-025-01709-7
bioRxiv. 2025 Jun 17. pii: 2025.06.12.658927. [Epub ahead of print]

Multitargeted Reduction of Inflammation and Atherosclerosis in Tet2 -deficient CHIP via XPO1 Inhibition and Atf3 restoration.

Nicole Prutsch, Amélie Vromman, Brittaney Leeper, Mengyu Chen, Julia Keating, Shuning He, Alla Berezovskaya, Siyang Ren, Mariana Janini Gomes, Eduardo J Folco, Philipp J Rauch, Prafulla C Gokhale, Mark W Zimmerman, Donna S Neuberg, Brian J Abraham, Peter Libby, A Thomas Look.

TET2 is the second most frequently mutated gene in clonal hematopoiesis of indeterminate potential (CHIP), driving hematopoietic stem cell clonal expansion and increasing the risk of myeloid malignancies. Affected individuals often develop atherosclerotic cardiovascular disease, exacerbated by hyperinflammatory TET2 -mutant macrophages. Here, we show that the XPO1 nuclear export inhibitor eltanexor significantly reduces atherosclerotic plaque formation in a mouse model of Tet2 -mutant CHIP. In addition, we investigated the mechanisms and gene expression pathways that underlie the proinflammatory phenotype that characterizes Tet2 -mutant CHIP. Single-cell CITE-seq identified increased expression of multiple proinflammatory mediators in Tet2 -mutant macrophages and in non-hematopoietic cells of the aortic wall, which was reduced by eltanexor treatment. Atf3 , which encodes a core transcriptional modulator of inflammation, occupies and regulates the largest enhancer in wild-type macrophages. Tet2 loss diminished ATF3 binding to the regulatory loci of inflammatory mediators, which was restored upon XPO1 inhibition. These results provide new insights into drivers of heightened inflammation in TET2 -mutant CHIP and highlight a novel therapeutic strategy for intervention.

DOI: https://doi.org/10.1101/2025.06.12.658927
Cell Death Dis. 2025 Jul 17. 16(1): 531

Humanized mouse models in MDS.

Raluca Munteanu, Diana Gulei, Cristian Silviu Moldovan, Emanuele Azzoni, Laura Belver, Richard Feder, Simina Pirv, Anca Dana Buzoianu, Hermann Einsele, Moshe Mittelman, Gabriel Ghiaur, Robert Hasserjian, Ciprian Tomuleasa.

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell disorders defined by ineffective hematopoiesis, multilineage dysplasia, and risk of progression to acute myeloid leukemia. Improvements have been made to identify recurrent genetic mutations and their functional roles, but translating this into preclinical models is still difficult. Traditional murine systems lack the human-specific cytokine support and microenvironmental support that is necessary to reproduce MDS pathophysiology. Humanized mouse models, particularly those incorporating human cytokines (e.g., MISTRG, NSG-SGM3, NOG-EXL), immunodeficient backgrounds, and co-transplantation strategies, have improved the engraftment and differentiation of human hematopoietic stem and progenitor cells. These models allow the study of clonal evolution, mutation-specific disease dynamics, and response to therapies in vivo. However, difficulties persist, such as limited long-term engraftment, incomplete immune reconstruction, and limited possibilities of modeling early-stage or low-risk MDS. This review presents an overview of current humanized and genetically engineered mouse models suitable for studying MDS, evaluating their capacity to replicate disease complexity, preserve clonal architecture, and support translational research. We highlight the need to develop new approaches to improve the actual methodologies and propose future directions for standardization and improved clinical relevance.

DOI: https://doi.org/10.1038/s41419-025-07861-0
Leukemia. 2025 Jul 11.

2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia.

Jane F Apperley, Dragana Milojkovic, Nicholas C P Cross, Henrik Hjorth-Hansen, Andreas Hochhaus, Hagop Kantarjian, Jeffrey H Lipton, Hemant Malhotra, Dietger Niederwieser, Jerald Radich, Philippe Rousselot, Susanne Saussele, Charles A Schiffer, Richard Silver, Simona Soverini, Leif Stenke, Anna Turkina, Luis Felipe Casado, Fausto Castagnetti, Francisco Cervantes, Richard E Clark, Jorge Cortes, Michael Deininger, Timothy P Hughes, Jeroen Janssen, Qian Jiang, Dong-Wook Kim, Richard A Larson, Francois X Mahon, Michael Mauro, Jiri Mayer, Franck E Nicolini, Fabrizio Pane, Delphine Rea, Johan Richter, Gianantonio Rosti, Giuseppe Saglio, Rüdiger Hehlmann.

In this 5th version of the European LeukemiaNet guidance for adult patients, there are important changes in several areas of management based on evidence available since 2020, including the World Health Organisation's reclassification of CML as a biphasic disease. Previous advice to switch the tyrosine kinase inhibitor (TKI) on failure of molecular milestones, is modified to better account for individual patient circumstances. Our recommendations are summarized in tables designed to be read in conjunction with the text which offers justification and additional advice. We describe decision-making for first-line treatment, both in available drugs and their initial dosing. Similarly we elaborate on dose reduction rather than drug switching to manage toxicities and discuss treatment sequencing. Data have matured for the outcome of treatment discontinuation and for management of parenting for both men and women. We acknowledge that most patients will remain on treatment for many years and emphasize the needs to minimize side effects, manage co-morbidities and optimize quality of life. Recent advances in allogeneic stem cell transplantation have broadened access to alternative donors, and lessened limitations of age and co-morbidities such that transplant remains a valuable option for patients for whom long-term disease control is not achieved through TKI therapy.

DOI: https://doi.org/10.1038/s41375-025-02664-w
Leukemia. 2025 Jul 16.

Evolution of clonal hematopoiesis on and off lenalidomide maintenance for multiple myeloma.

Jennifer H Cooperrider, Diren Arda Karaoglu, Tadeusz Kubicki, Can Rui Jiang, Ella Postich, Kathryn Shimamoto, Olivia Arnold, Jommel Macaraeg, Aubrianna Ramsland, Anna Pula, Ashwin Kishtagari, Yash Pershad, Taralynn M Mack, Angela Jones, Alexander G Bick, Michael Savona, Michael W Drazer, Dominik Dytfeld, Andrzej Jakubowiak, Benjamin A Derman, Caner Saygin.

DOI: https://doi.org/10.1038/s41375-025-02707-2
Haematologica. 2025 Jul 17.

Comparative single-cell lineage bias in human and murine hematopoietic stem cells.

Isaac Shamie, Meghan Bliss-Moreau, Jamie Casey Lee, Ronald Mathieu, Harold M Hoffman, Bob Geng, Nathan E Lewis, Yanfang Peipei Zhu, Ben A Croker.

The commitment of hematopoietic stem cells (HSC) to myeloid, erythroid, and lymphoid lineages is influenced by microenvironmental cues, and governed by cell-intrinsic and epigenetic characteristics that are unique to the HSC population. To investigate the nature of lineage commitment bias in human HSC, mitochondrial single cell (sc) ATAC-Sequencing (mtscATAC-Seq) was used to identify somatic mutations in mitochondrial DNA to act as natural genetic barcodes for tracking the ex vivo differentiation potential of HSC to mature cells. Clonal lineages of human CD34+ cells and their mature progeny were normally distributed across the hematopoietic lineage tree without evidence of significant skewing. To investigate commitment bias in vivo, mice were transplanted with limited numbers of long-term HSC (LT-HSC). Variation in the ratio of myeloid and lymphoid cells between donors, although suggestive of a skewed output, was not altered by increasing numbers of LT-HSC. These data suggest that the variation in myeloid and lymphoid engraftment is a stochastic process dominated by the irradiated recipient niche with minor contributions from the cell-intrinsic lineage bias of LT-HSC.

DOI: https://doi.org/10.3324/haematol.2025.287897
Leukemia. 2025 Jul 14.

DNA demethylation-mediated downregulation of MNX1 in acute myeloid leukemia.

Simge Kelekçi, Katherine Kelly, Ashish Goyal, Nick Wehrwein, Anna Riedel, Dieter Weichenhan, Michael Scherer, Birgitta E Michels, Cindy Körner, Irene Orzella, Mariam Hakobyan, Marion Bähr, Elena Everatt, James Dunford, Daniel B Lipka, Pavlo Lutsik, Udo Oppermann, Christoph Plass.

DOI: https://doi.org/10.1038/s41375-025-02680-w
Hemasphere. 2025 Jul;9(7): e70149

PRC2-mediated apoptosis evasion is a therapeutic target of MDS/AML harboring inv(3)/t(3;3) and monosomy 7.

Hiroyoshi Kunimoto, Ayaka Miura, Maiko Sagisaka, Mieko Ito, Ryoichi Maenosono, Hirofumi Yamauchi, Kazuki Nishimura, Daisuke Honma, Shinji Tsutsumi, Akiko Adachi, Takayuki Sakuma, Takuma Ohashi, Hiroshi Teranaka, Junji Ikeda, Sei Samukawa, Takashi Toya, Yuka Harada, Noriko Doki, Sheng F Cai, Hiroaki Maki, Hiroaki Goto, Akihide Yoshimi, Hideaki Nakajima.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) harboring both inv(3)/t(3;3) and monosomy 7 (-7) are highly aggressive myeloid cancers of which molecular pathogenesis and therapeutic vulnerability remain elusive. High throughput drug screens, CUT&Tag/RNA sequence, and functional assays using human MDS/AML cells revealed that EZH2 inhibitors efficiently induce apoptosis preferentially in MDS/AML with inv(3)/t(3;3) and -7 through the activation of GADD45γ-p38-p53 axis. EVI1 activated in 3q-rearranged MDS/AML was responsible for GADD45γ silencing by direct binding to its consensus sequence within GADD45γ promoter and recruitment of PRC2 complex via interaction with EZH2, which can be therapeutically targeted by EZH2 inhibition. MDS/AML with inv(3)/t(3;3) and -7 showed preferential sensitivity to EZH2 inhibition in both mouse model and patient samples. Thus, MDS/AML cells with inv(3)/t(3;3) and -7 possess apoptosis evasion mechanism through EVI1-PRC2-mediated repression of GADD45γ-p38-p53 axis, which is a potential therapeutic vulnerability in MDS/AML patients with these high-risk cytogenetic lesions.

DOI: https://doi.org/10.1002/hem3.70149
bioRxiv. 2025 Jun 29. pii: 2025.06.26.661633. [Epub ahead of print]

Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia.

Stefan Bjelosevic, Rahel Fauth, Brian T Do, Gabriela Alexe, Lucy A Merickel, Thomas D Jackson, Allen T Basanthakumar, Audrey Taillon, Silvi Salhotra, Birgitta Ryback, Constanze Schneider, Giulia DiGiovanni, Ryan Elbashir, Nils Burger, Muhammad Bin Munim, Shan Lin, Pere Puigserver, David E Root, Matthew G Vander Heiden, Kimberly Stegmaier.

Riboflavin is a diet-derived vitamin in higher organisms that serves as a precursor for flavin mononucleotide and flavin adenine dinucleotide, key cofactors that participate in oxidoreductase reactions. Here, using proteomic, metabolomic and functional genomics approaches, we describe a specific riboflavin dependency in acute myeloid leukemia and demonstrate that, in addition to energy production via oxidative phosphorylation, a key biological role of riboflavin is to enable nucleotide biosynthesis and iron-sulfur cluster metabolism. Genetic perturbation of riboflavin metabolism pathways or exogenous depletion in physiological culture medium induce nucleotide imbalance and DNA damage responses, as well as impair the stability and activity of proteins which utilize [4Fe-4S] iron-sulfur clusters as cofactors. We identify a window of therapeutic opportunity upon riboflavin starvation or chemical riboflavin metabolism perturbation and demonstrate that this strongly synergizes with BCL-2 inhibition. Our work identifies riboflavin as a critical metabolic dependency in leukemia, with functions beyond energy production.

DOI: https://doi.org/10.1101/2025.06.26.661633
Leuk Res. 2025 Jun 09. pii: S0145-2126(25)00095-5. [Epub ahead of print]156 107735

Phase 1 first-in-human dose-expansion study of the oral SF3B1 modulator H3B‑8800 in lower-risk myelodysplastic syndrome.

James M Foran, Guillermo F Sanz, Justin M Watts, Andrew M Brunner, Gaelle Fossard, Matteo Giovanni Della Porta, Xavier Cheng-Hong Tsai, Guillermo Garcia-Manero, Sophie Dimicoli-Salazar, Luke Fletcher, Yoo Jin Kim, Patricia Font, Ana Alfonso-Piérola, Juan Manuel Alonso-Dominguez, Christopher Benton, Junshik Hong, Luca Malcovati, Dominiek Mazure, Je-Hwan Lee, Su-Peng Yeh, Laure Goursaud, Wilma Barcellini, Elaine Wu, Deyanira Corzo, Keisuke Kuida, Richard M Stone.

   OBJECTIVE: To assess the efficacy and safety of H3B-8800 at two dose regimens in patients with transfusion-dependent lower-risk myelodysplastic neoplasms (LR-MDS) with somatic SF3B1 mutations.
METHODS: In this Phase 1 multicenter study, adults with LR-MDS with SF3B1 mutations were enrolled in two expansion cohorts: 10 mg and 5 mg twice a day (BID). Patients were red blood cell (RBC) transfusion-dependent, defined as ≥ 4 RBC units in 8 weeks in cohort 1 and ≥ 3 RBC units in ≥ 2 transfusions in 16 weeks in cohort 2 (patients naïve to hypomethylating agents and lenalidomide). The primary endpoint was RBC transfusion independence (TI) ≥ 8 weeks. Adverse events (AEs) during treatment were assessed in each dose cohort.
RESULTS: In cohort 1 (n = 7), the H3B-8800 starting dose was reduced to 5 mg BID in the last two patients due to thrombocytopenia; this dose was selected for cohort 2 (n = 36). The median number of 28-day cycles on therapy was 2.7 and 4.8, with dose adjustments due to AEs in five (71.4 %) and 25 (69.4 %) patients in cohorts 1 and 2, respectively. The most frequently experienced AE was diarrhea. Two (28.6 %) patients in cohort 1 and seven (19.4 %) in cohort 2 developed atrial fibrillation. Two patients in each cohort achieved one interval of RBC-TI ≥ 8 weeks.
CONCLUSION: The AE profile was similar to that reported previously, with a slightly higher incidence of atrial fibrillation. However, the low RBC-TI rate suggests insufficient efficacy of H3B-8800 at the dose levels tested. Further exploration of dosing schedules is warranted.
TRIAL REGISTRATION NUMBER AND DATE: NCT02841540. 22 July 2016.

Keywords:  Myelodysplastic syndrome; SF3B1; clinical trial; spliceosome

DOI:  https://doi.org/10.1016/j.leukres.2025.107735
Leukemia. 2025 Jul 12.

Aberrant splicing of CHEK1 is a driver of megakaryocytic dysplasia in U2AF1S34F mutant myelodysplastic neoplasms.

Wenjun Zhang, Bing Li, Jinqin Liu, Yiru Yan, Lin Yang, Tiejun Qin, Zefeng Xu, Qi Sun, Yujiao Jia, Huijun Wang, Gang Huang, Hongtao Wang, Lihong Shi, Jiaxi Zhou, Zhijian Xiao.

U2AF1 mutations are common in patients with myelodysplastic neoplasms (MDS), suggesting that aberrant splicing of pre-mRNAs driven by mutant U2AF1 could play a critical role in MDS pathogenesis. Previous studies have demonstrated that U2AF1S34F mutation impairs the differentiation of erythrocytes and granulocytes, but the impact on megakaryocytes (MKs) remains unclear. Here, by integrating data from MDS patients and cell lines with U2AF1 mutations, we determined that U2AF1 mutations are associated with dysmegakaryopoiesis, induce the generation of abnormal MKs, especially micro-MKs, and induce significant thrombocytopenia. We determined that mutant U2AF1-mediated aberrant splicing of DNA biosynthesis-related genes, such as CHEK1, is required for normal MK polyploidization. The mis-splicing of CHEK1, in turn, accounts for the increased number of abnormal MKs in U2AF1-mutant MDS patients. Moreover, U2AF1S34 mutations induce the deficiency of CHK1 and the activation of its phosphorylation, thereby further driving the impairment of MK polyploidization and maturation. Accordingly, treatment with selective CHK1 inhibitor significantly reduces abnormal MK production in vitro. Taken together, these findings demonstrate that U2AF1 mutations induce the generation of abnormal MKs by driving aberrant splicing of the CHEK1 cell cycle-related gene, revealing the molecular basis for dysmegakaryopoiesis in MDS and identifying a new potential target for MDS treatment.

DOI: https://doi.org/10.1038/s41375-025-02684-6
Blood. 2025 Jul 18. pii: blood.2025029584. [Epub ahead of print]

---RGI-2001 for the Prophylaxis of Acute Graft-Versus-Host Disease Following Allogeneic HCT.

Zachariah DeFilipp, Hannah K Choe, Yvonne A Efebera, Ayman Saad, Shatha Farhan, Lazaros J Lekakis, Jean A Yared, Gary J Schiller, Markus Y Mapara, Amer Assal, Ted A Gooley, Jack D Bui, Dana D Lee, Hayley Lane, Yi-Bin Chen.

RGI-2001, a liposomal glycolipid that binds CD1d receptor of antigen-presenting cells, can activate invariant natural killer T cells and stimulate cytokine-dependent proliferation of regulatory T-cells (Tregs). This open-label, single-arm, multicenter phase 2b trial evaluated the safety and efficacy of RGI-2001 in combination with standard graft-versus-host disease (GVHD) prophylaxis in participants receiving myeloablative allogeneic hematopoietic cell transplantation (HCT) for hematologic malignancies. RGI-2001 was infused at a dose of 100 ug/kg for six weekly doses starting on Day 0 of HCT. The primary endpoint was grades II-IV acute GVHD by Day 100 after HCT. Forty-nine participants received RGI-2001 in combination with tacrolimus and methotrexate. RGI-2001 was well tolerated, with no serious infusion reactions. Sixteen participants experienced grade ≥3 treatment-related adverse events, with the most common being decreased appetite, leukopenia, thrombocytopenia and stomatitis. The estimated probability of grades II-IV and III-IV acute GVHD were 24.9% and 4.1%, respectively. Compared to controls from the Center for International Blood and Marrow Research Transplant registry, participants receiving RGI-2001 experienced superior clinical outcomes, including Day-180 grades II-IV acute GVHD-free survival (70.8% vs 50.7%, adjusted hazard ratio 0.45, 95% CI 0.30-0.68). Increasing NKT and Treg populations were observed after HCT, consistent with the proposed action of RGI-2001. In conclusion, RGI-2001 was well tolerated and was associated with low rates of acute GVHD and encouraging survival after myeloablative HCT. These results support strategies that target NKT and Treg cell populations to augment immunological changes in allogeneic HCT recipients. This trial was registered at www.clinicaltrials.gov as NCT04014790.

DOI: https://doi.org/10.1182/blood.2025029584
Hemasphere. 2025 Jul;9(7): e70155

Surface downmodulation of TIM3 safeguards healthy cells but not acute myeloid leukemia from CAR T-cell therapy.

Jort J van der Schans, Paresh Vishwasrao, Renée Poels, Morgan Antti, Ziyu Wang, Marjolein Quik, Jennemiek van Arkel, Tom Reuvekamp, Niels W C J van de Donk, Maria Themeli, Gert J Ossenkoppele, Arjan A van de Loosdrecht, Rebecca Richards, Tuna Mutis.

T-cell immunoglobulin and mucin-domain containing-3 (TIM3), generally known as an immune checkpoint receptor, is expressed on leukemic stem and progenitor cells (LSPCs) in acute myeloid leukemia (AML), and has an active role in LSC self-renewal. Therefore, TIM3 has been suggested as a potential target for AML treatment. Hence, we explored the feasibility of targeting TIM3 with chimeric antigen receptor (CAR) T-cells. Despite the expression of TIM3 on activated T-cells, TIM3 CAR T-cells were successfully generated from different healthy individuals with excellent in vitro expansion without signs of fratricide and sustained central-memory phenotype with minimal expression of exhaustion-related markers, including complete loss of TIM3 expression. TIM3 loss also did not affect effector functions since TIM3 CAR T-cells efficiently lysed TIM3+ leukemic cell lines, produced Th1-predominant cytokines, successfully inhibited the colony-forming of TIM3+ AML-derived LSPCs, and showed excellent AML tumor control in xenogeneic mouse models. Notably, TIM3 CAR T-cells did not affect healthy hematopoietic progenitor cells and healthy mature hematopoietic cells that express TIM3 at moderate levels, suggesting an optimal therapeutic window for the treatment of AML.

DOI: https://doi.org/10.1002/hem3.70155
bioRxiv. 2025 Jun 12. pii: 2025.05.29.656798. [Epub ahead of print]

ASXL1 truncating mutations drive leukemic resistance to T cell attack.

Dustin McCurry, Zhongqi Ge, Jaehyun Lee, Rishi Pasumarthi, Xiaohong Leng, Thomas Koehnke, Oren Pasvolsky, Pranaya Raparla, Vinhkhang Nguyen, Katie Maurer, Shuqiang Li, Kenneth J Livak, Emerie Danson, Bijal Thakkar, Elham Azizi, Robert J Soiffer, Sachet A Shukla, Ravi Majeti, Jerome Ritz, Catherine J Wu, Jeffrey J Molldrem, Pavan Bachireddy.

We previously found that specific exhausted T cell subsets defined response, but not resistance, to donor lymphocyte infusions (DLI), a curative immunotherapy for leukemic relapse following allogeneic stem cell transplant (SCT). To identify leukemia molecular pathways that drive resistance, we analyzed whole exome and targeted mutation panel sequencing in two independent cohorts of DLI-treated patients, nominating oncogenic, truncating mutations in ASXL1 ( ASXL1 MUT ) as the genetic basis for DLI resistance. Deep interrogation of 138,152 bone marrow single myeloid cell transcriptomes (scRNA-seq) from this cohort linked DLI resistance to a transcriptional state notable for leukemic stem cell identity and HLA-I suppression. In silico analysis of publicly available scRNA- and ATAC-seq data in acute myeloid and chronic myelomonocytic leukemias, respectively, confirmed an association between ASXL1 MUT and HLA-I suppression across myeloid malignancies. CRISPR correction of the endogenous ASXL1 MUT in the K562 leukemic cell line increased HLA-I, but not HLA-II, surface protein expression through increased deposition of the activating H3K4Me3 mark with only modest effect on the repressive H3K27Me3 mark, suggesting a Polycomb-independent mechanism of action. Indeed, inhibitors of EZH2, a critical component of the PRC2 complex, significantly upregulated HLA-I surface protein expression independently of ASXL1 MUT , suggesting that EZH2 inhibition could bypass ASXL1 MUT -mediated HLA-1 suppression. Importantly, ASXL1 CORRECTION significantly increased CD8+ T cell recognition, activation and killing, and ASXL1 MUT -mediated T cell suppression could be overcome by EZH2 inhibition. Thus, by integrating molecular analyses with immuno-functional studies, we define a novel oncogene-driven pathway of immune evasion and propose a therapeutic strategy to re-engage T cell killing in ASXL1 MUT tumors.

DOI: https://doi.org/10.1101/2025.05.29.656798
Sci Signal. 2025 Jul 15. 18(895): eadt5931

Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib.

Serena Muratcioglu, Christopher A Eide, Chien-Lun Hung, Kent Gorday, Emily Sumpena, Wenqi Zuo, Jay T Groves, Brian J Druker, John Kuriyan.

Chromosomal translocations that fuse ABL1 to BCR or TEL cause human leukemias. In BCR-ABL and TEL-ABL fusion proteins, oligomerization and loss of an autoinhibitory myristoylation site in the SH3 domain of ABL lead to increased ABL tyrosine kinase activity. We assessed the ability of asciminib, an allosteric inhibitor of BCR-ABL that binds to the myristoyl-binding site in the ABL kinase domain, to inhibit these fusion proteins. Although the ABL components of the two fusion proteins have identical sequences, asciminib was much less effective against TEL-ABL than it was against BCR-ABL in cell-growth assays. In contrast, ATP-competitive tyrosine kinase inhibitors, such as imatinib and ponatinib, were equally effective against both fusion proteins. A helix in the ABL kinase domain that closes over bound asciminib was required for the sensitivity of BCR-ABL to the drug but had no effect on that of TEL-ABL, suggesting that the native autoinhibitory mechanism that asciminib engages in BCR-ABL is disrupted in TEL-ABL. Single-molecule microscopy demonstrated that BCR-ABL was mainly dimeric in cells, whereas TEL-ABL formed higher-order oligomers, which promoted trans-autophosphorylation, including of a regulatory phosphorylation site (Tyr89) in the SH3 domain of ABL. Nonphosphorylated TEL-ABL was intrinsically susceptible to inhibition by asciminib, but phosphorylation at Tyr89 disassembled the autoinhibited conformation of ABL, thereby preventing asciminib from binding. Our results demonstrate that phosphorylation determines whether an ABL fusion protein is sensitive to allosteric inhibition.

DOI: https://doi.org/10.1126/scisignal.adt5931
bioRxiv. 2025 Jun 27. pii: 2025.06.24.661416. [Epub ahead of print]

Effects of Calreticulin Mutations on HLA Class I Expression in Myeloproliferative Neoplasms.

Amanpreet Kaur, Harini Desikan, Grace Pagnucco, Malathi Kandarpa, Moshe Talpaz, Malini Raghavan.

Calreticulin (CRT) is important for human leukocyte antigen (HLA) class I assembly. Somatic mutations of the CRT gene ( CALR ) in hematopoietic lineage cells cause myeloproliferative neoplasms (MPNs). Typically, MPN patient cells have one copy each of the wild-type and mutant CALR allele. We find that heterozygous knock-in of a MPN CALR mutation into human cell lines maintains or slightly induces surface expression of HLA class I allotypes. However, full deficiency of wild-type CRT variably reduces the surface expression of HLA class I allotypes, and MPN CRT mutants fail to restore expression for all tested allotypes. Consistent with the largely heterozygous nature of CALR mutations in MPN, surface HLA class I expression in platelets and monocytes from MPN patients with CALR mutations generally falls within the normal range, with higher average expression measured in monocytes from patients treated with interferon alpha compared with other treatments. Overall, the studies indicate that loss of HLA class I expression in cells deficient in wild-type CRT (the CRT dependency) is allele-dependent and correlates with known effects of the assembly factor tapasin. Furthermore, heterozygous knock-in of a MPN-linked CALR mutation has no effect on some allotypes and slightly induces HLA class I expression for CRT-dependent allotypes.

DOI: https://doi.org/10.1101/2025.06.24.661416
Nat Rev Drug Discov. 2025 Jul 14.

CRISPR-based therapeutic genome editing for inherited blood disorders.

Sébastien Levesque, Daniel E Bauer.

Therapeutic genome editing promises to transform medicine. Pivotal discoveries have provided a diverse and versatile set of tools to correct pathogenic mutations or produce protective alleles using CRISPR-based technologies. These innovative therapies are especially adaptable for blood and immune disorders, where clinical methods allow haematopoietic stem cells (HSCs) to be mobilized, harvested, engineered ex vivo and transplanted back into a patient to permanently replace their blood system. This paradigm has been exemplified with the first US Food and Drug Administration (FDA)-approved CRISPR-Cas9 therapy for sickle cell disease and β-thalassaemia, exa-cel (Casgevy). Although promising, efficient delivery of gene edits involves complicated ex vivo manipulation and toxic myeloablative conditioning. The quiescent and elusive nature of HSCs also brings associated challenges. In this Review, we explore the state-of-the-art genome editing technologies of nucleases, base editors and prime editors, which hold promise to address unmet clinical needs for patients with inherited haematological disorders. We highlight the progress made for several disorders and discuss the challenges that remain for ex vivo and in vivo targeting of HSCs for next-generation gene therapies.

DOI: https://doi.org/10.1038/s41573-025-01236-y
bioRxiv. 2025 May 17. pii: 2025.05.14.653262. [Epub ahead of print]

Longitudinal single cell RNA-sequencing reveals evolution of micro- and macro-states in chronic myeloid leukemia.

David E Frankhouser, Dandan Zhao, Yu-Hsuan Fu, Anupam Dey, Ziang Chen, Jihyun Irizarry, Jennifer Rangel Ambriz, Sergio Branciamore, Denis O'Meally, Lucy Ghoda, Jeffery M Trent, Stephen Forman, Adam L MacLean, Ya-Huei Kuo, Bin Zhang, Russell C Rockne, Guido Marcucci.

Single cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cancer, yet identifying meaningful disease states from single cell data remains challenging. Here, we systematically explore the cancer specific information content encoded in single cell versus bulk transcriptomics to resolve this paradox and clarify how discrete disease-defining states emerge from inherently noisy single cell data. Using chronic myeloid leukemia (CML) progression as a model, we demonstrate that, while single cell transcriptomes exist along continuous transcriptional microstates, clinically relevant leukemia phenotypes clearly manifest only at the pseudobulk (macrostate) level. By leveraging state-transition theory, we reveal how robust disease phenotype state-transitions are governed by cell type specific contributions. Our results establish a theoretical framework explaining why discrete disease phenotypes remain hidden at the single cell scale but emerge clearly at the aggregated macrostate level, enabling previously inaccessible biological insights into leukemia evolution. Broadly applicable across cancers and other complex diseases, our approach fundamentally advances single cell analysis by clarifying how microscopic transcriptional variation collectively shapes macroscopic disease dynamics.

DOI: https://doi.org/10.1101/2025.05.14.653262
Br J Haematol. 2025 Jul 16.

Insights into the clinical, platelet and genetic landscape of inherited thrombocytopenia with malignancy risk.

Ana Marín-Quílez, Ana Sánchez-Fuentes, Ana Zamora-Cánovas, Pedro Luis Gómez-González, Lorena Diaz-Ajenjo, Rocío Benito, Agustín Rodríguez-Alén, Teresa Sevivas, Thais Murciano, Laura Murillo, Nora V Butta, Nuria Revilla, Rosa Campos, Paola Escribano, Jordi Esteve, Nuria Fernández-Mosteirin, Francisca Ferrer-Marín, Laura Hernández, Jorge Huerta-Aragonés, Antonio León, Mónica López-Duarte, Eugenia López, Mónica Martín-Salces, Meritxell Nomdedeu, Raquel Oña, Irene Peláez-Pleguezuelos, Fernando Ramos, Elena Sebastián, Claudia Serrano, Cristina Sierra-Aisa, Rosa Vidal-Laso, José Ramón González-Porras, María Luisa Lozano, José María Bastida, José Rivera.

  Inherited thrombocytopenia (IT) with germline variants in RUNX1, ETV6 or ANKRD26 carries a high risk (10%-45%) of developing haematological malignancy (IT-HM). We evaluated the clinical, platelet and molecular characteristics in 37 patients with RUNX1-related thrombocytopenia (RT), 9 with ETV6-RT and 20 with ANRKD26-RT. Genetic diagnosis was delayed by about 20 years from the identification of thrombocytopenia. Bleeding tendency was present in 25%-30% of RUNX1-RT and ANKRD26-RT patients. Platelet aggregation was impaired in 90% of all patients, while reduced activation and granule secretion were heterogeneous. Most RUNX1-RT patients had low glycoprotein Ia (GPIa) levels, which may be a useful disease biomarker. Sixteen distinct genetic variants in RUNX1, four in ETV6 and four in ANKRD26 were identified in patients. The clinical profile showed immune, skin, gastrointestinal and other comorbidities in many patients. One third of the cases developed a malignancy: This included eight RUNX1-RT patients with myelodysplastic syndrome (MDS), five with acute myeloid leukaemia (AML), and one with chronic myeloid leukaemia (CML) Ph+. One patient with ETV6-RT subsequently developed B-cell acute lymphoblastic leukaemia (B-ALL) during childhood. Three cases with ANKRD26-RT demonstrated a multifaceted clinical presentation, including B-ALL Ph+, MDS and breast cancer. The high incidence of HM development highlights the importance of early diagnosis in life.

Keywords:   ANKRD26 ; ETV6 ; RUNX1 ; IT; inherited thrombocytopenia; malignancy predisposition

DOI:  https://doi.org/10.1111/bjh.70001
Nature. 2025 Jul 16.

Neutrophils drive vascular occlusion, tumour necrosis and metastasis.

Jose M Adrover, Xiao Han, Lijuan Sun, Takeo Fujii, Nicole Sivetz, Juliane Daßler-Plenker, Clary Evans, Jessica Peters, Xue-Yan He, Courtney D Cannon, Won Jin Ho, George Raptis, R Scott Powers, Mikala Egeblad.

Tumour necrosis is associated with poor prognosis in cancer1,2 and is thought to occur passively when tumour growth outpaces nutrient supply. Here we report, however, that neutrophils actively induce tumour necrosis. In multiple cancer mouse models, we found a tumour-elicited Ly6GHighLy6CLow neutrophil population that was unable to extravasate in response to inflammatory challenges but formed neutrophil extracellular traps (NETs) more efficiently than classical Ly6GHighLy6CHigh neutrophils. The presence of these 'vascular-restricted' neutrophils correlated with the appearance of a 'pleomorphic' necrotic architecture in mice. In tumours with pleomorphic necrosis, we found intravascular aggregates of neutrophils and NETs that caused occlusion of the tumour vasculature, driving hypoxia and necrosis of downstream vascular beds. Furthermore, we found that cancer cells adjacent to these necrotic regions (that is, in 'perinecrotic' areas) underwent epithelial-to-mesenchymal transition, explaining the paradoxical metastasis-enhancing effect of tumour necrosis. Blocking NET formation genetically or pharmacologically reduced the extent of tumour necrosis and lung metastasis. Thus, by showing that NETs drive vascular occlusion, pleomorphic necrosis and metastasis, we demonstrate that tumour necrosis is not necessarily a passive byproduct of tumour growth and that it can be blocked to reduce metastatic spread.

DOI: https://doi.org/10.1038/s41586-025-09278-3