bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–08–09
twenty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Clonal and genomic determinants of e1a2 BCR::ABL1 chronic myeloid leukemia: A Fi-LMC study.
  2. Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
  3. Expansion of functional human long-term HSCs through restraining excessive cell cycle activation.
  4. Expression of RUNX1::RUNX1T1 deregulates the proteome, induces C/EBPβ suppression, and blocks myeloid differentiation.
  5. A Selective CK1α Degrader Targets Acute Myeloid Leukemia and Spares Normal Hematopoietic Cells.
  6. A quantitative definition of the clinical manifestations of GATA2 deficiency in adults.
  7. SLF2 and SMC5 dysfunction drives HSC aging and predisposes to MDS, defining a new inherited bone marrow failure syndrome.
  8. Fusion-subtype and single-cell analyses refine the interpretation of HDAC8 dependency in KMT2A-rearranged AML.
  9. Hierarchical mathematical modelling of patients with myeloproliferative neoplasms captures interferon-α treatment responses and allows for personalised and population predictions.
  10. SOHO State of the Art Updates and Next Questions | Best of Stem Cell Transplant: Recent Advances in Allogeneic Hematopoietic Cell Transplantation.
  11. Chronic Myelomonocytic Leukemia: History, Pathobiology, Diagnostic Controversies, and Evolving Classification.
  12. Recipient Endothelial IRF1 mediates IFNγ-driven tissue tolerance in mouse models of acute Graft-versus-Host Disease.
  13. Endoplasmic reticulum stress promotes leukemic plasmacytoid dendritic cell differentiation skewing and immune suppression in acute myeloid leukemia.
  14. Peripheral blood profiles reflecting progenitor lineage balance are associated with molecular response in chronic myeloid leukemia.
  15. MBNL1 hijacks a structured single-stranded distal DNA element to sustain FLT3 expression in KMT2A-rearranged leukemias.
  16. Non-invasive multiparametric characterization of essential thrombocythemia, premyelofibrosis, and overt myelofibrosis.
  17. Engineered lipid nanoparticles for in vivo and durable editing of haematopoietic stem cells within humanized mice.
  18. Self-supervised learning can distinguish myelodysplastic neoplasms from clinical mimics using bone marrow biopsies.
  19. Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
  20. Polarised dysplastic basophils in a TP53-mutated acute myeloid leukaemia.
  21. DCAF11-dependent molecular glue degrader activated by glutathionylation.
  22. A compendium of next-generation patient-derived models for diverse cancers.
  1. Hemasphere. 2026 Aug;10(8): e70454
    Clonal and genomic determinants of e1a2 BCR::ABL1 chronic myeloid leukemia: A Fi-LMC study.
    Fi‐LMC group
      The rarer p190 (e1a2) transcript in chronic myeloid leukemia (CML) is associated with atypical presentations; yet, its biological basis remains poorly understood. Using a cohort of 60 patients including 42 chronic phase patients age-matched 1:1 with 42 e13a2/e14a2 patients in the chronic phase, we investigated the clinical, genomic, and clonal features of e1a2 BCR::ABL1 CML. We identified 60 e1a2 BCR::ABL1 CML patients showing distinctive hematologic features including lower leukocyte and platelet counts and higher monocytosis (12.3% vs. 2.0%, P < 0.001). Additional somatic mutations were detected in 37/42 (88%) e1a2 BCR::ABL1 cases compared with 7/42 (17%) e13a2/e14a2 BCR::ABL1 cases. The mutational spectrum was dominated by ASXL1 and TET2, and closely resembled CMML-like profiles. Genomic breakpoint sequences of 34 e1a2 BCR::ABL1 cases showed that BCR and ABL1 coordinates were similar to those observed in 394 B-ALL. Longitudinal mutational tracking revealed two distinct clonal architectures. In 71% of patients, mutations disappeared with molecular response, consistent with BCR::ABL1 as the founding event. In contrast, 29% of patients had mutations with stable VAFs, while BCR::ABL1 transcript levels decreased after treatment, indicating that the fusion had been acquired within a pre-existing mutated clone. Single-cell genotyping experiments confirmed these clonal architectures. These patients frequently developed cytopenias under tyrosine kinase inhibitor therapy and half required red blood cell transfusions, reflecting persistence of the ancestral clone rather than BCR::ABL1-driven disease. These findings show that e1a2 BCR::ABL1 CML frequently arises within complex, premutated clonal backgrounds, providing a biological basis for its atypical presentation and heterogeneous treatment response.
    DOI:  https://doi.org/10.1002/hem3.70454
  2. Nat Cell Biol. 2026 Aug 06.
    Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
    Jayna J Mistry, Kira A Young, Anna Navarro Figueredo, Gibran Edun, Alicia G Aguilar-Navarro, Patricia A Colom Díaz, Maria Telpoukhovskaia, Inés Fernández Maestre, Sheng F Cai, Katharina S Götze, Anastasia N Tikhonova, Ross L Levine, Jennifer J Trowbridge.
      Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC senescence is induced by mutant haematopoietic cells in a contact-independent manner through production of soluble factors including TNF-α and IL-6. These cytokines activate a Stat3-driven pathway that is necessary and sufficient for MSC senescence induction. Genetic or pharmacological depletion of senescent non-haematopoietic cells reduces the burden of CH and delays progression to myeloid neoplasia. Our findings show that microenvironment remodelling modifies pre-malignant clonal fitness and identifies disruption of the crosstalk between pre-malignant cells and their niche as a cancer prevention strategy.
    DOI:  https://doi.org/10.1038/s41556-026-02025-4
  3. Blood. 2026 Aug 06. pii: blood.2026034240. [Epub ahead of print]
    Expansion of functional human long-term HSCs through restraining excessive cell cycle activation.
    Xinjian Mao, Ning Zhang, Xi He, Ruochen Dong, Zhe Yang, Michael Epp, Mark J Hembree, Linda Zhang, Yiran Meng, Allison R Scott, Kate Hall, Anoja Perera, Jose Javier, Amanda Kroesen, Zulin Yu, Shengping Huang, Seth Malloy, Jeffrey Haug, Hua Li, Negin Manshour, Dong Xu, Cheng Luo, William J Greenleaf, Toshio Suda, Claus Nerlov, Chuan He, Linheng Li.
      Ex vivo expansion of human hematopoietic stem cells (HSCs) holds promise for overcoming their limited availability, a major barrier to broader clinical application. Although recent advances in culture systems can increase HSC numbers, these conditions frequently impair self-renewal and induce myeloid bias, and the underlying molecular mechanisms remain poorly understood. Here, we performed single-cell multiome sequencing (scMultiome-seq) on human umbilical cord blood-derived CD34⁺ hematopoietic stem and progenitor cells to co-profile transcriptional and epigenetic adaptations within the same cells during ex vivo culture. Our analyses revealed reduced transcriptional and epigenetic HSC signatures, accompanied by markedly increased activity of myeloid-associated transcription factor motifs, providing molecular insight into the functional decline and myeloid bias of cultured HSCs. We further observed substantial functional heterogeneity among phenotypically defined HSCs following culture. To address these limitations, we established a niche-mimetic culture system that integrates intrinsic and extrinsic bone marrow regulatory cues, including pharmacologic inhibition of the m6A reader YTHDF2 using the small molecule Y13-27, a three-dimensional microenvironment, and N-cadherin-mediated adhesion. This condition (3D-NcadP-Y) robustly preserved long-term repopulating capacity. When combined with the self-renewal agonist UM729, the resulting platform (3D-NcadP-Y-UM) uniquely enabled the expansion of serially transplantable long-term HSCs with balanced multilineage potential. scMultiome-seq and cellular analyses demonstrated that this condition preserves transcriptional and epigenetic long-term HSC signatures, maintains multilineage-associated transcription factor motifs, and limits excessive cell-cycle activation. Together, these findings elucidate molecular mechanisms underlying culture-induced HSC dysfunction and establish a niche-mimetic strategy for expanding functional human long-term HSCs while preserving key features of stemness.
    DOI:  https://doi.org/10.1182/blood.2026034240
  4. Blood Neoplasia. 2026 Aug;3(3): 100259
    Expression of RUNX1::RUNX1T1 deregulates the proteome, induces C/EBPβ suppression, and blocks myeloid differentiation.
    Aleksandra Azevedo, Adam Leckenby, Rachael Nicholson, Ana Catarina Menezes, Sara Davies, Amanda F Gilkes, Sarah Baker, Raymond Toghill, Ellie McCracken, Andrew Pierce, Bethany Geary, Anthony D Whetton, Richard L Darley, Alex Tonks.
      Expression of RUNX1::RUNX1T1 (also known as RUNX1::ETO) is frequently observed in acute myeloid leukemia (AML) and has been shown to block myeloid development. Although several studies have shown RUNX1::RUNX1T1 transcriptional deregulation, the proteome in human hematopoietic stem and progenitor cells (HSPCs) is poorly characterized. Using mass spectrometry, we show that expression of RUNX1::RUNX1T1 in human HSPCs was linked to differential expression of 257 proteins, including CCAAT/enhancer-binding protein beta (C/EBPβ) downregulation. Consistent with this observation, although CEBPB mRNA is generally overexpressed in AML, patients with t(8;21) have comparatively low CEBPB expression. We show in human HSPCs that ectopic expression of C/EBPβ can promote proliferation of myeloid cells. Conversely, short hairpin RNA-mediated knockdown of C/EBPβ inhibited the growth of normal human myeloid cells; however, it promoted the growth of cells expressing RUNX1::RUNX1T1. C/EBPβ also influenced differentiation, with ectopic expression promoting monocyte development, whereas reduced expression favored granulocyte differentiation, which in turn suggests that C/EBPβ expression may act as a lineage discriminator for these myeloid cell types. In summary, our data reveal how RUNX1::RUNX1T1 drives deregulation of the HSPC proteome and suggest a mechanism by which RUNX1::RUNX1T1 expression contributes to leukemia development, including C/EBPβ, which itself affects normal myeloid development.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100259
  5. Cancer Res. 2026 Aug 03.
    A Selective CK1α Degrader Targets Acute Myeloid Leukemia and Spares Normal Hematopoietic Cells.
    Bo-Reum Kim, Hyemin Kim, Hoon Choi, Daehun Kwag, Yoon-Ju Kim, Hyunsong Son, Sohyun Park, Jisu Park, Hadong Kim, Woosuk Choi, Seunghoon Lee, Hee-Je Kim, Hyunseok Kang, Hyunsun Jo, Byung-Sik Cho.
      Casein kinase 1⍺ (CK1⍺) is a multifunctional serine/threonine kinase, serving as an upstream regulator of the p53 pathway and a potential therapeutic target for acute myeloid leukemia (AML). Small-molecule degraders show preclinical promise in AML by selectively degrading target proteins. Here, we developed and evaluated PinA1, a molecular glue degrader targeting CK1⍺, in preclinical AML models. PinA1 preferentially degraded CK1⍺ at nanomolar concentrations, resulting in enhanced p53 expression, cell-cycle arrest, and apoptosis in TP53 wild-type AML cell lines but not in TP53 mutated cells. PinA1 also induced CK1⍺ degradation and p53-dependent apoptosis in primary AML cells with wild-type TP53. Notably, PinA1 had minimal effects on the viability of human peripheral blood and bone marrow mononuclear cells, including CD34+ cells, with limited activation of the p53 pathway. In both cell lines and primary AML cells, PinA1 enhanced apoptosis when combined with targeted agents, including FLT3, BCL-2, or MDM2 inhibitors. PinA1 demonstrated robust anti-leukemic efficacy as a monotherapy and exhibited synergistic effects when combined with targeted agents in xenografts derived from human AML cell lines and primary AML cells. In conclusion, PinA1 degrades CK1⍺, activates the p53 pathway, and induces cell-cycle arrest and apoptosis in TP53 wild-type AML cells. The robust anti-leukemic efficacy of PinA1, both as monotherapy and further in combination with targeted agents, along with its minimal toxicity to normal hematopoietic cells, underscores its potential for future clinical applications.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3629
  6. Blood. 2026 Aug 06. pii: blood.2026034942. [Epub ahead of print]
    A quantitative definition of the clinical manifestations of GATA2 deficiency in adults.
    Shruthi Mohan, Tilda E Carlelycke, Ashwin Lakshman Koppayi, Taylor Walker, Eran Tallis, Amy M Trottier, Katherine R Calvo, Beatriz E Marciano, Amy P Hsu, Steven M Holland, Dennis D Hickstein, Marcin W Wlodarski, Emilia Kozyra, Matthew Collin, Christopher N Hahn, Anna L Brown, Piers Blombery, Ing Soo Tiong, Yamuna Kankanige, Lucy C Fox, Sioban B Keel, Marshall S Horwitz, Tom J Vulliamy, Inderjeet Dokal, Daniela P Mendes-de-Almeida, Rodrigo Tocantins Calado, Marcela Cavalcante de Andrade Silva, Elvira Deolinda Rodrigues Pereira Velloso, Courtney D DiNardo, Shai Izraeli, Joanne Yacobovich, Michaela Sherbeck, Julia T Warren, Minjie Luo, William J Smith, Zachary Hattig, Ryan J Stubbins, Simone K Feurstein, Panagiotis Baliakas, Xi Luo, Amagoia Ruiz Martin, Adam Gordon, Emery H Bresnick, Guimin Gao, Masha Kocherginsky, David Wu, Lucy A Godley.
      Germline GATA2 deficiency is a pleiotropic condition 1-8 characterized by numerous phenotypes, including monocytopenia, immunodeficiency, microbial susceptibilities, and high rates of myeloid malignancies 1,8. Accurate curation of germline GATA2 variants is critical for patient care and requires well-defined phenotypes associated with GATA2 deficiency. The many phenotypes attributed to the condition render a simple description of GATA2 deficiency difficult, complicating the development of GATA2 variant curation rules. Therefore, the Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) sought to define GATA2 deficiency based on a statistical comparison of phenotype data. To do so, the MM-VCEP systematically analyzed phenotype data and applied statistical comparisons to define the phenotypic features of GATA2 deficiency to inform germline variant curation. The MM-VCEP assembled an international cohort of 339 people with clinically diagnosed GATA2 deficiency from 16 centers in seven countries. The 73 phenotypes of these individuals were compared statistically to those of control participants from the UK Biobank (UKBB). We compared single phenotypes as well as combinations of two, three, and four phenotypes in people with clinically diagnosed GATA2 deficiency to UKBB controls. We defined GATA2 deficiency as any of the 2,903 combinations of two or three phenotypes with log10Odds Ratio ≥3 (OR ≥ 1000). This definition of GATA2 deficiency will inform gene-specific phenotypic criteria used in GATA2 variant curation guidelines that will facilitate standardized variant curation by clinical laboratories worldwide.
    DOI:  https://doi.org/10.1182/blood.2026034942
  7. Leukemia. 2026 Aug 07.
    SLF2 and SMC5 dysfunction drives HSC aging and predisposes to MDS, defining a new inherited bone marrow failure syndrome.
    Sho Shibata, Kazuhisa Chonabayashi, Hirofumi Nakamura, Yasuko Matsumura, Hiroki Kawahara, Yoshio Okamoto, Shohei Yamamoto, Misato Nishikawa, Yotaro Ochi, Yuri Uchiyama, Yukiko Oh, Akitsu Hotta, Kenta Masuda, Naomichi Matsumoto, Seishi Ogawa, Yoshinori Yoshida, Akifumi Takaori-Kondo.
      Inherited bone marrow failure syndromes (IBMFS) comprise a heterogeneous group of genetic disorders and are associated with an increased risk of myelodysplastic syndromes (MDS). We and others recently identified pathogenic variants in SLF2 and SMC5 as the cause of Atelis Syndrome, a neurodevelopmental disorder accompanied by hematological abnormalities, including anemia and lymphopenia. However, the mechanisms underlying the associated hematopoietic dysfunction remain unclear. Through longitudinal follow-up and re-evaluation, we found that some patients developed MDS at a young age. To elucidate the bases of these hematopoietic defects, we analyzed hematopoietic progenitor cells (HPCs) derived from patient-specific induced pluripotent stem cells harboring compound heterozygous SLF2 mutations. Mutant HPCs exhibited impaired colony-forming capacity, defective erythroid differentiation with a myeloid bias, and markedly reduced engraftment in xenotransplantation assays. SMC5 knockdown in cord blood CD34+ cells impaired colony formation. Mechanistically, disruption of the SLF2-SMC5 axis induced genomic instability, p53/p21 activation, and a senescence-like phenotype. ATAC sequencing revealed epigenetic features characteristic of hematopoietic stem cell (HSC) aging, including increased chromatin accessibility at PU.1 motifs associated with myeloid bias. These findings demonstrate that SLF2 and SMC5 dysfunction drives premature HSC aging, bone marrow failure, and predisposition to MDS, revealing Atelis Syndrome as a previously unrecognized IBMFS.
    DOI:  https://doi.org/10.1038/s41375-026-03061-7
  8. Leukemia. 2026 Aug 07.
    Fusion-subtype and single-cell analyses refine the interpretation of HDAC8 dependency in KMT2A-rearranged AML.
    Diguang Wen, Aijing You, Xingyue Li, Jianchuan Deng.
      
    DOI:  https://doi.org/10.1038/s41375-026-03107-w
  9. Math Biosci. 2026 Aug 07. pii: S0025-5564(26)00175-6. [Epub ahead of print] 109785
    Hierarchical mathematical modelling of patients with myeloproliferative neoplasms captures interferon-α treatment responses and allows for personalised and population predictions.
    Tobias Idor Boklund, Gurvan Hermange, Jordan Snyder, Johanne Gudmand-Hoeyer, Morten Kranker Larsen, Trine Alma Knudsen, Christina Schjellerup Eickhardt-Dalbøge, Vibe Skov, Lasse Kjær, Hans C Hasselbalch, Morten Andersen, Johnny T Ottesen, Thomas Stiehl.
      The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of haematological malignancies triggered by a driver mutation, most commonly the JAK2 V617F mutation, which is acquired in a haematopoietic stem cell. The diseases are characterised by an overproduction of myeloid cells and may result in severe complications such as thrombosis, myelofibrotic transition, and potentially progression to acute myeloid leukaemia. Treatment with interferon-α (IFN-α) can potentially deplete the disease-driving malignant stem cell population, thereby leading to long-term remission. We extend a mechanistic compartmental differential equation model of MPN progression to account for the effects of IFN-α treatment. In agreement with experimental mouse studies, we assume that IFN-α acts through effects on malignant stem cell differentiation and malignant progenitor and precursor cell apoptosis. We use a hierarchical Bayesian inference procedure to infer the drug response parameters of the model based on measurements of the JAK2 V617F variant allele frequency (VAF) for N=56 patients from the Danish DALIAH study, both on the individual and the population level, with 14 patients left out for subsequent testing. The model estimates are found to agree with data. The drug response parameters are found to act synergistically on the reduction of JAK2 VAF, with the model being able to capture qualitatively different types of treatment responses. Using the inferred information about the population distribution of drug response parameters is found to improve predictions compared to predictions without prior knowledge on a testing cohort. Such predictions may aid clinical decision-making regarding IFN-α treatment in patients with MPNs.
    Keywords:  haematopiesis; hierarchical Bayesian inference; interferon-α; mathematical modelling; myeloproliferative neoplasms; ordinary differential equations
    DOI:  https://doi.org/10.1016/j.mbs.2026.109785
  10. Clin Lymphoma Myeloma Leuk. 2026 Jul 15. pii: S2152-2650(26)00211-9. [Epub ahead of print]
    SOHO State of the Art Updates and Next Questions | Best of Stem Cell Transplant: Recent Advances in Allogeneic Hematopoietic Cell Transplantation.
    Molly Gilligan, Alexandra Gomez-Arteaga.
      Allogeneic hematopoietic cell transplantation is undergoing rapid transformation, propelled by a wave of practice-changing studies that are reshaping how donors are selected, how graft-versus-host disease (GVHD) is prevented, and how post-transplant relapse is managed. Here we review the major advances of the past several years, focusing on practice-changing studies from 2024 to 2026, and the questions they raise. The adoption of post-transplant cyclophosphamide (PTCy) as a near-universal GVHD prophylaxis backbone has diminished the long-standing primacy of human leukocyte antigen matching, enabling comparable outcomes with mismatched unrelated (MMUD) and haploidentical donors and expanding access for patients of non-European ancestry; contemporary guidelines now endorse concurrent donor searches and prioritization of younger donors. Building on the BMT CTN 1703 trial, PTCy-based prophylaxis has become a standard across conditioning intensities and donor types, while correlative studies illuminate both its mechanism and its trade-offs. Complementary strategies, including frontline and prophylactic ruxolitinib, adoptive regulatory T-cell (Treg) therapy, and the precision-engineered Orca-T graft, are broadening the prophylaxis repertoire and beginning to separate GVHD control from the loss of immune competence and graft-versus-leukemia activity. For FLT3-ITD AML, the MORPHO trial and subsequent analyses have established measurable residual disease-directed gilteritinib maintenance, advancing a molecularly individualized approach to relapse prevention. Together, these developments mark a decisive shift from a uniform transplant paradigm toward biomarker-guided, precision-based care, and they define the priorities for the next generation of clinical trials.
    Keywords:  Allogeneic hematopoietic stem cell transplant (allo-HCT); Graft-versus-host disease (GVHD); Measurable residual disease (MRD); Post-transplant cyclophosphamide (PTCy); Regulatory T cells
    DOI:  https://doi.org/10.1016/j.clml.2026.07.006
  11. Curr Hematol Malig Rep. 2026 Aug 03. pii: 15. [Epub ahead of print]21(1):
    Chronic Myelomonocytic Leukemia: History, Pathobiology, Diagnostic Controversies, and Evolving Classification.
    Sanam Loghavi, Robert P Hasserjian.
       PURPOSE OF REVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal myelodysplastic/myeloproliferative neoplasm characterized by sustained monocytosis, recurrent gene mutations, and a risk of transformation to acute myeloid leukemia (AML). This review examines the historical evolution of CMML as a diagnostic entity, its genetic landscape, fundamental controversies in definition, including the contentious boundaries of oligomonocytic CMML (OM-CMML), and the spectrum of associated phenomena, such as plasmacytoid dendritic cell proliferations, systemic mastocytosis, extramedullary disease, and autoimmune manifestations.
    RECENT FINDINGS: Since the publication of the most recent myeloid classification systems, genomic studies in large CMML cohorts have clarified that cases with borderline monocyte counts are biologically heterogeneous: a subset with bi-allelic TET2 inactivation or TET2 + SRSF2 co-mutation bears the greatest similarity to true CMML, while cases harboring SF3B1, bi-allelic TP53 inactivation (biTP53), or del(5q) may be better classified as myelodysplastic syndrome/neoplasm (MDS), irrespective of the presence of borderline monocytosis. Molecular evolution from clonal hematopoiesis through OM-CMML to overt CMML, and ultimately to acute myeloid leukemia (AML), follows a defined clonal trajectory characterized by the stepwise acquisition of spliceosome, epigenetic, and signaling mutations. Plasmacytoid dendritic cell proliferations, particularly blastic forms, arising in association with or following CMML, share clonal origin and represent a distinct spectrum of monocyte/plasmacytoid dendritic cell lineage dysregulation. In future classification systems, better biologic homogeneity of CMML may be achieved by incorporating specific molecular signatures in the diagnostic criteria and by excluding cases with biTP53 or AML-defining alterations. CMML is defined by its combination of proliferative (monocytic) and dysplastic features, but exhibits considerable genetic heterogeneity. Optimal diagnosis and distinction from related entities require integration of morphology, immunophenotype, and comprehensive genomic profiling.
    Keywords:   SRSF2 ; TET2 ; BPDCN; CMML; Clonal hematopoiesis; MDS/MPN; Oligomonocytic
    DOI:  https://doi.org/10.1007/s11899-026-00781-6
  12. Blood. 2026 Aug 04. pii: blood.2026033806. [Epub ahead of print]
    Recipient Endothelial IRF1 mediates IFNγ-driven tissue tolerance in mouse models of acute Graft-versus-Host Disease.
    Lotus Neidemire-Colley, Rathan Kumar, Elizabeth Ar Garfinkle, Camryn Steere, Annie Gordon, Giorgia Giordano, Adithe Rivaldi, Yogesh Budhathoki, Sonu Kalyan, Malith Karunasiri, Qiuhong Zhao, Jiasheng Wang, Alessandro La Ferlita, Katherine E Miller, Ivan Maillard, Hannah K Choe, Sumithira Vasu, Parvathi Ranganathan.
      Recipient endothelial cells (ECs) actively respond to inflammation during allogeneic hematopoietic cell transplant (allo-HCT), yet mechanisms by which ECs influence acute graft-versus-host-disease (GVHD) pathology remain incompletely defined. Single cell RNA-sequencing of ECs isolated from a GVHD target organ, the liver, showed rapid, subset-specific transcriptional reprogramming after allo-HCT, with induction of canonical interferon-γ (IFNγ)-inducible genes including interferon regulatory factor 1 (IRF1), MHC II, and PD-L1 in lymphatic ECs (LECs). In allo-HCT recipients, circulating IFNγ peaked on day 4 (early), decreased but remained elevated at day 14 (late), and declined by day 21, with a concordant induction of IRF1+ LECs in the liver and GI tract. IFNγ neutralization with anti-IFNγ monoclonal antibody at either early or late time points attenuated IRF1⁺MHCII⁺PD-L1⁺ LEC activation. Notably, early donor T cell expansion was IFNγ-independent, whereas late IFNγ blockade selectively impaired donor Treg, but not Th1, expansion, leading to accelerated GVHD. Using in vitro LEC-CD4 T cell co-cultures and allo-HCT in Irf1-/- bone marrow chimera recipients, we show that recipient ECs that cannot mediate IFNγ-IRF1 signaling exhibit reduced activation and apoptosis, but also have impaired Treg expansion, increased donor Th1/Treg ratios, and worsened GVHD severity. Finally, pharmacological JAK inhibition in allo-HCT recipient mice spares IRF1+ LECs and Tregs while reducing pathogenic Th1 cells, correlating with reduced GVHD severity and improved survival. Our findings identify a role for the lymphatic endothelial IFNγ-IRF1 axis in regulating early vascular remodeling, donor T cell mediated tolerance, underscoring a potential "goldilocks" level of pathway activation required to improve post-transplant outcomes.
    DOI:  https://doi.org/10.1182/blood.2026033806
  13. Leukemia. 2026 Aug 03.
    Endoplasmic reticulum stress promotes leukemic plasmacytoid dendritic cell differentiation skewing and immune suppression in acute myeloid leukemia.
    Xingcheng Yang, Juan Peng, Xia Mao, Lei Zhang, Shaolong He, Chunyan Wang, Yicheng Zhang, Yuting Tang, Jue Wang, Jia Wei.
      Mature plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia (pDC-AML) is a distinct entity with poor prognosis. Yet, the mechanisms underlying the immune evasion and aberrant pDC expansion remain poorly understood. We performed multi-omic profiling of 18 pDC-AML cases, along with 207 non-pDC-AML and 16 BPDCN cases as controls. Single-cell RNA-seq and proteomic analyses demonstrated that pDC-AML leukemia stem cells exhibited unfolded protein response activation, particularly the IRE1α-XBP1 axis, which preceded the acquisition of the pDC maturation program. Supporting this, pharmacological induction of endoplasmic reticulum stress in myeloid cells upregulated BCL11A, the master transcription factor in pDC differentiation, and induced a pDC immunophenotype (CD123+BDCA2+). Importantly, pDC-AML-derived pDCs exhibited functional impairment, including compromised antigen-presenting pathways and reduced interactions between pDCs and CD8+ T cells. scTCR-seq analysis revealed significantly restricted T-cell clonal expansion in the pDC-AML bone marrow microenvironment, which correlated with leukemic burden and reversed upon clinical remission. Notably, allogeneic hematopoietic stem cell transplantation (HSCT) significantly improved overall and progression-free survival, abrogating the prognostic disadvantage relative to non-pDC-AML. Collectively, these findings establish impaired anti-leukemia immunity as a hallmark of pDC-AML, support early HSCT as a clinical priority, and identify ER-stressed pDCs as a potential novel therapeutic target.
    DOI:  https://doi.org/10.1038/s41375-026-03080-4
  14. Exp Hematol. 2026 Aug 03. pii: S0301-472X(26)00121-9. [Epub ahead of print] 105488
    Peripheral blood profiles reflecting progenitor lineage balance are associated with molecular response in chronic myeloid leukemia.
    Kohjin Suzuki, Naoki Watanabe, Yutaka Tsukune, Tadaaki Inano, Shintaro Kinoshita, Kazuhiro Yamada, Miki Ando, Tomoiku Takaku.
      Early achievement of deep remission improves patients' outcome in chronic myeloid leukemia (CML) treatment, highlighting the need for predictive indicators before therapy initiation. This study aimed to investigate whether baseline hematologic profiles are associated with molecular response in CML. Using hierarchical clustering of complete blood count (CBC) data at diagnosis, patients were stratified into two clusters. Patients in Cluster 1 had higher BCR::ABL1IS mRNA levels at 3 and 6 months post-treatment and lower rates of major molecular response compared to cluster 2. Cluster 1 also showed increased granulocyte and immature white blood cell counts and decreased erythroid parameters. Flow cytometric analysis of bone marrow mononuclear cells revealed that cluster 1 had a significant increase in hematopoietic stem cell fractions and a higher ratio of granulocyte-macrophage progenitors to megakaryocyte-erythroid progenitors compared to cluster 2. These findings suggest that differences in bone marrow progenitor cell differentiation affect peripheral blood profiles. Artificial intelligence-driven ghost cytometry (GC) comprehensively captured these differences, distinguishing poor responders, with diagnostic GC scores correlating with BCR::ABL1IS mRNA levels. The study indicates that multivariate analysis of CBC and GC captures biological features associated with early molecular response in CML. TEASER ABSTRACT: Baseline complete blood count (CBC) profiles stratified patients with chronic myeloid leukemia (CML) into biologically distinct groups with different early molecular responses. Poor responders had higher BCR::ABL1IS levels, lower major molecular response rates, expanded hematopoietic stem cell fractions, and granulocyte-macrophage progenitor-biased differentiation. Artificial intelligence-driven Ghost Cytometry (GC) comprehensively captured these response-associated features of CBC with scores correlating with BCR::ABL1IS levels. Together, CBC and GC capture biological features associated with early molecular response in CML.
    Keywords:  Chronic myeloid leukemia; Complete blood count; Ghost cytometry; Hematopoietic stem and progenitor cells; Molecular response
    DOI:  https://doi.org/10.1016/j.exphem.2026.105488
  15. Sci Adv. 2026 Aug 07. 12(32): eaec2331
    MBNL1 hijacks a structured single-stranded distal DNA element to sustain FLT3 expression in KMT2A-rearranged leukemias.
    Meixia Che, Shaela Fields, Siqi Yi, Judith Hyle, Mengli Zhang, Beisi Xu, Yong Cheng, Peng Xu, Yajun Jiang, Chunliang Li.
      The molecular mechanisms by which KMT2A-rearranged (KMT2A-r) leukemias maintain the oncogenic FLT3 expression remain largely unclear, limiting therapeutic opportunities. Here, we identify the RNA binding protein MBNL1 as an unexpected positive regulator of FLT3 by DepMap dataset exploration and combinatorial CRISPR screens. MBNL1 promotes leukemia cell survival in cell lines and primary tumors by sustaining FLT3 expression in a KMT2A-r context-dependent manner. Mechanistically, we discover that MBNL1 recognizes a structured single-stranded DNA (ssDNA) element containing five consecutive guanines within the FLT3 enhancer, through MBNL1's zinc finger domains and the carboxyl-terminal unstructured region. Such MBNL1 protein/ssDNA interaction was evident in KMT2A-r leukemia using ChIP-seq and KAS-seq. Mutations of key amino acids of MBNL1's ssDNA binding surface or the critical guanines in ssDNA markedly abrogate the protein-ssDNA interactions. These findings implicate MBNL1 as a distinct FLT3 activator by recognizing a structured enhancer ssDNA element, highlighting an unexpected role for RNA binding proteins in transcriptional regulation through direct ssDNA recognition.
    DOI:  https://doi.org/10.1126/sciadv.aec2331
  16. Leukemia. 2026 Aug 03.
    Non-invasive multiparametric characterization of essential thrombocythemia, premyelofibrosis, and overt myelofibrosis.
    Carole Mosnier, Marie-Christine Copin, Isabelle Quintin-Roué, Eric Lippert, Yunjiao Lu, Jérémie Riou, Simon Blanchard, Nathalie Mérillon, Bertille Pawlicki, Françoise Boyer, Joris Argentin, Léa Sureau, Anaïs Malinge, Julie Sevestre, Marine Demoy, Christophe Aubé, Noémi Reboux, Jonathan Farhi, Aurélien Giltat, Christopher Nunes Gomes, Mathilde Hunault, Yves Delneste, Valérie Ugo, Jean-Christophe Ianotto, Corentin Orvain, Damien Luque Paz.
      Among myeloproliferative neoplasms (MPN), prefibrotic myelofibrosis (preMF) was defined as a distinct entity from essential thrombocythemia (ET) and primary overt myelofibrosis (PMF) since the 2016 revision of the World Health Organization (WHO) classification, while precise characterization may be difficult in some instances. In that context, several non-invasive parameters have shown potential to differentiate ET from PMF. The aim of the study was to prospectively evaluate non-invasive parameters in 128 patients (44 ET, 53 preMF, and 21 PMF). The mutational landscape became increasingly complex across diagnostic from ET to preMF and PMF. We observed significant differential expression of inflammatory mediators (IL-1RA, IL-1β, IL-6, S100A8/S100A9, CCL4), immune activation markers (CD25 and CXCL10), matrix regulator (YLK-40 and TIMP1), and lower levels of EGF and CXCL4 between ET and PMF with similar results between preMF and PMF. The two-step Lasso regression strategy to classify patients with internal bootstrap validation reliably identified PMF (AUC: 0.909 [0.804-0.994]) and reasonable discrimination between ET and preMF (AUC: 0.762 [0.656-0.847]). The non-invasive parameters studied enable effective discrimination of PMF and help to distinguish preMF from ET, although the low discriminatory power of these parameters supports the hypothesis of a pathophysiological continuum between these conditions.
    DOI:  https://doi.org/10.1038/s41375-026-03088-w
  17. Nat Biomed Eng. 2026 Aug 05.
    Engineered lipid nanoparticles for in vivo and durable editing of haematopoietic stem cells within humanized mice.
    Jingjing Du, Zijin Luo, Dan Xie, Yan Chen, Ming Yang, Qiang Li, Lisha Wang, Lu Han, Yiming Zhang, Haiwei Li, Zilin Lan, Haoping Shi, Yinghui Li, Qiang Cheng, Fang Dong, Yingdai Gao, Yao Yao, Tao Cheng, Tuo Wei, Shuquan Rao.
      In vivo genetic engineering of haematopoietic stem and progenitor cells (HSPCs) holds the potential to revolutionize the treatment landscape for numerous diseases. However, despite its transformative potential, it remains hindered by the difficulty in efficiently and specifically targeting quiescent human HSCs while maintaining their long-term functionality. Here, after screening 15 lipid nanoparticles (LNPs), we report an LNP that efficiently delivers reporter mRNA to human HSPCs both in ex vivo and in vivo settings when conjugated with the anti-CD34 antibody (CD34/LNPDP). Using CRISPR/Cas editing cargos, CD34/LNPDP achieves high editing efficiency in human HSPCs ex vivo. Intrafemoral administration of CD34/LNPDP in humanized mice results in efficient editing of the erythroid-specific BCL11A enhancer within human HSPCs, enabling the sustained long-term reactivation of fetal haemoglobin (HbF) expression in erythroid cells. In a humanized neutropaenia model harbouring an ELANE mutation, intrafemoral administration of CD34/LNPDP achieves robust editing, targeting exon 2 of ELANE in human HSPCs, partially restoring neutrophil development impairment under long-term observation. Collectively, CD34-targeted delivery enables in vivo HSPC modification without perturbing haematopoiesis, underscoring its suitability for clinical translation.
    DOI:  https://doi.org/10.1038/s41551-026-01765-w
  18. Blood Neoplasia. 2026 Aug;3(3): 100254
    Self-supervised learning can distinguish myelodysplastic neoplasms from clinical mimics using bone marrow biopsies.
    Vahid Mehrtash, Hortense Le, Bita Jafarzadeh, Mohamed Sharaf, Abdallah Flaifel, Xiaoyan Huang, Nicholas Ward, Robert Hasserjian, Sanam Loghavi, Guillermo Garcia-Manero, Aristotelis Tsirigos, Christopher Y Park.
      The diagnosis of myelodysplastic neoplasms (MDS) requires examination of the bone marrow for morphologic evidence of dysplasia. We sought to determine whether a self-supervised learning (SSL) artificial intelligence-based image analysis approach can be used to reliably distinguish MDS from its clinically relevant mimics using bone marrow biopsies (BMBx). The whole-slide images (WSIs) of hematoxylin and eosin (H&E)- and reticulin-stained BMBx sections from 243 unique patients (89 MDS, 55 non-MDS cytopenic controls [NMCCs], and 99 negative control [NC] cases) were partitioned into image tiles for analysis. These image tiles were then processed using the Barlow Twins SSL model to identify histomorphologic phenotype clusters (HPCs). Review of the HPCs revealed the clusters enriched in MDS cases captured known histopathologic features of the disease, including hypercellularity (characterized by enrichment in hypercellular image tiles), dysplastic and loosely clustered megakaryocytes, increased immature hematopoietic cells, increased vascularity, fibrosis, and cell streaming patterns. For external validation, 95 MDS BMBx WSIs from an independent institution were analyzed using the trained model. The model demonstrated consistent HPC enrichment patterns, supporting its robustness and generalizability. The trained ensemble model using H&E- and reticulin-stained slides distinguished MDS from NCs with an area under the curve (AUC) of 0.82, and from age-matched NMCCs with an AUC of 0.80. These findings demonstrate the potential of SSL approaches to capture diagnostically relevant morphologic patterns and to improve the reproducibility of MDS diagnosis.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100254
  19. Cell Metab. 2026 Aug 05. pii: S1550-4131(26)00324-4. [Epub ahead of print]
    Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
    Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.026
  20. Br J Haematol. 2026 Aug 02.
    Polarised dysplastic basophils in a TP53-mutated acute myeloid leukaemia.
    Quentin Amiot, Clara Assadi-Gazvini, Jean Maillot, Sarah Bugier, Xavier Phina-Ziebin, Carine Hejl.
      
    DOI:  https://doi.org/10.1111/bjh.70702
  21. Nature. 2026 Aug 05.
    DCAF11-dependent molecular glue degrader activated by glutathionylation.
    Hojong Yoon, Franziska Wachter, Katharine A Barrett, Cyrus Jin, Anna Rodríguez-Pöhnlein, Justine C Rutter, Ryan J Lumpkin, Rebecca J Metivier, Katherine A Donovan, Kheewoong Baek, Yongying Jiang, Minwoo Lee, Robert W Kalis, Jianwei Che, Yuan Xiong, Eric S Fischer, Benjamin L Ebert.
      Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18. Mechanistically, M12 functions as a prodrug that is activated through glutathione S-transferase-mediated glutathionylation. The glutathione moiety binds to an evolutionary conserved glutathione-binding site on DCAF11, and the exposed M12 moiety facilitates neo-substrate recruitment. We demonstrate that this glutathione-dependent mechanism readily enables targeted degradation of a range of proteins. Collectively, these findings establish that metabolically activated compounds can redirect E3 ligase function, thereby expanding the scope of targeted protein degradation and chemically induced proximity.
    DOI:  https://doi.org/10.1038/s41586-026-10873-1
  22. Nature. 2026 Aug 05.
    A compendium of next-generation patient-derived models for diverse cancers.
    HCMI Network
      The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.
    DOI:  https://doi.org/10.1038/s41586-026-10806-y
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒09 at 6:29.