bims-tremyl 2026-05-24 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2026–05–24
27 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Chromosome 5q deletion drives evolution of aneuploidy in myeloid neoplasms with complex karyotype.
A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53-mutated disease.
Prognostic impact of FLT3-ITD microclones in young adults with acute myeloid leukemia treated with intensive chemotherapy.
Current landscape and future directions for treatment of accelerated-phase and blast-phase myeloproliferative neoplasms.
Stag2 dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome.
Outcomes of Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide-Based GVHD Prophylaxis in Acute Myeloid Leukemia and Myelodysplastic Syndromes Patients Over 70 Years of Age: A Comparative Analysis by Age Group.
Ontogeny and Natural History of Therapy-Related Clonal Hematopoiesis From a Multidisciplinary CHIP Clinic.
HMA + venetoclax triplet regimens for the initial treatment of AML in adults- CONTRA.
Long term outcomes of idasanutlin therapy in hydroxyurea-refractory polycythemia vera patients.
Insights into clonal and complete blood count changes at disease evolution among patients with clonal cytopenia of undetermined significance.
Glutamine-dependent downregulation of FLT3-ITD is a mechanism of FLT3 inhibitor resistance in FLT3-ITD AML in hypoxia.
Inhibition of the Atypical Kinase WNK1 as a Therapeutic Strategy in TAL-related T-cell Acute Lymphoblastic Leukemia.
Initial leukemic epigenomic state determines hypomethylating agent response.
Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia.
Absolute Risk Trade-offs of Donor Age, Sex, and Graft Source in PTCy-Based Transplantation.
From fatal disease to functional cure: 25 years of tyrosine kinase inhibition in chronic myeloid leukemia.
Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk.
Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.
Extended Versus Standard Hypomethylating Agent Dosing in Combination With Venetoclax in Patients With Newly Diagnosed Acute Myeloid Leukemia.
Stromal Gasdermin D-mediated Pyroptosis Drives Maladaptive CD4⁺ T-cell Remodeling in Tet2-Deficient Hematopoiesis.
Venetoclax and azacytidine in childhood primary advanced myelodysplastic syndromes, refractory/relapsed acute myeloid leukemia and therapy-related myeloid neoplasms.
RAS pathway activation and microenvironmental adaptation as hallmarks of myeloid sarcoma.
Total marrow and lymphoid irradiation in combination with cyclophosphamide and etoposide before haematopoietic cell transplantation for relapsed or refractory acute leukaemia: a single-centre, open-label, phase 2 trial.
From a novel pathogenic SAMD9L variant to cohort-wide insights: Whole-genome sequencing highlights somatic genetic rescue and phenotypic heterogeneity.
Durable remission despite transplantation with active disease in therapy-related NUP98::TOP1-rearranged acute myeloid leukemia.
Fixed-time treatment of elderly patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) using hypomethylating agents and venetoclax - a case series.
Biallelic loss-of-function mutations in BPNT1 cause vitamin B12-dependent megaloblastic anemia.

Blood. 2026 May 21. pii: blood.2025031996. [Epub ahead of print]

Chromosome 5q deletion drives evolution of aneuploidy in myeloid neoplasms with complex karyotype.

J Philip Creamer, Suhita Ray, Sintra Stewart, Suleyman Gulsuner, Antoine N Saliba, Jieya Wu, Frank Y Huang, Aino-Maija Leppä, Bofei Wang, Hussein A Abbas, Janis L Abkowitz, Jacob S Appelbaum, Scott H Kaufmann, Pamela S Becker, Andreas Trumpp, Vaidehi Jobanputra, Min Fang, Elizabeth M Swisher, Sergei Doulatov.

Clonal acquisition of multiple chromosomal abnormalities in hematopoietic stem and progenitor cells (HSPCs) is a hallmark of high-risk acute myeloid leukemias with complex karyotype (AML-CK). AML-CK is associated with TP53 mutations and chromosome 5q deletions (del5q); however, the drivers and clonal trajectories of aneuploid evolution in HSPCs remain unknown. We have developed a patient-derived induced pluripotent stem cell (iPSC) model in which preleukemic HSPCs clonally evolve to distinct, highly aneuploid states following transient mitotic inhibition. By tracking chromosome evolution at single cell resolution, we show that TP53-mutant HSPCs with del5q, but not TP53- mutation alone, evolved complex chromosomal changes. Clonal evolution was marked by stepwise acquisition of numerical and structural chromosome changes seen in AML-CK patients, with individual abnormalities conferring fitness advantage. iPSC-derived aneuploid HSPCs and primary AML-CK patient samples exhibited a conserved gene expression signature marked by upregulation of PTEN, cohesins, and anti-apoptotic factor BCL2, indicative of a shared aneuploid cell state in HSPCs. Clinical BCL2 inhibitor venetoclax eradicated BCL2-dependent aneuploid clones, with resistant clones undergoing a lineage switch to upregulate alternative BCL2 factors. In summary, we demonstrate that mutant TP53 and del5q drive chromosome evolution marked by stepwise acquisition of individual abnormalities. Moreover, aneuploid HSPCs exhibit a shared gene expression state which confers unique targetable therapeutic vulnerabilities in AML-CK.

DOI: https://doi.org/10.1182/blood.2025031996
Blood Adv. 2026 May 20. pii: bloodadvances.2025019380. [Epub ahead of print]

A PBD-dimer containing antibody drug conjugate targeting CCRL2 for high-risk MDS/AML including TP53-mutated disease.

Nour Sabiha Naji, Taha Soueidatt Ahmedna, Xinghan Zeng, Yuju An, Yashvi Hemani, Brandy Perkins, Zanshé Thompson, Tushar D Nichakawade, Yanyan Wang, Bum Seok Lee, Evangeline Watson, Theodora Chatzilygeroudi, Li Z Luo, Bogdan Paun, Melanie Klausner, Teodora Diana Supeanu, Ivana Gojo, Gabriel Ghiaur, Amy E DeZern, Mark J Levis, Linda M S Resar, Richard J Jones, J David Peske, Styliani Karanika, Suman Paul, Theodoros Karantanos.

Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including TP53 mutations have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to healthy hematopoietic cells and we recently found that TP53-mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks leading to cancer cell death. The anti-CCRL2 ADC demonstrated strong CCRL2-selective cytotoxicity against cell lines derived from MDS/AML patients with TP53 mutations and erythroid features, surpassing the cytotoxic effects observed with gemtuzumab and PBD-conjugated anti-CD33 and anti-CD123 ADCs. It also induced apoptosis and suppressed the clonogenicity of primary MDS/AML bone marrow samples without affecting the survival, differentiation and clonogenicity of healthy hematopoietic stem and progenitor cells. This agent also suppressed the leukemic growth of TP53-mutated MDS/AML cell line xenografts, improving mice survival and decreasing the leukemic burden in patient-derived TP53-mutated MDS/AML xenografts. In conclusion, our study introduces CCRL2 as a potential new therapeutic target in high-risk MDS/AML including TP53-mutated subsets.

DOI: https://doi.org/10.1182/bloodadvances.2025019380
Blood. 2026 May 21. pii: blood.2025032829. [Epub ahead of print]

Prognostic impact of FLT3-ITD microclones in young adults with acute myeloid leukemia treated with intensive chemotherapy.

Nicolas Duployez, Romane Joudinaud, Augustin Boudry, Mathilde Hunault, Laurène Fenwarth, Emmanuelle Tavernier, Cecile Pautas, Sarah Bertoli, Suzanne Tavitian, Emmanuel Raffoux, Marie-Anne Hospital, Tony Marchand, Mael Heiblig, Sylvain P Chantepie, Martin Carre, Pierre Peterlin, Maria Pilar Gallego-Hernanz, Romain Guieze, Célestine Simand, Pascal Turlure, Anne Huynh, Emilie Lemasle, Ludovic Gabellier, Juliette Lambert, Felipe Suarez, Samy Chraibi, Laurence Sanhes, Karine Celli-Lebras, Ariane Mineur, Claude Gardin, Norbert Ifrah, Norbert Vey, Régis Peffault de Latour, Lucie Rigolot, Isabelle Luquet, Dominique Penther, Raphaël A Itzykson, Eric Delabesse, Jean-François Hamel-Broza, Stéphane de Botton, Arnaud Pigneux, Hervé Dombret, Christian Récher, Claude Preudhomme, Pierre-Yves Dumas.

FLT3 internal tandem duplications (FLT3-ITD) are major genetic events in acute myeloid leukemia (AML). Although the clinical impact of FLT3-ITD "macroclones" (allelic ratio [AR] ≥0.05) is well established, the significance of low-level FLT3-ITD subclones ("microclones") remains uncertain. We conducted a post-hoc analysis of 1 733 patients with newly diagnosed AML enrolled in the BIG-1 trial (NCT02416388). Using next-generation sequencing (NGS), we detected FLT3-ITD microclones (AR between 0.0004 and 0.05) in 17.4% of patients without FLT3-ITD macroclones. Microclones and macroclones (low and high AR) were independently associated with increased relapse risk (sHR 1.50 [95% CI 1.18-1.91], 1.98 [1.50-2.62], and 2.33 [1.69-3.22], respectively) after adjustment for age, white blood cell count, other gene mutations, midostaurin treatment, and allogeneic hematopoietic stem cell transplantation. At 2 years, cumulative incidence of relapse reached 42.5% (95% CI 37.0-47.9) in patients with macroclones, 45.1% (38.3-51.6) in patients with microclones, and 29.4% (26.6-32.3) in patients without FLT3-ITD. In NPM1-mutated AML, both microclones and macroclones were associated with higher levels of measurable residual disease (MRD) and increased relapse risk, without independent impact on overall survival after adjustment for MRD. Analysis of paired samples further revealed that 41.8% of relapses in patients with FLT3-ITD microclones at diagnosis were associated with a macroclone at relapse. These findings challenge current risk stratification models and support the integration of NGS-based FLT3-ITD detection into the diagnostic and prognostic workflow for AML. Prospective trials addressing the management of patients with FLT3-ITD microclones are warranted, as is their consideration in future ELN guidelines.

DOI: https://doi.org/10.1182/blood.2025032829
Semin Hematol. 2026 Apr 19. pii: S0037-1963(26)00029-6. [Epub ahead of print]

Current landscape and future directions for treatment of accelerated-phase and blast-phase myeloproliferative neoplasms.

Rohan K Achar, Jan Philipp Bewersdorf.

  Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders that carry the risk of transformation to accelerated-phase MPN (MPN-AP) and blast-phase MPN (MPN-BP) characterized by 10% to 19% and ≥20% peripheral or circulating blasts, respectively. This leukemic transformation is associated with less than 6 to 9 months of median overall survival and remains a major clinical challenge with limited effective treatment options. The biology of MPN-AP/BP is distinct from the pathophysiology of de novo acute myeloid leukemia (AML) and is characterized by complex clonal evolution with acquired somatic mutations in epigenetic regulators, RNA splicing factors, and TP53. Standardized risk stratification and treatment response frameworks built specifically for this disease group are not yet widely used. This limits optimal clinical trial design and meaningful cross-study comparison. The only curative treatment for MPN-AP/BP remains allogeneic hematopoietic stem cell transplant, but there is no standard of care for transplant-ineligible patients or for bridging therapy prior to transplant. Based on non-randomized trials and retrospective cohorts, less-intensive treatment regimens are often preferred except for fit patients with TP53 wild-type disease who may derive benefit from standard induction chemotherapy. Less-intensive strategies generally combine hypomethylating agents with anti-apoptotic or targeted agents. Given the role of IDH1 and IDH2 mutations in leukemic transformation, targeted therapies with IDH1 or IDH2 inhibitors are another option for selected patients. Current studies are investigating the role of next-generation Janus Kinase (JAK) inhibition, inhibition of epigenetic modulators, and blockade of anti-apoptotic pathways as paradigm shifts to make MPN-AP/BP a more manageable disease.

Keywords:  Accelerated-phase; Blast-phase; Myeloproliferative neoplasm; Secondary AML

DOI:  https://doi.org/10.1053/j.seminhematol.2026.04.003
Blood. 2026 May 18. pii: blood.2025030554. [Epub ahead of print]

Stag2 dependent chromatin remodeling enforces the erythroid-specific Gata1 cistrome.

Varun S Sudunagunta, Edna M Stewart, Yi Chen, Hongxia Yan, Sebastian Fernando, Viviana Scoca, John Pantazi, Rong Deng, Jane J Xu, Narla Mohandas, Aaron D Viny.

The transcription factor GATA1 has pleiotropic hematopoietic functions, particularly in erythroid and megakaryocytic ontogeny. While mechanistic investigations have uncovered many facets of GATA1 biology, how GATA1 co-regulates divergent cell fates remains incompletely characterized. We previously described that loss of Stag2, a member of the cohesin complex and a recurrent mutational target in myelodysplastic syndrome (MDS) and myeloid leukemia of Down Syndrome, results in altered chromatin accessibility, transcription factor function, and cell differentiation. Hence, we hypothesized that chromatin accessibility determines GATA1 cistrome specificity and lineage fate decisions. To understand the connection between chromatin accessibility and GATA1, we comprehensively studied erythropoiesis in Stag2∆ mice. Defects in Stag2-deficient hematopoiesis included reduced numbers of erythroid progenitors (EryPs), impaired terminal erythroid differentiation, increased number of MkPs, and increased megakaryocytes. RNA- and ATAC-sequencing of EryPs revealed altered patterns of Gata1 target gene expression with altered accessibility in conjunction with loss of expression of erythroid targets and gain of megakaryocyte targets. Despite unchanged Gata1 expression, Gata1 occupancy was reprogrammed from erythroid to megakaryocyte targets with Fli1 motifs enriched at Stag2∆ Gata1 binding sites. Functionally, we observed that Stag2-deficient EryPs have diminished erythroid output and augmented megakaryocyte output in orthogonal differentiation assays, which was partially reversed with Fli1 knockdown. Human models and primary MDS patients recapitulated the essential phenotypic and molecular features of our in vivo murine MDS model. Collectively, this study establishes chromatin accessibility as a determinant of transcription factor binding specificity, revealing an accessibility-driven Gata1 retargeting mechanism underlying MDS dyserythropoiesis.

DOI: https://doi.org/10.1182/blood.2025030554
Clin Lymphoma Myeloma Leuk. 2026 Apr 28. pii: S2152-2650(26)00129-1. [Epub ahead of print]

Outcomes of Hematopoietic Cell Transplantation With Post-Transplant Cyclophosphamide-Based GVHD Prophylaxis in Acute Myeloid Leukemia and Myelodysplastic Syndromes Patients Over 70 Years of Age: A Comparative Analysis by Age Group.

Muhammad Umair Mushtaq, Muhammad Kashif Amin, Amir Kasaeian, Shajadi Patan, Aqeeb Ur Rehman, Amna Zaheer, Fatma Ozge Sayali, Shah Rukh, Mohammad Ma'koseh, Anurag K Singh, Mehdi Hamadani, Joseph P Mcguirk, Moazzam Shahzad.

   BACKGROUND: We aimed to study outcomes of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients aged above 70 with using post-transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis.
METHODS: We performed a retrospective multicenter analysis on the Center for International Blood and Marrow Transplant Research registry of adult patients with acute myeloid leukemia or myelodysplastic syndromes who underwent their first allogeneic hematopoietic cell transplantation (2012-2017) with post-transplant cyclophosphamide-based GVHD prophylaxis. Patients were stratified by age (>70 vs. 18-70 years; the comparator was predominantly older, with a median age of 61.9). Primary outcomes included overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), acute and chronic GVHD, and GVHD-free relapse-free survival. Multivariable Cox and cause-specific hazards models assessed the independent effect of age >70 years.
RESULTS: Of 431 patients, 71 (16%) were aged >70 years. Haploidentical donors were used in 84% of older versus 69% of younger patients. With a median follow-up of 4.0 years, 1-year OS was 54% in patients >70 years versus 63% in those 18 to 70 years; 1-year DFS was 38% versus 42%. In multivariable analysis, age >70 years was associated with inferior OS (hazard ratio 1.57, 95% CI 1.06-2.34) and higher NRM (hazard ratio 2.21, 95% CI 1.29-3.80), but not with relapse, DFS, GVHD-free relapse-free survival, acute GVHD, chronic GVHD, or neutrophil engraftment.
CONCLUSION: Allogeneic hematopoietic cell transplantation with PTCy is feasible in carefully selected patients aged >70 years with AML/MDS. Although higher NRM and modestly inferior OS persist, comparable relapse rates, DFS, and GVHD control support individualized rather than age-based decision-making for transplantation in this population.

Keywords:  Geriatric oncology; Graft versus host disease; Hematologic malignancies; Survival; Transplant outcomes

DOI:  https://doi.org/10.1016/j.clml.2026.04.017
Am J Hematol. 2026 May 19.

Ontogeny and Natural History of Therapy-Related Clonal Hematopoiesis From a Multidisciplinary CHIP Clinic.

Shyam A Patel, Valerie Zhu, William K Gerber, Sakiko Suzuki, Charlotte Barker, Lloyd Hutchinson, Salwa Khedr, David Cachia, Abhishek A Mangaonkar, Matthew E McGuiness, Anne W Higgins, Patricia M Miron, Jonathan M Gerber.

  Age-related changes in human hematopoietic stem cells (HSCs) often form the basis for clonal hematopoiesis (CH), which presages the development of overt myeloid neoplasm with variable risk. CH can also arise after exposure to chemotherapy, radiotherapy, or immune interventions. In this study, we performed clinico-genomic profiling of therapy-related CH (t-CH) (n = 67) versus de novo CH (n = 123) from a multidisciplinary CHIP Clinic. The most enriched mutations in t-CH were TET2 (26.2%), DNMT3A (22.4%), and TP53 (8.4%). Median latency period from the time of initial exposure to the diagnosis of t-CH was 6.96 ± 1.10 years. Patients with t-CH had inferior event-free survival compared to de novo CH (median 29.9 months versus 122.1 months, p = 0.0045). Overall survival was also shorter in t-CH versus de novo CH (median 55.3 months vs. 129.2 months, p = 0.043). Genes that imparted significantly increased risk for progression from t-CH to overt therapy-related myeloid neoplasm (t-MN) included JAK2 (relative risk (RR) 9.42, p = 0.0001), RUNX1 (RR 7.11, p = 0.001), EZH2 (RR 7.11, p = 0.001), and TET2 (RR 13.4, p = 0.01). Clonal dynamic modeling of patients with t-CH who progressed to overt t-MN showed an increase in the relative clonal fraction and new clonal outgrowth. In the t-CH cohort, higher mean variant allele frequency was observed in progressors versus non-progressors (77.1% vs. 30.6%, p = 0.017). This study sheds light onto outcomes for CH based on differing clinical ontogeny and has implications for previvorship for secondary malignancies.

Keywords:  CHIP; acute myeloid leukemia; clonal hematopoiesis; myelodysplastic neoplasms

DOI:  https://doi.org/10.1002/ajh.70374
Blood Adv. 2026 May 21. pii: bloodadvances.2025018556. [Epub ahead of print]

HMA + venetoclax triplet regimens for the initial treatment of AML in adults- CONTRA.

Maximilian Stahl, Richard M Stone.

DOI: https://doi.org/10.1182/bloodadvances.2025018556
Leuk Lymphoma. 2026 May 18. 1-4

Long term outcomes of idasanutlin therapy in hydroxyurea-refractory polycythemia vera patients.

Megan Metzger, Julian A Waksal, Jayanshu Jain, Natalia Rosas, Margherita Maffioli, Grace Van Hyfte, Aaron Gerds, Vikas Gupta, Francesco Passamonti, Abdulraheem Yacoub, Ronald Hoffman, John O Mascarenhas.

  Idasanutlin is a small molecule inhibitor that restores p53 activity, triggering apoptosis. Two trials (phase 1/2) of idasanutlin therapy in polycythemia vera patients that were intolerant or refractory to hydroxyurea resulted in substantial clinical and molecular responses. Here the long term outcomes of these patients are reported.

Keywords:  Myeloproliferative neoplasm; idasanutlin; polycythemia vera

DOI:  https://doi.org/10.1080/10428194.2026.2666850
Haematologica. 2026 May 21.

Insights into clonal and complete blood count changes at disease evolution among patients with clonal cytopenia of undetermined significance.

Yazan Jabban, Rong He, Kurt Bessonen, Patricia T Greipp, Dragan Jevremovic, David S Viswanatha, James M Foran, Talha Badar, Cecilia Arana Yi, Yael N Kusne, Antoine N Saliba, Mehrdad Hefazi, Aasiya Matin, William J Hogan, Abhishek A Mangaonkar, Mithun Vinod Shah, Hassan B Alkhateeb, Mrinal M Patnaik, Aref Al-Kali.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.300039
bioRxiv. 2026 May 15. pii: 2026.05.02.722336. [Epub ahead of print]

Glutamine-dependent downregulation of FLT3-ITD is a mechanism of FLT3 inhibitor resistance in FLT3-ITD AML in hypoxia.

Giovannino Silvestri, Aditi Chatterjee, Blair P Rendina, Eli E Bar, Maria R Baer.

FLT3 inhibitors have improved outcomes in acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), but responses are not durable. Notably, FLT3 inhibitors clear blasts from the blood, but not the bone marrow, a hypoxic niche. We investigated effects of hypoxia and the key nutrient glutamine on FLT3 inhibitor response. FLT3-ITD AML cell lines and patient blasts were cultured with FLT3 inhibitors under normoxia (21%) or hypoxia (<1% O₂) with or without glutamine or the glutaminase inhibitor telaglenastat (CB-839). Cytotoxicity was measured in WST-1 assays and drug combination effects by Chou-Talalay analysis. Protein expression was measured by immunoblotting, turnover and proteasomal degradation by cycloheximide chase with and without MG-132, and mRNA expression by RT-qPCR. Effect of the ubiquitin ligase c-CBL was tested by siRNA knockdown. FLT3 inhibitor IC₅₀s were 3-5-fold higher in hypoxia than normoxia, associated with FLT3-ITD and p-STAT5 downregulation and accelerated FLT3-ITD proteasomal degradation (half-life, 1.0 vs. 2.5 hours). c-CBL expression increased in hypoxia, and c-CBL knockdown restored FLT3-ITD expression and FLT3 inhibitor sensitivity. Glutamine deprivation or telaglenastat treatment abrogated c-CBL upregulation in hypoxia and preserved FLT3-ITD and p-STAT5 expression and FLT3 inhibitor sensitivity. Telaglenastat synergized with FLT3 inhibitors in hypoxia, supporting clinical testing.

DOI: https://doi.org/10.64898/2026.05.02.722336
Blood. 2026 May 19. pii: blood.2025029901. [Epub ahead of print]

Inhibition of the Atypical Kinase WNK1 as a Therapeutic Strategy in TAL-related T-cell Acute Lymphoblastic Leukemia.

Anna Montanaro, Gregorio Monica, Raffaella Zamponi, Anna D'Antuono, Alice Andreani, Pietro Andrei, Angela Su, Alessia Ciringione, Gabriella Sammarelli, Giannalisa Todaro, Roberto Rosati, Roberta La Starza, Cristina Mecucci, Loredana Elia, Andrea Gherli, Federica Vento, Elisa Simoncini, Bruno Lorusso, Costanza Anna Maria Lagastra, Mariateresa Giaimo, Luca Pagliaro, Matteo Marchesini, Connie R Jimenez, Federico Quaini, Kimberly Stegmaier, Giovanni Roti.

Driver mutations in T-cell acute leukemia (T-ALL) rarely affect druggable kinases. However, these kinases can be aberrantly activated or repressed as secondary oncogenic events. Thus, integrating unbiased phosphoproteomics with genomic approaches may offer novel opportunities for target discovery and therapeutic interventions. In our study, we identified WNK1 as a potential target in T-ALL by pairing a list of vulnerable kinases with data from a phosphoproteomic screen of T-ALL cell lines. We subsequently validated WNK1 by loss-of-function-based studies and tested WNK inhibitors in several in vitro and in vivo T-ALL models and clinical T-ALL samples. We showed that therapeutic WNK1 repression promotes polyploidy, resulting in cell proliferation arrest, and morphometric changes, such as incomplete cell division or chromosome segregation through altered mitotic spindle assembly and abscission defects. Furthermore, we found that WNK1 is overexpressed in the TAL1/2-related subgroup, but not in normal thymus or lymph nodes, suggesting a potential translational area for clinical exploitation in poor-prognosis T-ALL carrying PTEN mutations and del(6q). Our work also reports a functional contribution of WNK1 in the leukemia establishment and progression. Structurally WNK1 is an atypical serine/threonine kinase that diverge from canonical kinases by lacking the conserved lysine in subdomain II, instead featuring a cysteine in subdomain I, which is critical for ATP-binding. This unusual structural configuration creates a distinct ATP-binding pocket with limited sequence similarity to conventional kinases, offering a unique opportunity to develop highly selective small-molecules. Targeting this atypical ATP-domain could thus provide a therapeutic advantage and broaden the treatment landscape for T-ALL.

DOI: https://doi.org/10.1182/blood.2025029901
Nat Commun. 2026 May 22.

Initial leukemic epigenomic state determines hypomethylating agent response.

Aparna Gopal, Derek Tam, Franziska Mey, Diana Lin, Christina May, Jihong Jiang, Joshua Bridgers, Brett Caswell, Kieran O'Neill, Frederick S Vizeacoumar, Mackenzie MacAuley, Emilie Haniak, Charles Craddock, Paresh Vyas, Luca Malcovati, Rena Buckstein, Michelle Moksa, Martin Hirst, Franco J Vizeacoumar, Nadia Medvedev, Michael Heuser, Ryan J Stubbins, Yu Deng, Aly Karsan.

Hypomethylating agents (HMAs) are a mainstay of therapy for myeloid cancers, but genetic biomarkers do not predict who will respond to treatment. Using a variety of single-cell sequencing approaches to define the epigenomic state of responder and nonresponder leukemic cells, we demonstrate that leukemic stem cells (LSC) exist in at least two different epigenomic states: a hematopoietic stem cell (HSC)-or multipotent progenitor (MPP)-like state that is sensitive to HMAs, independent of genetic mutations, or a lymphoid-primed MPP (LMPP)-like nonresponder state. Hypomethylation and chromatin accessibility at ZNF143- and CTCF-binding sites results in activation of HOXB4, which defines the HSC/MPP-like state and HMA-sensitivity. Our study provides evidence that the epigenomic state of the LSC is a major determinant of response to HMAs, and demonstrates that a routine clinical assay can identify patients who will respond.

DOI: https://doi.org/10.1038/s41467-026-73334-3
Blood Cancer Discov. 2026 May 18.

Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia.

Goichi Tatsumi, Rajni Kumari, Yutaro Suzuki, Shuting Li, Russell Scharf, Samuel J Taylor, Sriram Sundaravel, Amit Verma, Justin C Wheat, Ulrich Steidl.

Chemotherapy resistance remains a critical challenge in the treatment of patients with cancer, including acute myeloid leukemia (AML). While genetic alterations can contribute to resistance, the role of rapid-adaptive non-genetic mechanisms, particularly transcription dynamics, remains poorly understood. Here, we demonstrated that short-term treatment of AML cells with the widely used chemotherapeutic cytarabine (AraC) leads to the rapid emergence of a cell population with significant RNA induction and increased AraC resistance in cell lines and primary patient samples. Mechanistically, transcriptomic and targeted high-resolution analysis of transcription dynamics using single-molecule RNA FISH revealed rapid induction of transcriptional dynamics and upregulation of key transcription factors (TFs) - which we term "AraC rapid response TFs". Functionally, short-term pre- and co-treatment with RNA transcription inhibitors suppressed chemotherapy-induced RNA induction and prevented resistance acquisition in vitro and in vivo. Furthermore, CRISPR-mediated suppression of TFs PU.1 and GATA1 significantly attenuated AraC resistance. Our findings reveal a role of rapid-adaptive transcriptional dynamics in AML chemotherapy resistance.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0317
Blood Adv. 2026 May 20. pii: bloodadvances.2026020359. [Epub ahead of print]

Absolute Risk Trade-offs of Donor Age, Sex, and Graft Source in PTCy-Based Transplantation.

Yosra M Aljawai, Mariam T Nawas, Shannon R McCurdy, Christopher G Kanakry, Jennifer A Kanakry, Joseph C Rimando, Jennifer N Saultz, Taha Al-Juhaishi, Aleksandr Lazaryan, Filippo Milano, Rohtesh S Mehta.

DOI: https://doi.org/10.1182/bloodadvances.2026020359
Leukemia. 2026 May 22.

From fatal disease to functional cure: 25 years of tyrosine kinase inhibition in chronic myeloid leukemia.

Andreas Hochhaus, Moshe Talpaz, Giuseppe Saglio, Jorge E Cortes, Timothy Hughes, Jane Apperley, Oliver Hantschel, Delphine Rea, Peter Schuld, Hagop Kantarjian.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome, which results from a translocation between chromosomes 9 and 22. This alteration gives rise to the BCR::ABL1 fusion oncogene, whose constitutive tyrosine kinase activity promotes uncontrolled proliferation and survival of leukemic cells. The discovery of this molecular driver laid the foundation for the development of tyrosine kinase inhibitors (TKIs), which transformed CML management from treatment with non-specific modalities to establishing a new paradigm for precision oncology with targeted therapies. Imatinib, the first TKI, demonstrated unprecedented hematologic, cytogenetic, and molecular responses, rapidly becoming the standard of care in CML. Subsequent generations of TKIs were developed to overcome resistance and intolerance to imatinib. These advances improved survival in CML, bringing life expectancy close to that of the general population for the patients who respond to treatment, and shifting treatment goals towards quality of life and the possibility of treatment-free remission (TFR). Landmark discontinuation studies showed that approximately half of eligible patients can maintain TFR. Despite these achievements, important challenges remain, including TKI resistance, safety considerations, and the relatively low proportion of patients who achieve and maintain TFR. Newer-generation TKIs, combination strategies, immunomodulatory approaches, and emerging treatment modalities such as degraders offer promising avenues to further improve outcomes, expand TFR eligibility, ensure optimal quality of life, address resistance mechanisms, and render therapy available and affordable to all patients with CML worldwide.

DOI: https://doi.org/10.1038/s41375-026-02984-5
Nat Commun. 2026 May 21.

Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk.

Kara M Barnao, Aubrey K Hubbard, Irenaeus C C Chan, Weiyin Zhou, Yasminka A Jakubek, Giulio Genovese, Wendy S W Wong, Rebecca L Kelly, Corey D Young, Derek W Brown, Wen-Yi Huang, Neal D Freedman, Kristine Jones, Amy Hutchinson, Belynda Hicks, Duc Tran, Donna Arnett, Kathleen C Barnes, Joshua C Bis, Eric Boerwinkle, Jennifer A Brody, April P Carson, Daniel I Chasman, Michael H Cho, Pinkal Desai, Margaret F Doyle, Myriam Fornage, Xiuqing Guo, Nancy Heard-Costa, Marguerite Ryan Irvin, Andrew D Johnson, Sharon L R Kardia, Charles Kooperberg, Daniel Levy, Joshua P Lewis, Yun Li, Ruth J F Loos, Taralynn M Mack, Rasika A Mathias, Braxton D Mitchell, Kari E North, Nathan Pankratz, Patricia A Peyser, Michael H Preuss, Bruce M Psaty, Laura M Raffield, Susan Redline, Stephen S Rich, Jerome I Rotter, Edwin K Silverman, Albert V Smith, Jennifer A Smith, Adrienne Stilp, Yin Cao, Paul Scheet, Alexander P Reiner, Alexander G Bick, Stephen J Chanock, Paul L Auer, Kelly L Bolton, Mitchell J Machiela.

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are two types of clonal hematopoiesis (CH) associated with hematological parameters and malignancy risk. Here we show, in genomic data from 546,090 biobank participants, that co-occurring CH (≥2 CH mutations detected) is present in 1.6% of cancer-free individuals and shows strong evidence for selection (up to 804x enrichment). Co-occurrence is more frequent in those with a prior cancer (3.6%), suggesting treatment-induced selection. Acquisition of CHIP usually precedes mCAs with co-occurrences manifesting stronger phenotypic disruptions in telomere attrition and hematologic parameters than component CH events. Individuals with co-occurring CH have pronounced elevations in risk of myeloid and lymphoid malignancies (HRs>40), particularly when CHIP and mCAs overlap genomically. Our findings indicate CH co-occurrences are selected for in the aging population and identify CH clones with notable implications for future malignancy risk.

DOI: https://doi.org/10.1038/s41467-026-73302-x
Oncogenesis. 2026 May 16.

Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.

Dominik A Nahotko, Brian Lee, Emely Lopez Fajardo, Aneta H Baran, Szymon K Filip, Peter A Faull, Elizabeth T Bartom, Masha Kocherginsky, Peng Gao, Jason Miska, Diana Saleiro, Elspeth M Beauchamp, Leonidas C Platanias.

La-related protein 1 (LARP1) is an RNA-binding protein and downstream effector of mTOR and CDK9 signaling that regulates translation of mRNAs containing a 5'-terminal oligopyrimidine motif. While elevated LARP1 expression has been linked to poor prognosis in acute myeloid leukemia (AML), its mechanistic role remains unclear. Using CRISPR/Cas9-mediated LARP1 knockout and multi-omics analyses, we investigated LARP1's role in AML. LARP1 loss impaired proliferation, clonogenicity, and tumor growth in xenografts, and enhanced sensitivity of AML cells to 5-azacytidine and cytarabine. Polysome profiling and RNA sequencing revealed that LARP1 modulates a distinct set of transcripts involved in mitochondrial function, amino acid metabolism, and cell cycle regulation, independently of mTOR and CDK9. Proteomics analysis uncovered additional effects of LARP1 loss on immune signaling, lysosomal pathways, and protein stability, including changes not evident at the RNA level. Metabolomic profiling showed reprogramming of arginine/creatine metabolism and depletion of pyrimidine biosynthesis intermediates. Cytidine deaminase, a known resistance factor, was downregulated across omics layers upon LARP1 loss. These findings define LARP1 as a key integrator of translational regulation and metabolic control in AML, supporting leukemic cell survival and promoting drug resistance. Targeting LARP1 may uncover vulnerabilities in leukemia cells, not addressed by current therapies.

DOI: https://doi.org/10.1038/s41389-026-00623-3
Hematol Oncol. 2026 May;44(3): e70198

Extended Versus Standard Hypomethylating Agent Dosing in Combination With Venetoclax in Patients With Newly Diagnosed Acute Myeloid Leukemia.

Georgio Medawar, Jean-Sebastien Anoma, Elizabeth Hill, Serena Tharakan, Dahniel L Sastow, Vincent Lok, Su Bin Hahn, Sarah Chen, Thomas Kehoe, Chidambaram Ramasamy, Julian Guetta-Weiss, Kapil Meleveedu, Chenyu Lin, David M Swoboda, Douglas Tremblay, Alexander Coltoff.

  The optimal duration of hypomethylating agent (HMA) therapy combined with venetoclax (Ven) in newly diagnosed acute myeloid leukemia (ND-AML) remains uncertain. Standard of care (SOC) uses 5-day decitabine (Dec-5) or 7-day azacitidine (Aza-7), while extended HMA regimens (e.g., 10-day decitabine [Dec-10] during cycle 1) have also been explored, although direct comparative data between these approaches are limited. We conducted a large retrospective analysis of 335 patients with ND-AML treated at five US centers with Dec-10/Ven (n = 102) or SOC HMA/Ven (n = 233). Baseline characteristics were largely balanced, though the Dec-10 group had more treated secondary AML, and the SOC group had more intermediate risk by ELN-2024. Dec-10/Ven exhibited significantly higher composite complete remission rates (CRc) (82% vs. 70%, p = 0.029), but similar measurable residual disease (MRD) negativity rates (27% vs. 25%, p = 0.6) at best response. Median overall survival (OS) was significantly longer for Dec-10/Ven, 22.2 versus 9.1 months for SOC (p < 0.001). Transplantation was more frequent following Dec-10/Ven (25% vs. 6%, p < 0.001). The 30-day and 60-day mortality rates were similar (7% vs. 11%, p = 0.4; 13% vs. 23%, p = 0.1). On multivariable analysis, the Dec-10 regimen, de novo AML, non-complex karyotype, and IDH2 mutation were associated with a significantly lower risk of death. Our findings suggest that Dec-10/Ven may lead to improved transplant rates and survival, providing valuable real-world support for this intensified approach in appropriate patients. Prospective randomized evaluation is warranted.

Keywords:  acute myeloid leukemia; azacitidine; decitabine; duration; outcomes

DOI:  https://doi.org/10.1002/hon.70198
bioRxiv. 2026 May 05. pii: 2026.05.01.722102. [Epub ahead of print]

Stromal Gasdermin D-mediated Pyroptosis Drives Maladaptive CD4⁺ T-cell Remodeling in Tet2-Deficient Hematopoiesis.

Kehan Ren, Xu Han, Ermin Li, Pan Wang, Honghao Bi, Wenjie Cai, Inci Aydemir, Ching Man Wai, Hongshen Niu, Jing Yang, Yijie Liu, Brian Vadasz, Madina Sukhanova, Deyu Fang, Weiguo Cui, Peng Ji.

An inflammatory bone marrow microenvironment is increasingly recognized as critical in myeloid disease evolution, yet how stromal inflammation interfaces with adaptive immunity remains poorly defined. Here, we show that stromal pyroptosis drives mutation-specific myeloid expansion by coordinating monocytic remodeling and CD4⁺ T-cell activation. Genetic ablation of gasdermin D in the bone marrow stroma suppressed stromal pyroptosis and attenuated Tet2-deficient myeloid expansion. Tet2 deficiency skewed monocyte and macrophage differentiation toward an activated, antigen-presenting state that interacted with pyroptotic stromal cells to promote expansion of a distinct CD4⁺ T-cell population. These cells expressed canonical T follicular helper markers ( Bcl6 , Cxcr5 , Il21 , and Cd40l ) together with interferon-responsive and tissue-interaction programs, consistent with an inflammation-adapted T FH -like state. CD40L produced by these cells reinforced the expansion of Tet2-deficient monocytes and macrophages, establishing a feed-forward stromal-immune circuit. Disruption of this axis through stromal gasdermin D deficiency or CD40L blockade attenuated myeloid expansion in vivo. Consistent with these findings, patients with isolated TET2 loss-of-function mutations exhibited CD4⁺ T-cell skewing and CD40L + T-cell-rich tertiary lymphoid structures in the bone marrow. Together, these data identify a pyroptosis-dependent stromal-immune axis that links early myeloid inflammation to maladaptive remodeling of adaptive immunity and reveals a context-dependent therapeutic vulnerability in Tet2-deficient hematopoiesis.

DOI: https://doi.org/10.64898/2026.05.01.722102
Haematologica. 2026 May 21.

Venetoclax and azacytidine in childhood primary advanced myelodysplastic syndromes, refractory/relapsed acute myeloid leukemia and therapy-related myeloid neoplasms.

Francesco Baccelli, Pietro Merli, Martina Pigazzi, Barbara Buldini, Marco Becilli, Katia Girardi, Valeria Paganelli, Gennaro Pagano, Davide Leardini, Edoardo Muratore, Francesca Vendemini, Giuliana Beneduce, Manuela Tumino, Francesco Saglio, Elena Sieni, Elena Mastrodicasa, Marianna Maffeis, Francesco Paolo Tambaro, Riccardo Masetti, Franco Locatelli.

Pediatric refractory/relapsed acute myeloid leukemia (r/r-AML), myelodysplastic syndromes with excess blasts (MDSEB), and therapy-related MDS/AML (t-MDS/AML) remain a clinical challenge due to high rate of treatment failure. Venetoclax plus azacytidine (ven/aza) has transformed adult myeloid neoplasm treatment, but pediatric data are limited and heterogeneous. This AIEOP retrospective, multicenter study analyzed 50 patients (M/F=1.8/1; median age 11 years) with r/r-AML (n=32), MDS-EB (n=10), or t-MDS/AML (n=8) treated with ven/aza. Responses were defined as complete (CR), partial (PR), or non-response (NR) based on bone marrow (BM) blast evaluation. Adverse events (AEs) were graded per CTCAE v5.0; outcomes were evaluated with Kaplan-Meier and Cox-regression analysis. Patients received a median of 2 cycles (range, 1-7). Grade ≥3 AEs occurred in 34% of patients. Overall, 30 patients (60%) achieved CR (24 MRD-negative), 9 (18%) PR, and 11 (22%) NR. CR were 58%, 57% and 100% in KMT2A-AML, FLT3-ITD-AML (ven/aza+FLT3-inhibitors) and UBTF-TD myeloid neoplasms, respectively. In 10 MDS-EB, 7 CR and 2 PR were recorded. In 8 t-MDS/AML, we observed 5 CR and 2 PR. Thirty-three patients (66%) underwent hematopoietic cell transplantation (HCT), after a median of 97 days (range: 33-933) from ven/aza start. Median follow-up was 389 days (range 36-1405). Two-year event-free survival (EFS) was 54.5% (CI:46.7-62.3), being 75.8% in transplanted patients, and 77.2% in those achieving CR. CR and HCT were associated with better EFS. Ven/aza shows substantial activity and manageable toxicity in pediatric high-risk myeloid diseases, especially as a bridge to HCT and in specific molecular subgroups, supporting future, prospective, genetically-guided studies.

DOI: https://doi.org/10.3324/haematol.2026.300775
Blood Cancer Discov. 2026 May 20.

RAS pathway activation and microenvironmental adaptation as hallmarks of myeloid sarcoma.

Bettina Nadorp, Audrey Lasry, Sanam Loghavi, Ravi Patel, Hager Mansour, Pier Edoardo Rovatti, Benjamin J Kelly, Christopher J Walker, Jill Buss, Isaiah Boateng, Wafa Al-Santli, Zoe Ciantra, Rebecca Austin, Helee Desai, Hasan Abaza, Linda Procell, Tejas Patel, Bejamin Kaffenberger, Saranga Wijeratne, Maria Guillamot, Maria Velegraki, Luis A Chiriboga, Zihai Li, Daniel A Pollyea, Christine M McMahon, Arwa Shanaah, John C Byrd, Manel Esteller, Eirini P Papapetrou, Aristotelis Tsirigos, Alice S Mims, Elaine R Mardis, Iannis Aifantis, Ann-Kathrin Eisfeld.

Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in approximately 20% of patients, and remains strikingly understudied in large-scale genomic and multiomic investigations. The key drivers of its tumor evolution are largely unknown, timely detection in asymptomatic patients poses a clinical challenge, and effective treatment options are limited as patients are often excluded from clinical trials, rendering it a largely neglected disease entity. Here, we demonstrate that myeloid sarcoma evolves from medullary AML but exhibits distinct site-specific clonal evolution. This is supported by unique transcriptional signatures of myeloid sarcoma, reflecting adaptation to the extramedullary microenvironment. We establish a proof of concept that circulating tumor DNA sequencing captures the molecular composition of myeloid sarcoma, offering a potential non-invasive approach for molecular profiling of extramedullary AML. Our findings highlight marked differences between medullary AML and myeloid sarcoma, including universal molecular evolution and RAS pathway activation as disease hallmarks.

DOI: https://doi.org/10.1158/2643-3230.BCD-26-0160
Lancet Haematol. 2026 May 18. pii: S2352-3026(26)00014-1. [Epub ahead of print]

Total marrow and lymphoid irradiation in combination with cyclophosphamide and etoposide before haematopoietic cell transplantation for relapsed or refractory acute leukaemia: a single-centre, open-label, phase 2 trial.

Anthony Stein, Yan Wang, Monzr M Al Malki, Ibrahim Aldoss, Haris Ali, Ahmed Aribi, Andrew Artz, Brian Ball, Savita Dandapani, Len Farol, Chunhui Han, An Liu, Vinod Pullarkat, Eric Radany, Firoozeh Sahebi, James F Sanchez, Karamjeet Sandhu, Amandeep Salhotra, Eileen Smith, Ricardo Spielberger, Susanta Hui, Guido Marcucci, Ryotaro Nakamura, Stephen J Forman, Joycelynne Palmer, Jeffrey Wong.

BACKGROUND: Total marrow and lymphoid irradiation delivers augmented doses of radiation to the bone marrow and lymph nodes while maintaining low doses to vital organs. We aimed to assess the effectiveness of combining total marrow and lymphoid irradiation (2000 cGy to bone marrow and lymph nodes) with high-dose cyclophosphamide and etoposide as a conditioning regimen before allogeneic haematopoietic cell transplantation (HCT) in patients with relapsed or refractory acute leukaemia.
METHODS: This single-centre, open-label, phase 2 trial with an initial six-patient safety lead-in, conducted in the USA, enrolled patients aged between 16 and 60 years with relapsed or refractory acute myeloid leukaemia or acute lymphoblastic leukaemia. Total marrow and lymphoid irradiation was given on days -9 to -5, etoposide 60 mg/kg on day -4, and cyclophosphamide 100 mg/kg on day -2. Bone marrow or peripheral blood stem cells from sibling or matched or one allele mismatched unrelated donors were infused on day 0. Graft versus host disease prophylaxis consisted of tacrolimus and sirolimus. The primary endpoint for the initial safety lead-in segment was toxicity and for the phase 2 study was 2-year progression-free survival. All patients who began treatment were included in the analysis. This trial is registered with ClinicalTrials.gov, NCT02094794, and is closed to accrual.
FINDINGS: Between May 9, 2014, and Mar 5, 2024, 107 patients were enrolled and screened for eligibility. One did not meet eligibility criteria (uncontrolled cytomegalovirus). 106 received conditioning radiation and HCT per protocol. Median follow-up was 1·8 years (IQR 0·6-3·0) for all patients and 3·1 years (2·1-4·9) for patients who were alive at last contact. None of the six patients in the safety lead-in experienced unacceptable toxicity. 49 (46%) of 106 patients were female and 57 (54%) were male. 72 (68%) of patients were White and 22 (21%) were Asian or Pacific Islander. The 2-year estimate of progression-free survival in all patients was 34% (95% CI 25-43%). The most common grade 3-4 adverse events were cytopenias 96 (91%), metabolic disorders 83 (78%), oral mucositis 45 (42%), diarrhoea 25 (24%), nausea 21 (20%), and palmar-plantar erythrodysesthesia syndrome 11 (10%). One patient died of sinusoidal obstruction syndrome attributed to the conditioning regimen.
INTERPRETATION: Adverse events were few, probably due to organ sparing by total marrow and lymphoid irradiation. Total marrow and lymphoid irradiation 2000 cGy could be safely delivered in combination with high-dose etoposide and cyclophosphamide. The regimen was associated with encouraging 2-year progression-free survival rates.
FUNDING: National Institutes of Health and Accuray.

DOI: https://doi.org/10.1016/S2352-3026(26)00014-1
Br J Haematol. 2026 May 19.

From a novel pathogenic SAMD9L variant to cohort-wide insights: Whole-genome sequencing highlights somatic genetic rescue and phenotypic heterogeneity.

AURAGEN Consortium

  Germline gain-of-function variants in sterile alpha motif domain-containing 9-like (SAMD9L), located on chromosome 7q, cause a multisystem disorder characterized by bone marrow failure, immunodeficiency and variable neurological involvement. Disease evolution is frequently shaped by somatic genetic rescue (SGR), most commonly through monosomy 7, somatic loss-of-function (LOF) variants in cis or uniparental disomy of 7q (UPD7q). We report a 6-month-old girl presenting with pancytopenia and severe infections, in whom we identified a novel heterozygous SAMD9L variant. Trio-based whole-genome sequencing demonstrated maternal transmission and revealed distinct SGR mechanisms in both the proband and her asymptomatic mother, including UPD7q and an additional somatic LOF variant. Longitudinal molecular follow-up showed dynamic clonal evolution associated with haematological improvement. To assess the broader relevance of SAMD9/SAMD9L variants, we also performed a gene-centred analysis of the 2025 French Genomic Medicine Initiative (PFMG2025), enabling the identification and classification of additional candidate variants. These findings support systematic screening for SGR, including mosaic UPD7q, even in cases with apparently normal variant allele frequency, and highlight the importance of integrating haematopoietic and non-haematopoietic tissues in diagnostic workflows for inherited bone marrow failure syndromes.

Keywords:   SAMD9 ; SAMD9L ; bone marrow failure; clonal evolution; somatic genetic rescue (UPD7q); trio whole‐genome sequencing

DOI:  https://doi.org/10.1111/bjh.70563
Ann Hematol. 2026 May 23. pii: 293. [Epub ahead of print]105(6):

Durable remission despite transplantation with active disease in therapy-related NUP98::TOP1-rearranged acute myeloid leukemia.

Gaetano Cimino, Rebecca Sembenico, Francesco Zorutti, Simonetta Saldi, Matteo Caridi, Valeria Cardinali, Sofia Sciabolacci, Barbara Crescenzi, Caterina Matteucci, Roberta La Starza, Alessandra Pucciarini, Tiziana Zei, Roberta Iacucci Ostini, Cynthia Aristei, Alessandra Carotti, Cristina Mecucci, Loredana Ruggeri, Maria Paola Martelli, Antonio Pierini.

  Nucleoporin 98 (NUP98) rearrangements occur in approximately 2-3% of myeloid neoplasms and involve more than 40 partner genes. In acute myeloid leukemia (AML), they define distinct entities associated with adverse prognosis, high rates of chemoresistance, and frequent relapse even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report two patients with therapy-related NUP98-rearranged AML carrying the rare NUP98::TOP1 fusion that occurred after treatment for relapsed/refractory lymphoma. Both patients received CPX-351 as induction therapy and proceeded to allo-HSCT with persistent disease, with approximately 5-10% residual bone marrow blasts. The transplant strategy consisted of an irradiation-based allo-HSCT platform combining total marrow/lymphoid irradiation (TMLI, 20 Gy) with adoptive transfer of regulatory and conventional T cells (Treg/Tcon), administered in the absence of post-transplant pharmacologic immunosuppression to preserve graft-versus-leukemia (GvL) activity while controlling graft-versus-host disease (GvHD). Both patients achieved sustained long-term remission and are alive at 69 and 55 months after allo-HSCT, respectively, without significant transplant-related complications. While no conclusions on treatment efficacy can be drawn from this limited case series, these observations document durable remission despite the active disease at transplant in an ultra-high-risk setting and support further investigation of immune-based transplant strategies in NUP98-rearranged AML.

Keywords:   NUP98 rearrangements; AML; T-regulatory cells; TMLI; allo-HSCT; tAML

DOI:  https://doi.org/10.1007/s00277-026-07073-2
Ann Hematol. 2026 May 22. pii: 292. [Epub ahead of print]105(6):

Fixed-time treatment of elderly patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) using hypomethylating agents and venetoclax - a case series.

Albrecht Lindemann, Gerhard Göckel, Guillermo Garcia-Pardillos.

  Standard therapy for elderly patients with acute myeloid leukemia (AML) consists of hypomethylating agents (HMAs) combined with venetoclax (VEN), administered long term until disease progression. However, several retrospective studies have shown that patients in complete remission (CR) who discontinued treatment electively or because of poor tolerance did not experience a negative impact on relapse-free or overall survival. Therefore, after obtaining informed consent, we offered treatment discontinuation to patients in CR after six months of HMA-VEN therapy. Here, we report the outcomes of seven consecutively treated patients who achieved CR between May 2021 and June 2025 and opted for discontinuation of therapy. Five of the seven patients showed clearance of somatic mutations to < 1% and resolution of cytogenetic abnormalities. Six of the seven patients remain in continuous remission for 7-50 months. One patient with FLT3-ITD experienced relapse after 14 months and achieved a second hematologic remission after resuming HMA-VEN therapy. These findings suggest that treatment-free remission after time-limited HMA-VEN therapy may be a feasible approach in selected patients.

Keywords:  AML; Hypomethylating agents; MDS; Venetoclax

DOI:  https://doi.org/10.1007/s00277-026-07076-z
Blood. 2026 May 21. pii: blood.2026033550. [Epub ahead of print]

Biallelic loss-of-function mutations in BPNT1 cause vitamin B12-dependent megaloblastic anemia.

Yi-Heng Zeng, Yun-Hong Li, Ru-Ying Yuan, Dan-Dan Zuo, Xiao-Sheng Zheng, Wen-Hao Xiao, Min-Kun Fang, Bin-Bin Lin, Chun-Yan Cao, Xue-Wen Cheng, Ning Wang, Ting Yang, Wei Luo, Wan-Jin Chen.

We identified biallelic loss-of-function BPNT1 mutations in three patients with recurrent vitamin B12-dependent megaloblastic anemia. Mechanistically, BPNT1 deficiency caused accumulation of 3'-phosphoadenosine 5'-phosphate (PAP), impaired ribosome biogenesis, and reduced ileal expression of the cubam receptor complex in Bpnt1-null mice.

DOI: https://doi.org/10.1182/blood.2026033550