bims-tremyl 2025-06-29 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2025–06–29
33 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Multiple TET2 mutations confer additional survival benefit in both myelodysplastic and myeloproliferative chronic myelomonocytic leukemia subtypes.
Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in NPM1-mutant AML.
Integrated Immune Landscape Analysis of RNA Splicing Factor-Mutant AML and Higher risk MDS Treated with Azacitidine ± Durvalumab.
Karyotypic clonal fraction predicts adverse outcome in TP53-mutated myeloid neoplasms: an International TP53 investigators Network (iTiN) study.
A Phase 1b/2 Study of TP-0903 and Decitabine Targeting Mutant TP53 and/or Complex Karyotype in Patients with Untreated Acute Myeloid Leukemia (AML) ≥ Age 60 years.
Germline and somatic genetic landscape of pediatric myelodysplastic syndromes.
Intensive chemotherapy after hypomethylating agent and venetoclax in adult acute myeloid leukemia.
Hematopoietic Stem Cell Hierarchies As Novel Biomarkers of Drug Response in Myelodysplastic Syndromes and Acute Myeloid Leukemia.
SF3B1K700E neoantigen is a CD8+ T-cell target shared across human myeloid neoplasms.
The TET protein family interactor PROSER1 sustains hematopoietic stem cell function.
Transposable elements as novel therapeutic targets for PARPi-induced synthetic lethality in PcG-mutated blood cancer.
Clinical significance of preleukemic somatic GATA1 mutations in children with Down syndrome.
The role of ASXL1, SRSF2, and EZH2 mutations in chromatin dysregulation of myelodysplastic neoplasia and acute myeloid leukemia.
Impact of ETV6 mutations on clinical outcomes in acute myeloid leukemia: a real-world retrospective cohort study.
A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics.
IPSS-M risk and specific sex-associated somatic mutations predict response to ESA therapy in LR-MDS: building a new score.
The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.
Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML.
Downregulation of S6 Kinase and Hedgehog-Gli1 by Inhibition of Fatty Acid Synthase in AML with FLT3-ITD Mutation.
Intermediate-Dose Cytarabine as Postinduction AML Therapy.
Non-curative therapies and their impact on the prognosis of patients with myelodysplastic syndromes- a retrospective matched-pairs analysis.
Pharmacological targeting of CBX7 alters the epigenetic landscape and induces differentiation of leukemic cells.
Cytarabine Pharmacogenomics and Outcomes Among Children and Young Adults With Acute Myeloid Leukemia.
Five-year molecular response and overall survival with first- and second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a prospective, observational study - SIMPLICITY.
Comparison of induction with arsenic trioxide or chemotherapy in a real-world cohort of patients with high-risk acute promyelocytic leukemia.
A prospective clinical trial of GVHD prophylaxis with Post-Transplant Cyclophosphamide and Abatacept.
Multipotent lineage potential in B cell acute lymphoblastic leukemia is associated with distinct cellular origins and clinical features.
Allogeneic Stem Cell Transplantation: The Relevance of Conditioning Regime Intensity for Myelodysplastic Syndromes (MDS).
Clinical and molecular features of immunodeficiency in patients with telomere biology disorders.
Ruxolitinib in Patients With Corticosteroid-Refractory or Corticosteroid-Dependent Chronic Graft-Versus-Host Disease: 3-Year Final Analysis of the Phase III REACH3 Study.
Clinical management of CMML-State of the art.
Long-term outcomes of patients with refractory cytopenia of childhood under observation only.
Primary myelofibrosis with increased haemoglobin concentration at presentation.

Leukemia. 2025 Jun 24.

Multiple TET2 mutations confer additional survival benefit in both myelodysplastic and myeloproliferative chronic myelomonocytic leukemia subtypes.

Clifford M Csizmar, Anuya Natu, Mark Gurney, Saubia Fathima, Ali Khalid A Alsugair, Rashmi Kanagal-Shamanna, Sanam Loghavi, Alexandre Bazinet, Kelly Chien, Danielle Hammond, Courtney DiNardo, Tapan Kadia, Farhad Ravandi-Kashani, Naveen Pemmaraju, Koji Sasaki, Terra L Lasho, Christy M Finke, Aref Al-Kali, Hassan Alkhateeb, Kebede Begna, Naseema Gangat, Mehrdad Hefazi Torghabeh, Aasiya Matin, Abhishek A Mangaonkar, Antoine N Saliba, Ayalew Tefferi, Guillermo Garcia-Manero, Hagop M Kantarjian, Rami S Komrokji, Zhuoer Xie, Najla A Ali, David Sallman, Eric Padron, Guillermo Montalban-Bravo, Mrinal M Patnaik.

DOI: https://doi.org/10.1038/s41375-025-02648-w
Blood. 2025 Jun 25. pii: blood.2024026113. [Epub ahead of print]

Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in NPM1-mutant AML.

Aristi Damaskou, Rachael Wilson, Malgorzata Gozdecka, George Giotopoulos, Ryan Asby, Maria Eleftheriou, Muxin Gu, Christian Récher, Véronique Mansat-De Mas, Francois Vergez, Ambrine Sahal, Binje Vick, Evangelia K Papachristou, Ashley Sawle, Eliza Yankova, Monika Dudek, Xiaoxuan Liu, James Russell, Justyna Rak, Christine Hilcenko, Clive S D'Santos, Irmela Jeremias, Jean-Emmanuel Sarry, Konstantinos Tzelepis, Brian Jp Huntly, Alan J Warren, Omid Tavana, George S Vassiliou.

NPM1 is a multifunctional phosphoprotein with key roles in ribosome biogenesis amongst its many functions. NPM1 gene mutations drive 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal (NoLS) and create a novel nuclear export signal (NES), leading to cytoplasmic displacement of the protein (NPM1c). NPM1c mutations prime hematopoietic progenitors to leukemic transformation, but their precise molecular consequences remain elusive. Here, we first examine the effects of isolated NPM1c mutations on the global proteome of pre-leukemic hematopoietic stem and progenitor cells (HSPCs) using conditional knock-in Npm1cA/+ mice. We discover that many proteins involved in ribosome biogenesis are significantly depleted in these murine HSPCs, but also importantly in human NPM1-mutant AMLs. In line with this, we found that pre-leukemic Npm1cA/+ HSPCs display higher sensitivity to RNA polymerase I inhibitors, including Actinomycin D (ActD), compared to Npm1+/+ cells. Combination treatment with ActD and Venetoclax inhibited the growth and colony forming ability of pre-leukemic and leukemic NPM1c+ cells, whilst low-dose ActD treatment was able to re-sensitize resistant NPM1c+ cells to Venetoclax. Furthermore, using data from CRISPR dropout screens, we identified and validated TSR3, a 40S ribosomal maturation factor whose knock-out preferentially inhibited the proliferation of NPM1c+ AML cells by activating a p53-dependent apoptotic response. Similarly to low-dose ActD treatment, TSR3 depletion could partially restore sensitivity to Venetoclax in therapy-resistant NPM1c+ AML models. Our findings propose that targeted disruption of ribosome biogenesis should be explored as a therapeutic strategy against NPM1-mutant AML.

DOI: https://doi.org/10.1182/blood.2024026113
Ther Adv Hematol. 2025 ;16 20406207251347344

Integrated Immune Landscape Analysis of RNA Splicing Factor-Mutant AML and Higher risk MDS Treated with Azacitidine ± Durvalumab.

Jan Philipp Bewersdorf, Vanessa Hasle, Rory M Shallis, Ethan Thompson, Daniel Lopes de Menezes, Shelonitda Rose, Isaac Boss, Lourdes Mendez, Nikolai Podoltsev, Maximilian Stahl, Tariq Kewan, Stephanie Halene, Torsten Haferlach, Brian A Fox, Amer M Zeidan.

   Background: RNA splicing factor (SF) mutations are associated with adverse outcomes in patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes/neoplasms (HR-MDS). Preclinical data suggest that aberrant RNA splicing can lead to the generation of neoantigens, which renders these tumors more susceptible to immune checkpoint inhibitors. However, dedicated studies on immune checkpoint inhibitors in AML and MDS patients with SF mutations are limited.
Objectives: To characterize the immune and epigenetic landscape of AML and MDS patients with SF mutations.
Design: Post hoc analysis of the impact of RNA SF mutations (defined as any of SF3B1, SRSF2, U2AF1, and ZRSR2) on outcomes of newly diagnosed, older or intensive chemotherapy-ineligible patients with AML or HR-MDS treated with azacitidine ± the anti-PD-L1 antibody durvalumab as part of the randomized, phase II FUSION trial.
Methods: Primary endpoint was the overall response rate (ORR). Flow cytometry and gene expression profiling using bulk RNA sequencing were performed on pretreatment bone marrow aspirate samples.
Results: One hundred twenty-six patients with AML (51 SF-mutant and 75 wild type) and 79 patients with MDS (33 SF-mutant and 46 wild type) were included. ORR was independent of SF mutation status for both AML (SF-mutant: 35.3% vs wild-type: 33.3%; p = 0.47) and MDS patients (51.5% vs 56.5%; p = 0.63). Median overall survival was similar for SF-mutant and wild-type AML (14.9 months vs 12.2 months; p = 0.50) and MDS patients (23.5 months vs 10.6 months; p = 0.16). There were no differences in key cell populations from bone marrow aspirate flow cytometry samples. Gene expression analyses showed an increase in MKI-67 expression in SF wild-type patients, but no differences were observed in several immune-related genes including IL7R and PD-L1.
Conclusion: Addition of durvalumab to azacitidine did not improve ORR or OS among older patients with newly diagnosed AML and HR-MDS independent of SF mutation status.Trial registration: NCT02775903.

Keywords:  AML; MDS; gene expression; immune phenotype; outcomes; splicing mutation

DOI:  https://doi.org/10.1177/20406207251347344
J Clin Pathol. 2025 Jun 26. pii: jcp-2024-209954. [Epub ahead of print]

Karyotypic clonal fraction predicts adverse outcome in TP53-mutated myeloid neoplasms: an International TP53 investigators Network (iTiN) study.

Madhavi Pandiri, Anna Stengel, Jingjing Zhang, Peng Wang, Haipeng Shao, Sinthujaa Velmurugan, Anisha Jacob, Emily Symes, Amandeep Kaur, Alexandra Rojek, Payal Sojitra, Danica Wiredja, Qianghua Zhou, Hong Chang, Esha Patil, Jay L Patel, Ami B Patel, Madhu Menon, Sharmila Ghosh, Geoffrey D Wool, Daniel A Arber, Zenggang Pan, Anthony Findley, Talha Badar, Hamza Tariq, David Sallman, Robert C Bell, Anamarija Perry, Claudia Haferlach, Carrie Fitzpatrick, Girish Venkataraman.

  We investigated the prognostic impact of blast counts, TP53 allelic state determinants (number of hits, del(17p), variant allele frequency, complex karyotype),and a novel karyotypic clonal cell fraction (≤50% clonal cells vs >50% clonal cells (termed 'CK50')) in 495 individuals with TP53-mutated (TP53MUT ) myeloid neoplasms. Outcome examined was 24-month survival (OS24). The cohort (median age 71) included 29% (144/495) myelodysplastic syndromes (MDS)/MDS-acute myeloid leukaemia (AML) (1%-19% blasts) and 71% (351/495) AML (≥20% blasts), with 18% (81/460) having low CK50. Overall, 83% received front-line hypomethylating agents. Higher blast counts (<20% vs ≥20%) were marginally associated with CK50 (p=0.08). In the OS24 analysis, blast count showed a marginal association with OS24 (HR 1.3 (95% CI 1.0 to 1.6); p=0.07), while CK50 predicted significantly inferior outcomes (HR=1.7 (95% CI 1.2 to 2.3); p=0.002). In a multivariable model including all TP53 allelic state determinants, only CK50 and complex karyotype remained relevant for predicting adverse outcomes.

Keywords:  BONE MARROW; CYTOGENETICS; Genes, p53; Myelodysplastic Syndromes; Pathology, Molecular

DOI:  https://doi.org/10.1136/jcp-2024-209954
Cancer Res Commun. 2025 Jun 25.

A Phase 1b/2 Study of TP-0903 and Decitabine Targeting Mutant TP53 and/or Complex Karyotype in Patients with Untreated Acute Myeloid Leukemia (AML) ≥ Age 60 years.

Eric D Eisenmann, Ronan Swords, Ying Huang, Shelley Orwick, Daelynn Buelow, Nicole Abbott, Mitch Phelps, Joshua Zeidner, Matthew C Foster, Tara L Lin, Maria R Baer, Yazan F Madanat, Tibor Kovacsovics, Robert Redner, Zeina Al-Mansour, Bhavana Bhatnagar, Mona Stefanos, Molly Martycz, Franchesca Druggan, Timothy L Chen, Ashley O Yocum, Uma Borate, Brian J Druker, Amy Burd, Ross L Levine, John C Byrd, Sharyn D Baker, Alice S Mims.

PURPOSE: Older patients who have acute myeloid leukemia (AML) with mutant TP53 and/or complex karyotype have a dismal prognosis and lack treatment options. Having previously demonstrated that TP-0903, a multikinase inhibitor, has compelling preclinical activity in drug-resistant AML, including TP53 mutant AML, we evaluated the clinical activity of TP-0903 in combination with decitabine.
METHODS: This was a multicenter, open-label, Phase 1b/2 substudy of the Beat AML Master Trial (ClinicalTrials.gov: NCT03013998). The Phase 1b portion used a 3+3 design, and the Phase 2 portion used a Simon two-stage design. Eligible patients aged ≥60 years who had newly diagnosed AML with mutations in TP53 and/or complex karyotype (≥3 cytogenetic abnormalities) received either 37 mg (Group 1) or 25 mg (Group 2) TP-0903 orally on Days 1-21 with decitabine 20 mg/m2 on days 1-10 for up to three 28-day induction cycles, followed by up to 30 maintenance cycles in which the decitabine was reduced to days 1-5. The primary endpoint was complete remission (CR) by the end of six cycles of treatment.
RESULTS: The overall composite remission rate (CR/CRi/CRh) was 33.3% in Group 1 and 50.0% in Group 2, with CR rates of 13.3% and 25%, respectively. The median overall survival for Groups 1 and 2 was 7.6 months and 7.5 months, respectively.
CONCLUSIONS: The combination of TP-0903 and decitabine was reasonably tolerated and had activity in this patient population. Further research and novel treatment strategies are necessary to improve outcomes for patients with these high-risk subtypes of AML.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0091
Haematologica. 2025 Jun 26.

Germline and somatic genetic landscape of pediatric myelodysplastic syndromes.

Lili Kotmayer, Alyssa L Kennedy, Marcin W Wlodarski.

Pediatric myelodysplastic syndromes (MDS) represent a rare group of clonal hematopoietic stem cell disorders accounting for ~5% of pediatric hematological malignancies. They are characterized by ineffective hematopoiesis, cytopenia, and dysplastic changes in the bone marrow with variable risk of progression to acute myeloid leukemia. Unlike adult MDS, pediatric cases predominantly present with hypocellular bone marrow, with monosomy 7 and trisomy 8 as the most common cytogenetic aberrations. Pediatric MDS can manifest as primary disease or arise secondary to classical inherited bone marrow failure syndromes, prior cytotoxic therapy, or acquired aplastic anemia. In recent years, new germline syndromes have been identified in a substantial proportion of patients with "primary" MDS. The most common are GATA2 deficiency and SAMD9/SAMD9L syndromes, accounting for at least 7% and 8%, respectively. The somatic mutational landscape is different from adult MDS, with recurrent mutations affecting SETBP1, ASXL1, RUNX1, and RAS pathway genes (PTPN11, NRAS, KRAS, CBL), while mutations in spliceosome components and epigenetic regulators which are common in adults, are virtually absent in children. Monosomy 7 serves as a "central hub" in disease evolution, associating with somatic leukemia driver mutations. On the other hand, somatic UBTF-TD and NPM1 mutations define a subtype of MDS with excess blasts with predominantly normal karyotype without known germline predisposition. Hematopoietic stem cell transplantation is the only curative option for pediatric MDS. Understanding the unique genetic profile of pediatric MDS has implications for diagnosis, therapy, donor selection and longterm surveillance, particularly for patients with germline predisposition syndromes. This review discusses current classification systems (WHO and ICC), provides a detailed overview of the germline and somatic genetic landscape of pediatric MDS, and highlights clinical implications of these genetic alterations.

DOI: https://doi.org/10.3324/haematol.2024.285700
Blood Neoplasia. 2024 Dec;1(4): 100038

Intensive chemotherapy after hypomethylating agent and venetoclax in adult acute myeloid leukemia.

Kuo-Kai Chin, Yannis Valtis, Andriy Derkach, Meira Yisraeli Salman, Leora Boussi, Jenna Ciervo, Mark B Geyer, Jae H Park, Martin S Tallman, Jacob L Glass, Aaron D Goldberg, Eytan M Stein.

The combination of a hypomethylating agent (HMA) and venetoclax (VEN) is approved for adults aged >75 years with newly diagnosed acute myeloid leukemia (AML) as well as those ineligible for intensive chemotherapy (IC). HMA/VEN is increasingly substituted for IC in adults with AML aged <75 years, particularly in those with adverse cytogenetic and molecular features. When patients fail to respond or relapse after HMA/VEN, the utility of salvage IC is largely unknown. We performed a retrospective single-institution study and identified 46 patients who received IC after HMA/VEN, including 24 patients who received HMA/VEN as their first treatment for AML. This population had complete remission (CR)/CR with incomplete count recovery (CRi)/morphologic leukemia-free state rate of 37%, CR/CRi rate of 28%, and a median overall survival (mOS) of 7.2 months (95% confidence interval, 5.0-10.3). Patients who relapsed after an initial response to HMA/VEN and subsequently received IC were more likely to achieve a CR/CRi than those refractory to HMA/VEN (50% vs 19%; P = .04), although there was no statistically significant difference in survival (mOS, 8.8 vs 5.4 months; P = .64). Age >65 years predicted poorer survival (mOS, 4.3 vs 10.6 months; P < .001). IC after HMA/VEN should be further studied and chosen with caution.

DOI: https://doi.org/10.1016/j.bneo.2024.100038
Clin Cancer Res. 2025 Jun 26.

Hematopoietic Stem Cell Hierarchies As Novel Biomarkers of Drug Response in Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Teresa Ezponda, Ana Aldaz, Ana Alfonso-Pierola, Irene Ganan-Gomez.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell malignancies characterized by high clinical and molecular heterogeneity and poor outcomes. Effective treatments for these disorders remain unmet clinical needs, particularly after failure to first-line therapies. Recent studies have uncovered that the hierarchical organization of MDS and AML stem cells and their progeny, which sustain and propagate the disease, follows specific patterns that reflect the founding stem cells' differentiation capacity and transcriptional states. These cell identity traits determine signaling dependencies, thereby dictating drug sensitivity. The association between hematopoietic hierarchies and drug response has been best described for venetoclax, a proapoptotic agent that has emerged as a powerful therapeutic tool for the treatment of AML and, possibly in the near future, high-risk (HR) MDS. The finding that hematopoietic hierarchies define biologically-distinct disease subtypes has important translational and clinical implications. It will not only be critical in the near future for the selection, follow-up and post-failure management of AML and HR-MDS patients treated with venetoclax, but it should also be considered in drug discovery, therapy selection and patient stratification in clinical trials. This review provides an overview of the current understanding of healthy hematopoiesis and abnormal hematopoietic stem cell hierarchies in MDS and AML, and summarizes the growing body of evidence that these hierarchies determine sensitivity to venetoclax and other agents. Lastly, we address the translational and clinical implications of these findings and offer a critical discussion on how they may be used toward improving patient outcomes.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0591
Cancer Immunol Res. 2025 Jun 26.

SF3B1K700E neoantigen is a CD8+ T-cell target shared across human myeloid neoplasms.

Melinda A Biernacki, Jessica Lok, Kim A Foster, Carrie Cummings, Stephanie Busch, R Graeme Black, Suhita Ray, Laura Baquero Galvis, Tim Monahan, Stephen T Oh, Vivian G Oehler, Derek L Stirewalt, David Wu, H Joachim Deeg, Sergei Doulatov, Marie Bleakley.

Acquired mutations in spliceosome genes in early hematopoietic stem/progenitor cells are common events in myelodysplastic neoplasms (MDS) and related myeloid malignancies. Mutations in the spliceosome factor subunit B1 (SF3B1) gene occur in ≥20% of MDS cases at conserved hotspots and in early neoplastic clones as driver events. Neoantigens from aberrant SF3B1 proteins could serve as shared T-cell therapy targets for SF3B1-mutated myeloid neoplasms. We identified a candidate neoantigen from the prevalent SF3B1K700E variant using in silico predictions of epitope processing and presentation, then validated presentation and immunogenicity in vitro. CD8+ T cells recognizing SF3B1K700E demonstrated high functional avidity and killed neoplastic myeloid cell lines and primary cells in an antigen-specific manner. We then sequenced, cloned, and transduced a SF3B1K700E-specific T-cell receptor (TCR) into 3rd-party T cells and confirmed that TCR transfer conferred antigen specificity and killing of neoplastic myeloid cells in vitro and in vivo. The data indicate that the SF3B1K700E neoantigen represents a promising T-cell target for patients with SF3B1-mutated MDS and acute myeloid leukemia.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0091
Blood Adv. 2025 Jun 24. pii: bloodadvances.2024015683. [Epub ahead of print]

The TET protein family interactor PROSER1 sustains hematopoietic stem cell function.

Elena V Knatko, Anna Fleming, Xiang Li, Phoebe Crawley, Ieva Budriunaite, Kasper D Rasmussen.

Ten-Eleven-Translocation (TET) enzymes are epigenetic regulators important for prevention of hematological malignancies. PROSER1, a known TET protein interactor, has a critical role in modulating TET-mediated DNA demethylation during development. However, the potential involvement of PROSER1 in regulation of hematopoiesis and leukemogenesis remains unknown. Here, we demonstrate that the leukemia suppressive functions of TET2 are preserved in the absence of PROSER1. Nonetheless, we find that loss of PROSER1 partially recapitulates the aberrant enhancer DNA methylation phenotype observed upon TET2 knockout, suggesting that PROSER1 and TET2 play both cooperative and distinct roles in the regulation of DNA methylation in hematopoiesis. Importantly, using serial hematopoietic stem cell (HSC) transplantation assays, we find progressive exhaustion of HSC activity and reduction in hematopoietic lineage output upon loss of PROSER1. Our findings imply that, beyond the established role of TET2 loss-of-function mutations in promoting HSC expansion and leukemic transformation, accurate TET activity, regulated by PROSER1, is equally important to prevent HSC exhaustion and sustain normal hematopoiesis.

DOI: https://doi.org/10.1182/bloodadvances.2024015683
Blood. 2025 Jun 25. pii: blood.2025028560. [Epub ahead of print]

Transposable elements as novel therapeutic targets for PARPi-induced synthetic lethality in PcG-mutated blood cancer.

Bernd Zeisig, Chiou-Tsun Tsai, Clemence Virely, Tsz Kan Kan Fung, Ali Tugrul Akin, Estelle Troadec, Bo Jiao, Richard Thompson, Priscilla Nga Ieng Lau, Nanjun Li, Andriani Charalambous, Larissa Bomfim, Jennifer Lynch, Athina Georgiou, Robbert Hoogeboom, Claire Lynn, Si Yi Zhang, Piers Em Patten, Cynthia Fisher, Anna Schuh, Seishi Ogawa, Ghulam J Mufti, Mohammad M Karimi, Chi Wai Eric So.

Loss-of-function (LoF) mutations frequently found in human cancers are generally intractable by classical small molecule inhibitor approaches. Among them are mutations affecting polycomb-group (PcG) epigenetic regulators, EZH2 and ASXL1 frequently found in haematological malignancies of myeloid or lymphoid lineage, and their concurrent mutations associates with particularly poor prognosis. While there is clear need to develop novel and effective treatments for these patients, the lack of appropriate disease models and mechanistic insights have significantly hindered the progresses. Here we show that genetic inactivation of Asxl1 and Ezh2 in murine haematopoietic stem/progenitor cells results in highly penetrant haematological malignancies as observed in corresponding human diseases. These PcG proteins regulate both coding and non-coding genomes, leading to marked reactivation of transposable elements (TEs) and DNA damage responses in PcG LoF mutated cells, which create a novel vulnerability for PARP inhibitors (PARPi)-induced synthetic lethality. Using both mouse models and primary patient samples, we demonstrate that Asxl1/Ezh2 mutated cells are highly sensitive to PARPi that induce excessive DNA damage and significantly extend disease latency. Intriguingly the observed PARPi-sensitivity can be specifically overridden by reverse transcriptase inhibitors that interrupt target-site primed reverse transcription (TPRT) and life cycle of TEs. This mechanism is contrastingly different from the current concept of BRCAness associated PARPi-induced synthetic lethality, which largely rely on deficient homologous recombination and is independent on reverse transcriptase inhibitors. Together, this study reveals a novel application and mechanism of PARPi-induced synthetic lethal targeting of blood cancers with reactivated TEs such as those carrying PcG epigenetic mutations.

DOI: https://doi.org/10.1182/blood.2025028560
Blood. 2025 Jun 25. pii: blood.2025029250. [Epub ahead of print]

Clinical significance of preleukemic somatic GATA1 mutations in children with Down syndrome.

Natalina Elliott, Neha Bhatnagar, Gemma Buck, David Cruz Hernandez, Kelly Perkins, Adam J de Smith, Amélie Chaussade, Nizery Laure, Marlen Metzner, Garnett Catherine, Alice Norton, Kennedy Alison, Triya Chakravorty, Dylan Zhao, Lars Hanssen, Georgina W Hall, Paresh Vyas, Irene Roberts.

Children with Down syndrome (DS) have a high risk of GATA1-associated myeloid leukemia (ML-DS) before age 4. Somatic N-terminal GATA1 mutations (GATA1s) are necessary, but not sufficient, for ML-DS, but their significance at birth for individual babies and whether mutations occur after birth is unclear. To address these questions, we performed a prospective study of DS newborns using next-generation sequencing-based GATA1 mutation analysis with detailed hematologic and clinical evaluation and follow-up for the window of ML-DS risk. Of 450 DS neonates, 113 (25%) had GATA1s mutations of which 20/113 (17.7%) were multiple and 59 (52%) were clinically silent. Variant allele frequency (VAF) varied from 0.3-89%. VAF positively correlated (p<0.0001) with % blasts, leukocytes, dyserythro- and dysmegakaryopoiesis scores and clinical disease and negatively with hemoglobin, although only 4/113 were anemic. GATA1s mutations were detected from 28 weeks(w) gestation; the highest frequency (45%) was at 34-35w while mutation frequency in early fetal samples (<20w) was only <4% (2/57). GATA1s clones (VAF, % blasts) fell rapidly post-natally becoming undetectable by 6 months (6m) except in neonates who developed ML-DS. 7/110 surviving neonates (6.4%) developed ML-DS at a median age of 17.5m. GATA1s clone size at birth was the only predictor of subsequent ML-DS. No neonates lacking GATA1s mutations acquired mutations after birth or developed ML-DS. Taken together, the fetal environment is essential for GATA1s mutation selection and expansion of GATA1s clones. Rates of leukemic transformation of GATA1s clones detected at birth are low but clones that persist beyond 6 months transformed.

DOI: https://doi.org/10.1182/blood.2025029250
Leukemia. 2025 Jun 25.

The role of ASXL1, SRSF2, and EZH2 mutations in chromatin dysregulation of myelodysplastic neoplasia and acute myeloid leukemia.

Hosang Yu, Junshik Hong, Dong-Yeop Shin, Chul-Hwan Lee.

Mutations in chromatin-regulating genes play a critical role in the pathogenesis of myelodysplastic neoplasia (MDS) and acute myeloid leukemia (AML), as genetic mutations affecting chromatin structure and function are key drivers of these hematologic malignancies. Central to the discussion are key emerging genes such as ASXL1, SRSF2, and EZH2, which are recognized as adverse prognostic markers. Mutations in these genes, coupled with subsequent alterations in epigenetic mechanisms, disrupt normal gene expression by impairing histone modification and RNA splicing processes. Specifically, mutations in ASXL1 enhance removal of ubiquitylation at histone H2AK119, leading to altered gene expression and impaired hematopoietic stem cell differentiation. Mutations in SRSF2, an RNA splicing factor, alter RNA-binding specificity, inducing aberrant splicing of key genes such as EZH2. Loss-of-function mutations in EZH2 disrupt PRC2-mediated transcriptional repression, promoting leukemic progression. However, while the effects of these mutations are understood, treatment options for high-risk patients remain limited. Emerging strategies, such as venetoclax combined with hypomethylating agents, showing promise in mitigating the poor prognosis associated with these mutations. This review consolidates recent findings on these epigenetic regulators and their interactions, providing insights into the multifaceted mechanisms of leukemogenesis in the interest of inspiring targeted therapeutic strategies and bridging extant treatment gaps for MDS/AML.

DOI: https://doi.org/10.1038/s41375-025-02657-9
Ann Hematol. 2025 Jun 21.

Impact of ETV6 mutations on clinical outcomes in acute myeloid leukemia: a real-world retrospective cohort study.

Xueqian Li, Hong Wang, Haohao Han, Jiaqian Qi, Yifang Yao, Xiaoyan Xu, Tingting Pan, Depei Wu, Yue Han.

  As a member of the ETS family, ETV6 has been demonstrated to be implicated with the molecular etiology of various hematopoietic diseases. However, the clinical impact of ETV6 mutations (ETV6mut) in acute myeloid leukemia (AML) remains unclear. Hereon, we included 879 consecutive newly diagnosed AML patients in our institution to elucidate the prognostic impact of ETV6 mutation status. In the overall cohort, ETV6mut were found in 24 cases (2.7%) and were associated with lower hemoglobin levels. The predominant common mutation types were missense mutations (15/31, 48.4%) and frameshift mutations (14/31, 45.2%). ETV6 mutations often occurred in conjunction with U2AF1 and ASXL1 mutations. Moreover, ETV6mut was associated with a lower complete remission (CR) rate (45.8% vs. 69.1%, P = 0.015) and shorter OS (P = 0.048) compared to the ETV6 wild-type (ETV6wt) group. Notably, the achievement of CR did not contribute to survival benefit in AML with ETV6mut. In multivariate analysis, ETV6 mutation was shown to be an independent adverse factor for OS in AML patients (HR: 1.72, 95% CI: 1.03-2.89; P = 0.040). Taken together, our study shows a mutational profile of ETV6 in AML and suggests that ETV6 mutations are associated with poor prognosis in AML patients.

Keywords:  Acute myeloid leukemia; ETV6; Overall survival; Prognosis

DOI:  https://doi.org/10.1007/s00277-025-06451-6
Nat Med. 2025 Jun 27.

A reference model of circulating hematopoietic stem cells across the lifespan with applications to diagnostics.

N Furer, N Rappoport, O Milman, S Tavor, A Lifshitz, A Bercovich, O Ben-Kiki, A Danin, M Kedmi, Z Shipony, D Lipson, E Meiri, G Yanai, S Shapira, N Arber, S Berdichevsky, J Tyner, S Joshi, D Landau, S Ganesan, N Dusaj, P Chamely, N Kaushansky, N Chapal-Ilani, R Shamir, A Tanay, L Shlush.

With aging, deviation of human blood counts from their normal range accompanies the transition from health to disease. Hematopoietic stem and progenitor cells (HSPCs) deliver life-long multi-lineage output, but their variation across healthy humans with aging, and their diagnostic utility, haven't been characterized in depth thus far. To address this, we introduced an HSPC reference model using single-cell RNA profiling of circulating CD34+ HSPCs from 148 healthy age- and sex-diverse individuals. We characterized physiological circulating HSPC composition, showed that age-related myeloid bias is predominant in older men and defined age-related transcriptional signatures in lymphoid progenitors. We further demonstrated the potential of this resource to facilitate the diagnosis of myelodysplastic syndrome (MDS) from peripheral blood without bone marrow sampling, defining classes of patients with MDS and abnormal lymphocyte, basophil or granulocyte progenitor frequencies. Our resource provides insights into HSPC reference ranges across the lifespan and has the potential to facilitate the clinical applications of single-cell genomics in hematology.

DOI: https://doi.org/10.1038/s41591-025-03716-5
Blood. 2025 Jun 25. pii: blood.2024027540. [Epub ahead of print]

IPSS-M risk and specific sex-associated somatic mutations predict response to ESA therapy in LR-MDS: building a new score.

Marco Gabriele Gabriele Raddi, Sophie Park, Michaela Fontenay, Olivier Kosmider, María Díez-Campelo, Juan Carlos Caballero Berrocal, Marie Sébert, Lionel Adès, Uwe Platzbecker, Matteo G Della Porta, Giorgio Mattiuz, Sven Julien Maria De Pourcq, Lorenzo Tofani, Giulia Maggioni, Elena Tofacchi, Angela Consagra, Luca Rigodanza, Gloria Andreossi, Cristina Amato, Mathieu Meunier, Célia Orlando, Emmanuelle Clappier, Nicolas Chapuis, Pierre Walczak, Katharina Zoldan, Anne Sophie Kubasch, Valeria Santini.

Acquired somatic mutations are incorporated in the classification and prognosis of myelodysplastic syndromes/neoplasms (MDS). However, the predictive role of molecular features in MDS need to be elucidated, especially in the lower-risk subtypes (LR-MDS), where treatment has become more heterogenous, and specific predictive biomarkers are lacking. In this study we investigated genetic markers associated with erythropoiesis stimulating agent (ESA) response in LR-MDS. A European cohort of 535 LR-MDS patients was analyzed using targeted next-generation sequencing (t-NGS) to calculate molecular prognostic scores (IPSS-M) and explore the relationship between somatic mutations and ESA response. The integration of IPSS-M score among the 2 known variables sEPO and transfusion dependence, refined the capability to predict response (AUC 0.71 vs 0.63, p=0.0004). Based on these 3 variables, a molecular predictive score, that we named ESA-PSS-M (-0.05*[sEPO U/L]-4.5*[IPSS-M score]-5*[TD, yes =1, no =0]; specificity 76%, sensitivity 57%), was generated and validated in an external cohort of 223 LR-MDS cases. Despite the impact of IPSS-M score, no single mutated gene was linked to ESA response, however, when we stratified cases by sex at birth, we observed that mutations in the X-linked STAG2 gene were significantly associated with ESA resistance in LR-MDS males (OR 0.13, p=0.003). To our knowledge, this is the first study based on a large multicenter cohort of patients suggesting that the integration of IPSS-M score and sex-specific mutations can characterize erythropoiesis defects and guide first line therapeutic choices for anemic LR-MDS (i.e. ESAs vs Luspatercept).

DOI: https://doi.org/10.1182/blood.2024027540
J Clin Invest. 2025 Jun 26. pii: e180913. [Epub ahead of print]

The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.

Siera A Tomishima, Dale D Kim, Nadia Porter, Ipsita Guha, Asif A Dar, Yohaniz Ortega-Burgos, Jennifer Roof, Hossein Fazelinia, Lynn A Spruce, Christopher S Thom, Robert L Bowman, Paula M Oliver.

  The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny is controlled by the JAK/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (Cul5), can regulate JAK/STAT signaling by degrading signaling intermediates. Here we report that mice lacking Cul5 in hematopoietic cells (Cul5Vav-Cre) have increased numbers of HSPCs, splenomegaly, and extramedullary hematopoiesis. Differentiation in Cul5Vav-Cre mice is myeloid- and megakaryocyte-biased, resulting in leukocytosis, anemia and thrombocytosis. Cul5Vav-Cre mice increased HSC proliferation and circulation, associated with a decrease in CXCR4 surface expression. In bone marrow cells, we identified LRRC41 co-immunoprecipitated with CUL5, and vice versa, supporting that CRL5 forms a complex with LRRC41. We identified an accumulation of LRRC41 and STAT5 in Cul5Vav-Cre HSCs during IL-3 stimulation, supporting their regulation by Cul5. Whole cell proteome (WCP) analysis of HSPCs from Cul5Vav-Cre bone marrow identified upregulation of many STAT5 target genes and associated pathways. Finally, JAK1/2 inhibition with ruxolitinib normalized hematopoiesis in Cul5Vav-Cre mice. These studies demonstrate the function of Cul5 in HSC function, stem cell fate decisions, and regulation of IL-3 signaling.

Keywords:  Bone marrow differentiation; Hematology; Hematopoietic stem cells; Immunology; Stem cells; Ubiquitin-proteosome system

DOI:  https://doi.org/10.1172/JCI180913
Blood Neoplasia. 2024 Dec;1(4): 100037

Targeting SLFN11-regulated pathways restores chemotherapy sensitivity in AML.

Sara H Small, Ricardo E Perez, Elspeth M Beauchamp, Aneta H Baran, Stephen D Willis, Mariafausta Fischietti, Michael Schieber, Masha Kocherginsky, Diana Saleiro, Leonidas C Platanias.

Chemoresistance represents an ongoing challenge in treating patients with acute myeloid leukemia (AML), and a better understanding of the resistance mechanisms can lead to the development of novel AML therapies. Here, we demonstrated that low expression of the DNA damage response gene Schlafen 11 (SLFN11) correlates with poor overall survival and worse prognosis in patients with AML. Moreover, we showed that SLFN11 plays an essential role in regulating chemotherapy sensitivity in AML. AML cells with suppressed levels of SLFN11 do not undergo apoptosis in response to cytarabine because of aberrant activation of the Ataxia telangiectasia and Rad3-related protein (ATR)/Checkpoint kinase 1 (Chk1) pathway, allowing for DNA damage repair, whereas sensitivity to cytarabine can be restored by inhibiting the ATR pathway. Importantly, SLFN11 knockout AML cells retain sensitivity to hypomethylating agents and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. Altogether, these results reveal SLFN11 as an important regulator and predictor of chemotherapy sensitivity in AML and suggest that targeting pathways suppressed by SLFN11 may offer potential combination therapies to enhance and optimize chemotherapy responses in AML.

DOI: https://doi.org/10.1016/j.bneo.2024.100037
Int J Mol Sci. 2025 Jun 14. pii: 5721. [Epub ahead of print]26(12):

Downregulation of S6 Kinase and Hedgehog-Gli1 by Inhibition of Fatty Acid Synthase in AML with FLT3-ITD Mutation.

Maxim Kebenko, Ruimeng Zhuang, Konstantin Hoffer, Anna Worthmann, Stefan Horn, Malte Kriegs, Jan Vorwerk, Nikolas von Bubnoff, Cyrus Khandanpour, Niklas Gebauer, Sivahari Prasad Gorantla, Walter Fiedler, Carsten Bokemeyer, Manfred Jücker.

  Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase domain (FLT3-TKD; 25%). FLT3-ITD mutations are linked to poor prognosis and offer significant clinical predictive value, whereas the implications of FLT3-TKD mutations are less understood. The Hedgehog-Gli pathway is an established therapeutic target in AML, and emerging evidence suggests crosstalk between FLT3-ITD signaling and Gli expression regulation via non-canonical mechanisms. Post-translational modifications involving myristic and palmitic acids regulate various cellular processes, but their role in AML remains poorly defined. In this study, we investigated the role of fatty acid synthase (FASN), which synthesizes myristic and palmitic acids and catalyzes palmitoyl-acyltransferation, in regulating FLT3-ITD-Gli signaling. FASN knockdown using shRNA and the FASN inhibitor TVB-3166 was performed in FLT3-ITD-mutated AML cell lines (MOLM13, MV411) and Baf3-FLT3-ITD cells. The impact of FASN inhibition was assessed through Western blot and kinome profiling, while biological implications were evaluated by measuring cell viability and proliferation. FASN inhibition resulted in reduced levels of phospho-Akt (pAkt) and phospho-S6 kinase (pS6) and decreased expression of Hedgehog-Gli1, confirming non-canonical regulation of Gli by FLT3-ITD signaling. Combining TVB-3166 with the Gli inhibitor GANT61 significantly reduced the survival of MOLM13 and MV411 cells.

Keywords:  AML; Akt; FLT3-ITD mutation; Gli1; Hedgehog signaling; MAPK; S6 kinase; TVB-3166; fatty acid synthase (FASN); palmitoylation

DOI:  https://doi.org/10.3390/ijms26125721
NEJM Evid. 2025 Jul;4(7): EVIDoa2400326

Intermediate-Dose Cytarabine as Postinduction AML Therapy.

Mathilde Hunault, Cécile Pautas, Sarah Bertoli, Pierre-Yves Dumas, Emmanuel Raffoux, Marie-Anne Hospital, Tony Marchand, Maël Heiblig, Sylvain Chantepie, Martin Carré, Pierre Peterlin, Maria-Pilar Gallego-Hernanz, Emilie Lemasle, Romain Guièze, Célestine Simand, Pascal Turlure, Anne Huynh, Thibaut Leguay, Raynier Devillier, Stéphanie Nguyen Quoc, Nicolas Duployez, Isabelle Luquet, Dominique Penther, Karine Celli-Lebras, Ariane Mineur, Nicole Raus, Claude Gardin, Gérard Socié, Jean-Yves Cahn, Norbert Ifrah, Norbert Vey, Régis Peffault de Latour, Eric Delabesse, Claude Preudhomme, Jean-François Hamel, Arnaud Pigneux, Christian Récher, Hervé Dombret.

BACKGROUND: We conducted a randomized controlled trial to compare intermediate doses (IDAC) with high doses of cytarabine (HDAC) as postinduction therapy in patients 18 to 60 years of age with newly diagnosed acute myeloid leukemia (AML). The main objectives were to evaluate noninferiority in overall survival (OS) after IDAC and safety.
METHODS: Patients 18 to 60 years of age with newly diagnosed AML, except those with core-binding factor, acute promyelocytic, Philadelphia chromosome-positive, or post-myeloproliferative neoplasm AML, were eligible. After the induction course, we randomly assigned patients to either IDAC (1500 mg/m2/12 hours) or HDAC (3000 mg/m2/12 hours). Patients with intermediate- and adverse-risk AML were eligible for allogeneic hematopoietic stem cell transplantation (HSCT) in first remission. The primary end point was OS in a predefined per-protocol analysis population. The primary analyses were performed in 1132 randomly assigned patients, with a noninferiority outcome adjusted on the European Leukemia Net (ELN) 2022 risk group, the use of induction anthracycline, the response to induction, and HSCT as a function of time following treatment.
RESULTS: At 5 years, OS was estimated at 59.3% (95% confidence interval [CI], 55.0 to 63.3) in the IDAC group versus 57.5% (95% CI, 53.3 to 61.5) in the HDAC group (adjusted hazard ratio, 0.96; 95% CI, 0.80 to 1.15; noninferiority test, P=0.0042). A preplanned analysis was unable to detect any interaction between IDAC or HDAC treatment effect and patient subgroups, including those defined by the ELN 2022 risk group or response to induction prior to random assignment. In addition, the severity of chemotherapy-induced myelosuppression and the incidence of related adverse events were lower after IDAC.
CONCLUSIONS: Our trial shows noninferior outcomes in patients 18 to 60 years of age with newly diagnosed AML treated with low- versus high-dose cytarabine; this occurred with similar or lower toxicities. (Funded by the Regional Clinical Research Office, Angers and others; EudraCT number, 2014-000699-24; ClinicalTrials.gov number, NCT02416388.).

DOI: https://doi.org/10.1056/EVIDoa2400326
Ann Hematol. 2025 Jun 27.

Non-curative therapies and their impact on the prognosis of patients with myelodysplastic syndromes- a retrospective matched-pairs analysis.

Katharina Anna Rauhe, Annika Kasprzak, Felicitas Schulz, Kathrin Nachtkamp, Corinna Strupp, Andrea Kündgen, Sascha Dietrich, Karin Mayer, Katharina S Götze, Wolf-Karsten Hofmann, Aristoteles Giagounidis, Norbert Gattermann, Ulrich Germing.

  Allogeneic stem cell transplantation (SCT) remains the only curative therapy for patients with high-risk myelodysplastic syndromes (MDS). Due to age, comorbidities, or lack of urgency, many receive only palliative therapies to improve quality of life. Some patients remain untreated due to a lack of symptoms or low progression risk. Data on the impact of palliative therapies on overall survival (OS) and leukemia-free survival (LFS) are limited. Using the Düsseldorf MDS Registry, we compared outcomes of patients receiving red blood cell transfusions (RBCT) alone to the outcome of patients receiving RBCT combined with iron chelation therapy (ICT), erythropoietin (EPO), antithymoglobulin (ATG), or lenalidomide (LENA). Matched-pairs analysis was conducted using age, gender, and prognostic scores (Revised International Prognostic Scoring System or Chronic Myelomonocytic Leukemia-specific Prognostic Scoring System). ICT-treated patients (n = 85) had significantly improved OS (70 vs. 21 months, p < 0.001) and lower 5-year AML progression (3.5% vs. 28.2%, p < 0.001). Similar benefits were seen with EPO (n = 210; OS: 63 vs. 24 months, p < 0.001; AML: 5.7% vs. 19%, p = 0.007) and LENA (n = 30; OS: 92 vs. 57 months, p = 0.049; AML: 0% vs. 16.7%, p = 0.024). ATG (n = 11) showed no significant improvement in OS (79 vs. 64 months) or AML progression (0% vs. 18.2%). While recognizing the limitations of matched-pairs analysis versus randomized trials, our findings indicate a survival benefit from ICT, EPO, or LENA versus RBCT alone. The year of diagnosis did not independently affect OS or LFS. These results support the use of selected palliative therapies to improve long-term outcomes in MDS patients. KEY POINTS: Treating patients with myelodysplastic syndromes with non-curative therapies beyond red blood cell transfusions like iron chelation therapy, erythropoietin, or lenalidomide has a positive impact on overall survival and leukemia-free survival.

Keywords:  IPSS-R; Myelodysplastic syndromes; Non-curative therapies; Prognosis

DOI:  https://doi.org/10.1007/s00277-025-06485-w
Blood Neoplasia. 2024 Dec;1(4): 100052

Pharmacological targeting of CBX7 alters the epigenetic landscape and induces differentiation of leukemic cells.

Anne P de Groot, Chelsea R Wilson, Ellen Weersing, Jacobine S Pouw, Albertina Dethmers-Ausema, Huong Nguyen, Evan F W Chen, Alok Shaurya, Linda Smit, Fraser Hof, Gerald de Haan.

Self-renewal of leukemic cells results in the accumulation of dysfunctional blood cells and suppression of normal hematopoiesis. The polycomb group protein chromobox 7 (CBX7) is an epigenetic regulator that represses genes required for differentiation and cell cycle arrest and thereby promotes self-renewal. Because leukemic cells are highly self-renewing, we tested whether pharmacological targeting of CBX7 would reduce self-renewal and induce differentiation of human leukemic cells. We found that existing and newly developed CBX7 inhibitors derepress the epigenome, resulting in reduced ubiquitination of histone 2A and reduced binding of CBX7 to its target genes. This led to reduced cell growth, increased differentiation of leukemic cells in vitro, and delayed engraftment of primary leukemic cells in xenotransplant models. Therefore, pharmacological targeting of CBX7 constitutes a novel therapeutic approach for leukemia.

DOI: https://doi.org/10.1016/j.bneo.2024.100052
JAMA Netw Open. 2025 Jun 02. 8(6): e2516296

Cytarabine Pharmacogenomics and Outcomes Among Children and Young Adults With Acute Myeloid Leukemia.

Richard J Marrero, Vivek M Shastri, Deedra Nicolet, Krzysztof Mrózek, Christopher J Walker, William G Blum, Bayard L Powell, Jonathan E Kolitz, Joseph O Moore, Geoffrey L Uy, Wendy Stock, Andrew J Carroll, John C Byrd, Richard Aplenc, Todd M Cooper, Alan S Gamis, Huiyun Wu, Stanley Pounds, Yi-Cheng Wang, Todd A Alonzo, Soheil Meshinchi, Ann-Kathrin Eisfeld, Edward A Kolb, Jatinder K Lamba.

Importance: Therapeutic responses in acute myeloid leukemia (AML) demonstrate considerable variability both across and within established risk stratifications and age groups. Moreover, significant racial disparities persist, with Black patients experiencing inferior survival outcomes compared with their White counterparts.
Objective: To validate the association of the previously reported 10 single nucleotide variant (SNV)-based ara-C pharmacogenomics score (ACS10) with survival outcomes in a large cohort of pediatric AML patients; to evaluate whether ACS10 remains relevant in an adolescent and young adult (AYA) population of patients with AML treated with similar intensive induction chemotherapy protocols; and to assess the association of ACS10 with race and treatment outcomes in both cohorts.
Design, Setting, and Participants: This cohort study included patients from the Children's Oncology Group's AAML1031 trial, a multicenter, open-label randomized clinical trial that enrolled pediatric patients with newly diagnosed, treatment-naive primary AML from June 2011 to July 2017 (aged 0 to 29.5 years) and from the Alliance for Clinical Trials in Oncology frontline protocols, which included AYA patients from 9 different trials that enrolled patients with newly diagnosed AML from 1992 to 2010. Data were analyzed from September 2022 to March 2025.
Exposures: Patients in the AAML1031 trial were randomized to 2 arms, standard chemotherapy alone or standard chemotherapy with the addition of bortezomib. Patients in the Alliance for Clinical Trials in Oncology cohorts were treated with similar intensive induction chemotherapy protocols.
Main Outcomes and Measures: ACS10 scores were evaluated for association with outcomes according to race, treatment arm, and hematopoietic stem cell transplant (HSCT) status.
Results: The study included 1086 patients with AML. There were 717 patients from the pediatric AML cohort (median [range] age, 9.6 [0.04-29.2 years]; 379 [53%] male; 33 [5%] Asian, 84 [12%] Black, and 522 [73%] White) and 369 AYA patients with AML from the Alliance for Clinical Trials in Oncology group (median [range] age, 30 [17-39] years; 196 [53%] male; 7 [2%] Asian, 32 [9%] Black, and 288 [78%] White). Within the standard treatment arm of AAML1031, patients in the low ACS10 group had significantly worse event-free survival (EFS) compared with those in the high ACS10 group (all patients: hazard ratio [HR], 1.42; 95% CI, 1.05-1.95; P = .02; non-HSCT cohort: HR, 1.48; 95% CI, 1.06-2.07; P = .02). The ACS10 score remained significantly associated with EFS in multivariable analysis after adjusting for age, race, risk group and white blood cell count, within the standard treatment arm (HR, 1.44; 95% CI, 1.03-2.02; P = .03). In the Alliance for Clinical Trials in Oncology AYA non-HSCT cohort, the low ACS10 score group had significantly inferior overall survival (OS) and a higher point estimate for EFS compared with patients with a high ACS10 score (OS: HR, 1.50; 95% CI, 1.05-2.14; P = .03; EFS: HR, 1.32; 95% CI, 0.95-1.83; P = .10). A higher number of early deaths was observed in the low ACS10 group compared with the high ACS10 group, but the difference was not statistically significant (death within 30 days of treatment initiation: 6 of 112 [5%] vs 2 of 257 [1%]; P = .07). Across both cohorts, a low ACS10 score was significantly more abundant in Black patients compared with White patients (eg, in Alliance for Clinical Trials in Oncology cohort, 27 of 32 Black patients [84%] had low ACS10 scores compared with 64 of 288 White patients [22%]; P < .001) and inferior survival was observed in Black patients (eg, OS of Black compared with White patients in AAML1031 cohort: HR, 1.47; 95% CI, 1.02-2.13; P = .04). In the AAML1031 cohort, there were no significant differences in EFS or OS between Black and White patients receiving augmented treatment, suggesting that the addition of bortezomib was associated with benefit for Black patients.
Conclusions and Relevance: In this study of 717 pediatric and 369 AYA patients with AML, the ACS10 score was associated with EFS in pediatric and AYA patients when treated with a standard induction regimen. There was a higher abundance of low ACS10 scores in Black patients, and Black patients treated with augmented therapy (ie, the addition of bortezomib) seemed to have improved outcomes. Integrating the ACS10 score into a prospective clinical trial to personalize induction therapy based on an individual's genetic profile has the potential to improve treatment outcomes.

DOI: https://doi.org/10.1001/jamanetworkopen.2025.16296
Leuk Lymphoma. 2025 Jun 22. 1-10

Five-year molecular response and overall survival with first- and second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a prospective, observational study - SIMPLICITY.

Michael J Mauro, Rüdiger Hehlmann, Loretta A Williams, Stuart L Goldberg, Mauricette Michallet, Carlo Gambacorti-Passerini, Derek Tang, Irene S DeGutis, Ali McBride, Lori Parsons, Monica Montelongo, Jorge E Cortes.

  SIMPLICITY (NCT01244750) was an observational study evaluating first-line (1 L) tyrosine kinase inhibitors (TKIs; dasatinib, nilotinib, imatinib) in patients with chronic myeloid leukemia in the chronic phase in routine clinical practice. At data cutoff (January 28, 2020), 810 prospective US patients were included/analyzed (dasatinib, 302; nilotinib, 264; imatinib, 244). Within 5 years, 95.4% of patients (dasatinib, 96.5%; nilotinib, 93.5%; imatinib, 95.9%) had major molecular response (BCR::ABL1 ≤ 0.1%), and 79.2% (dasatinib, 79.8%; nilotinib, 81.7%; imatinib, 75.9%) deep molecular response (MR4.5; BCR::ABL1 < 0.0032%) demonstrating major improvement during the study period. Of 734 patients followed for 5 years, 5-year overall survival rate was 89.8% (dasatinib, 92.9%; nilotinib, 88.6%; imatinib, 87.0%); similar to that in randomized studies. Patients who switched treatment had a poorer outcome regardless of TKI, indicating that non-kinase domain mutations may play a role. Despite missing data on outcomes in routine care, these results demonstrate excellent response and survival rates.

Keywords:  Chronic-phase chronic myeloid leukemia; SIMPLICITY; molecular response; observational study; overall survival; routine care; treatment switch; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1080/10428194.2025.2495369
Leukemia. 2025 Jun 24.

Comparison of induction with arsenic trioxide or chemotherapy in a real-world cohort of patients with high-risk acute promyelocytic leukemia.

Delphine Lebon, Audrey Da Rocha, Bruno Cassinat, Maël Heiblig, Sarah Bertoli, Caroline Bonmati, Anne Zilliox, Marie Laloi, Céline Berthon, Nicolas Duployez, Christophe Willekens, Maria Pilar Gallego Hernanz, Marlène Ochmann, Thomas Cluzeau, Fatiha Chermat, Alexis Caulier, Christian Récher, Mathilde Hunault-Berger, Emmanuel Raffoux, Pierre Fenaux, Jean Pierre Marolleau, Lionel Adès.

Front-line treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in patients with low-/intermediate-risk acute promyelocytic leukemia (APL). However, for high-risk (HR) patients (defined as those with a white blood cell count ≥ 10×10⁹/L), the role of ATRA-ATO is subject to debate, and study data are scarce. The objective for the present real-world cohort study was to assess the outcomes in 135 HR APL patients treated with ATRA-CHT or ATRA-ATO during induction at 12 French hospitals between 2010 and 2021. Of the 135 patients, 50 (37%) received ATRA-ATO as induction therapy (though combination with cytoreductive treatment was usually necessary), and 85 received standard ATRA-CHT ("CHT group"). The complete response rates were 90% in the ATRA-ATO group and 76% in the CHT group (p = 0.052). The five-year overall survival (OS) rate was significantly higher in the ATRA-ATO group (89.86% [95% confidence interval: 81.81-98.70]) than in the CHT group (72.69% [63.30-83.47]; p = 0.035). The combination of ATRA and ATO was effective and safe in this large, real-world cohort of HR APL patients. The forthcoming results of the APOLLO trial (a direct comparison of ATRA-ATO with ATRA-CHT) might validate our present findings.

DOI: https://doi.org/10.1038/s41375-025-02663-x
Blood Adv. 2025 Jun 24. pii: bloodadvances.2024015094. [Epub ahead of print]

A prospective clinical trial of GVHD prophylaxis with Post-Transplant Cyclophosphamide and Abatacept.

Divya Koura, Kaitlyn C Dykes, Aaron Michael Goodman, Caitlin L Costello, Carolyn Mulroney, James K Mangan, Tiffany N Tanaka, Edward D Ball, Ayad Hamdan, Ah-Reum Jeong, James Mirocha, Qingyang Zhang, Paula Ogrodnik, Kimberly McConnell, Joseph J Maroge, Michelle Padilla, Gerald P Morris, Dimitrios Tzachanis.

We conducted a prospective randomized clinical trial to investigate the combination of post-transplant cyclophosphamide (PTCy) and abatacept for GVHD prophylaxis. Patients with hematologic malignancies undergoing an allogeneic transplant from an 8/8 matched related or unrelated donor were randomized 1:1 to tacrolimus and methotrexate (SOC arm) or PTCy on days +3 and +4 followed by abatacept on an extended schedule: days +5, +14, +28 and every 4 weeks up to D+168 (PTCy+aba arm). All patients received peripherally collected stem cells. The primary endpoint was moderate and severe chronic GVHD at one year. Following Food and Drug Administration (FDA) approval of abatacept for GVHD prophylaxis leading to change in SOC, we amended our trial and subsequently only enrolled onto the PTCy+aba arm. 25 patients were treated on PTCy+aba and 15 on SOC arm. The trial met its primary endpoint: Kaplan-Meier estimates of moderate/severe chronic GVHD were 0% on the PTCy+aba and 65.8% on the SOC arm (p < 0.0001). GVHD-Free, Relapse-Free Survival (GRFS) was 62.5% on PTCy+aba and 24.1% on SOC (p=0.010). There were no treatment related deaths on PTCy+aba and two on SOC. There was no difference in the overall survival rates (92% aba, 80% SOC, p=0.28), disease free survival (68% aba, 92.9% SOC, p=0.105) and infection at one year. Grade III/IV acute GVHD rate was 4.2% on PTCy+aba and 21.4% on SOC (p=0.092). Proliferation of regulatory T-cells was preserved on PTCy+aba compared to SOC and PTCy and abatacept treatment was associated with increased CD16+CD56dim cytotoxic NK cells. In conclusion, the combination of PTCy and abatacept is well tolerated and associated with reduced chronic GVHD and a favorable GRFS rate. This trial was registered at www.ClinicalTrials.gov as #NCT03680092.

DOI: https://doi.org/10.1182/bloodadvances.2024015094
Nat Cancer. 2025 Jun 27.

Multipotent lineage potential in B cell acute lymphoblastic leukemia is associated with distinct cellular origins and clinical features.

Ilaria Iacobucci, Andy G X Zeng, Qingsong Gao, Laura Garcia-Prat, Pradyumna Baviskar, Sayyam Shah, Alex Murison, Veronique Voisin, Michelle Chan-Seng-Yue, Cheng Cheng, Chunxu Qu, Colin Bailey, Matthew Lear, Matthew T Witkowski, Xin Zhou, Airen Zaldivar Peraza, Karishma Gangwani, Anjali S Advani, Selina M Luger, Mark R Litzow, Jacob M Rowe, Elisabeth M Paietta, Wendy Stock, John E Dick, Charles G Mullighan.

Developmental origins and their associations with lineage plasticity and treatment response in B-cell progenitor acute lymphoblastic leukemia (B-ALL) are mostly unexplored. Here, we integrated single-cell transcriptome sequencing (scRNA-seq) of 89 B-ALL samples with a single-cell atlas of normal human B cell development incorporating functional and molecular assays. We observed subtype- and sample-dependent correlation with normal developmental stage, with intra-subtype and intra-patient heterogeneity. We show that subtypes prone to shift from the B-lineage (for example BCR::ABL1, KMT2A-R and DUX4-R B-ALL) are enriched for multipotent progenitors and show this developmental stage exhibits CEBPA activation and retains myeloid potential, providing a mechanistic explanation for this clinical observation. We developed a 'multipotency score' most enriched in subtypes exhibiting lineage plasticity that was independently associated with inferior survival. Thus, multipotent B-ALL states reflect the early progenitor origins of a subset of patients with B-ALL and may be relevant for understanding lineage shifting following conventional chemotherapy or immunotherapies.

DOI: https://doi.org/10.1038/s43018-025-00987-2
Curr Oncol. 2025 May 30. pii: 319. [Epub ahead of print]32(6):

Allogeneic Stem Cell Transplantation: The Relevance of Conditioning Regime Intensity for Myelodysplastic Syndromes (MDS).

Tobias Berg, Brittany Salter, Michael Radford, He Tian Tony Chen, Brian Leber.

  Allogeneic hematopoietic cell transplantation (alloHCT) is the sole curative therapy for myelodysplastic syndrome (MDS). While alloHCT clearly confers a significant survival advantage in high-risk MDS, it is less clear how the disease burden and impact of conditioning intensity impact survival. This review addresses critical issues surrounding this topic, emphasizing the unique cell biology of MDS and the evolving concepts of conditioning intensity compared to other diseases, including acute myeloid leukemia (AML). The review is structured around three interconnected themes. First, it clarifies the varying interpretations of conditioning intensity. Second, it examines the interplay between disease burden at transplant and conditioning intensity in determining outcomes, including a comparative analysis with acute myeloid leukemia (AML) to highlight similarities and differences. Third, it explores the relationship between conditioning regimen intensity and immune reconstitution, particularly focusing on the graft-versus-tumor (GvT) effect and its potential modulation by conditioning intensity. Understanding the stem cell target of conditioning regimens is emphasized, as the persistence of the underlying MDS stem cell necessitates a thorough understanding of this concept for improved therapeutic strategies.

Keywords:  conditioning regime; myelodysplastic syndrome; transplant

DOI:  https://doi.org/10.3390/curroncol32060319
Blood. 2025 Jun 25. pii: blood.2024026735. [Epub ahead of print]

Clinical and molecular features of immunodeficiency in patients with telomere biology disorders.

Luiz Fernando B Catto, Nidhi Aggarwal, Ruba N Shalhoub, Xiaoyang Ma, Ivana Darden, Tania Machado, Yue Zhang, Neelam Redekar, Natthakan Thongon, Simona Colla, Geraldine Aubert, Cynthia E Dunbar, Colin O Wu, Neal S Young, Bhavisha A Patel, Fernanda Gutierrez-Rodrigues, Emma M Groarke.

Immunodeficiency in telomere biology disorders (TBDs) has been described in pediatric patients with severe phenotypes, but less characterized within the broader TBD spectrum. We collected complete blood counts, lymphocyte subsets, and infection history from 88 consecutive TBD patients with a median age of 37 years (range 6-76). Most patients were >18 years old (80/88; 90%) and harbored either a TERT (45%) or TERC (32%) germline mutation. Thirty-two patients (36%) experienced significant infections (opportunistic, recurrent, and/or requiring hospitalization); 47% had lymphopenia, and 3% severe neutropenia. Absolute lymphocyte counts (ALC) <0.96 and <1.1 x103/µL, but not severe neutropenia, associated with increased infection risk and lower overall survival, respectively. Decreased CD3+ T-cells, both CD4+ and CD8+, associated with BMF, increased infection risk, and reduced survival. Low CD3+ and CD4+ associated with solid cancers. Telomere length was shortened across the cohort without correlation with ALC or lymphocyte subsets. In a predominantly adult cohort of TBDs, immunodeficiency was marked by T lymphopenia, possibly a consequence of accelerated aging in the hematopoietic compartment. An ALC cut-off of <1.1 x103/µL may be a useful biomarker to identify patients with an increased risk of infection, a major cause of death of TBD patients.

DOI: https://doi.org/10.1182/blood.2024026735
J Clin Oncol. 2025 Jun 25. JCO2402477

Ruxolitinib in Patients With Corticosteroid-Refractory or Corticosteroid-Dependent Chronic Graft-Versus-Host Disease: 3-Year Final Analysis of the Phase III REACH3 Study.

Robert Zeiser, Domenico Russo, Ron Ram, Shahrukh K Hashmi, Ronjon Chakraverty, Jan Moritz Middeke, Maurizio Musso, Sebastian Giebel, Ant Uzay, Peter Langmuir, Nada Hamad, Karin Burock, Maanasa Gowda, Tommaso Stefanelli, Stephanie J Lee, Takanori Teshima, Franco Locatelli.

In REACH3 (ClinicalTrials.gov identifier: NCT03112603), ruxolitinib was investigated versus best available therapy (BAT) for 3 years in patients with steroid-refractory/dependent chronic graft-versus-host-disease (SR/D-cGVHD). Patients received ruxolitinib (10 mg twice daily) or BAT for 24 weeks; thereafter (weeks 24-156), patients continued randomized treatment, entered long-term survival follow-up, or crossed over from BAT to ruxolitinib. In 329 randomly assigned patients (ruxolitinib: 165; BAT: 164), the median failure-free survival (FFS) was 38.4 months for ruxolitinib versus 5.7 months for BAT (hazard ratio, 0.36 [95% CI, 0.27 to 0.49]). Median duration of response (DOR) was not reached for ruxolitinib versus 6.4 months for BAT. Ruxolitinib-treated patients had a higher probability of FFS (ruxolitinib: 56.5%; BAT: 18.2%) and maintaining a response (ruxolitinib: 59.6%; BAT: 26.7%) at 36 months. Median overall survival was not reached. Nonrelapse mortality and malignancy relapse/recurrence events were low. In 70 patients who crossed over to ruxolitinib, the overall response rate (50.0%) at week 24 and best overall response (81.4%) during the crossover period were consistent with the primary analysis of randomly assigned patients. No new safety signals were observed. Ruxolitinib provided longer FFS and DOR than BAT, demonstrating sustained efficacy and manageable safety over 3 years of follow-up in patients with SR/D-cGVHD.

DOI: https://doi.org/10.1200/JCO-24-02477
Br J Haematol. 2025 Jun 24.

Clinical management of CMML-State of the art.

K Nachtkamp, F Schulz, N Gattermann, U Germing.

  Chronic myelomonocytic leukaemias (CMML) are myeloid neoplasms characterized by a sustained increase in monocyte counts in the peripheral blood, accompanied by dysplasia, abnormal proliferation, chromosomal anomalies and somatic mutations of haematopoietic cells. More than 95% of CMML patients harbour somatic mutations. CMML must be separated from other myeloid neoplasms and reactive monocytosis. The clinical presentation of CMML varies, but most frequently shows signs and symptoms of haematopoietic insufficiency or myeloproliferation. Robust instruments are available for assessing the prognosis of patients with CMML, such as the CMML-specific prognostic scoring system molecular. Treatment options for patients with CMML are still inadequate and generally less effective than those for other myeloid neoplasms. The only curative approach is allogeneic stem cell transplantation. This article explains essential aspects of CMML pathophysiology and provides an overview of diagnostic considerations, prognostic assessment and therapeutic options.

Keywords:  CPSSmol; MDS/MPN overlap; chronic myelomonocytic leukaemia; treatment of CMML

DOI:  https://doi.org/10.1111/bjh.20213
Blood Adv. 2025 Jun 24. pii: bloodadvances.2025016136. [Epub ahead of print]

Long-term outcomes of patients with refractory cytopenia of childhood under observation only.

Beatrice Drexler, Stephan Schwarz-Furlan, Irith Baumann, Martina Rudelius, Peter Nöllke, Dirk Lebrecht, Senthilkumar Ramamoorthy, Natalia Rotari, Axel Karow, Shinsuke Hirabayashi, Fabian Beier, Yvonne Lisa Behrens, Gudrun Göhring, Reinhard Kalb, Marcin W Wlodarski, Brigitte Strahm, Miriam Erlacher, Charlotte M Niemeyer, Ayami Yoshimi.

Refractory Cytopenia of Childhood (RCC) is a well-recognized type of bone marrow failure patients defined by persistent cytopenia, dysplastic changes and a unique histopathologic pattern in the bone marrow. While hematopoietic stem cell transplantation (HSCT) is generally indicated for patients with severe cytopenia or abnormal karyotype, a subset of RCC patients may be candidates for an observational approach. We evaluated the long-term outcome of RCC patients without evidence of a genetic predisposition who had a normal karyotype and had not received HSCT or immunosuppressive therapy (IST) within 2 years from diagnosis. The median age at diagnosis of the 100 patients analyzed was 10.9 (1.4-17.3) years. Eighty-four percent presented with a hypocellular bone marrow. Clonal evolution with abnormal karyotype occurred in three patients (3%), and one case progressed to myelodysplastic syndrome with excess blasts (MDS-EB). Three patients (3%) developed paroxysmal nocturnal hematuria. Overall, nine (9%) patients received HSCT, and the 5- and 10-year HSCT-free survival was 94% and 88%, respectively. At last follow-up, all patients were alive with a median follow-up time of 7.2 years. These results indicate that an observational approach is safe for selected RCC patients with a normal karyotype following an exclusion of a germline predisposition syndrome. However, persistence of cytopenia in most of these patients underscores the importance of long-term surveillance and transition to adult hematology care. NCT00047268, NCT00662090.

DOI: https://doi.org/10.1182/bloodadvances.2025016136
Br J Haematol. 2025 Jun 23.

Primary myelofibrosis with increased haemoglobin concentration at presentation.

Giovanni Barosi, Rita Campanelli, Paolo Catarsi, Carlotta Abbà, Adriana Carolei, Margherita Massa, Annalisa De Silvestri, Robert Peter Gale, Vittorio Rosti.

  One hundred of 963 consecutive registrants with primary myelofibrosis (PMF) in the Pavia-CSM database had haemoglobin concentration at diagnosis ≥160 g/L in females or ≥ 165 g/L in males. These subjects were more often female and younger; had higher white blood cell (WBC) and platelet concentrations; and higher frequency of JAK2V617F and JAK2V617F variant allele frequency (VAF) compared with those without increased haemoglobin at diagnosis. They had less active disease defined as smaller spleen, lower plasma lactate dehydrogenase, lower blood CD34-positive cell concentration and less bone marrow fibrosis. They also had a lower plasma high-sensitivity C-reactive protein concentration consistent with less inflammation. These subjects were more likely to evolve towards an increased WBC concentration and had a lower risk of progressing to a myelodepletive phenotype compared with those without increased haemoglobin concentration at diagnosis and longer survival (22 vs. 15 years; p < 0.001). In subjects with increased haemoglobin concentration at diagnosis, age >50 years and JAK2V617F VAF > 75% correlated with worse survival. Our findings suggest that PMF with increased haemoglobin concentration at diagnosis is a unique variant characterized by JAK2V617F-driven hyperproliferation with less inflammation. These features impact prognosis and therapy.

Keywords:  haematological malignancy; myelofibrosis; myeloproliferative disorder; polycythaemia vera

DOI:  https://doi.org/10.1111/bjh.20233