bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2026–09–27
nineteen papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Characterization of disease-initiating hematopoietic stem cells in calreticulin-mutated myeloproliferative neoplasms.
  2. Mutant ASXL1 Cooperates with MECOM and BRD4 to Drive Transcriptional Dysregulation in Human Hematopoiesis.
  3. SLIT2 modulates leukaemic cell proliferation and stromal support in acute myeloid leukaemia models.
  4. A CRISPR-Based Humanized Model Reveals Cooperative Role of STAG2 Loss in Familial GATA2-Deficient MDS Progression.
  5. Cladribine and low-dose cytarabine as first salvage after hypomethylating agent and venetoclax in acute myeloid leukemia.
  6. Selective dependency of CALR-mutant myeloproliferative neoplasms on TYK2 signaling.
  7. Tamibarotene with venetoclax and azacitidine in RARA+ acute myeloid leukemia: results from the SY-1425-202 study.
  8. How I Treat: MRD testing to personalize allogeneic HCT for adults with AML.
  9. Multipotent Progenitor-3 Cells Are Reprogrammed by Bone-derived DKK1 to Drive Myelopoiesis in Breast Cancer.
  10. Nucleolin Alterations and ROS Production Associate With Sensitivity of AML Cells to Venetoclax.
  11. Search for leukemia-restricted targets: a new paradigm for precision immunotherapy in acute myeloid leukemia.
  12. Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells.
  13. Systemic delivery of phagocytosis-shielded retroviral vectors enables in vivo HSC gene therapy for sickle cell disease.
  14. p38 MAPK inhibition safeguards genome integrity during gene editing of hematopoietic stem and progenitor cells.
  15. Unbiased, systematic surfaceome profiling of Acute Leukemia to identify novel immunotherapy targets.
  16. Oral vitamin C supplementation in patients with clonal cytopenia of undetermined significance or lower-risk myeloid malignancies: Results from EVITA, a phase 2 randomized, placebo-controlled trial.
  17. Concentrating cell-type-specific transcriptional signatures in bone marrow from interspecies comparisons.
  18. Lenalidomide Exposure and TP53-Mutated Myelodysplastic Syndromes/Neoplasms.
  19. Cumulative Hematologic Morbidity and Outcomes in Shwachman-Diamond Syndrome.
  1. Blood. 2025 Sep 25. pii: blood.2026033236. [Epub ahead of print]
    Characterization of disease-initiating hematopoietic stem cells in calreticulin-mutated myeloproliferative neoplasms.
    Camélia Benlabiod, Laetitia Borderon, Gurvan Hermange, Quentin Blampey, Maxime Evrard, Antonio Rodriguez-Romera, Stephanie G Moreno, Nathalie Gault, Philippe Rameau, Cyril Catelain, Elodie Rosa, Guillemette Fouquet, Lionel Faivre, Florence Pasquier, Bethan Psaila, Claus Nerlov, Sten Eirik W Jacobsen, William Vainchenker, Hana Raslova, Paul-Henry Cournède, Isabelle Plo, Caroline Marty.
      Myeloproliferative neoplasms (MPNs) arise following the acquisition of a mutation in a hematopoietic stem cell (HSC) that causes oncogenic cytokine receptor signaling. Mutations in the calreticulin (CALR) gene are the second most common key driver mutations in MPNs, yet the identity of the disease-initiating HSCs and the mechanisms underlying their clonal expansion remain elusive. Knock-in mice bearing CALRdel52 and CALRins5 mutations recapitulate disease phenotypes, with a greater HSC amplification in CALRdel52 mice. Here, we crossed these strains with transgenic reporter mice expressing GFP under the control of the Von willebrand factor (Vwf) promoter, enabling discrimination between different HSC subsets. We show that CALR-mutated MPNs are mainly initiated from the expansion of platelet-biased, Vwf-positive HSCs, without substantially altering their lineage bias. Notably, the selective amplification of Vwf-positive CALRdel52 compared to CALRins5 HSCs is associated with increased signaling of the thrombopoietin receptor MPL and activation of the integrated stress response as evidenced by eIF2a phosphorylation downstream of PERK kinase triggered by endoplasmic reticulum stress. This pathway is also transcriptionally upregulated in CALRdel52-like compared with CALRins5-like patient hematopoietic stem and progenitor cells (HSPCs), as supported by reanalysis of a previous dataset, and is associated with increased phosphorylation of eIF2a. Pharmacological inhibition of PERK markedly reduces the proliferation of mouse CALRdel52 HSCs and impairs the megakaryocytic differentiation of CALRdel52-like HSPCs from patients while sparing cells from healthy donors. These findings identify the PERK/eIF2a pathway as a mechanistic vulnerability in the MPN cell-of-origin and offer a rationale for exploring new treatment approaches.
    DOI:  https://doi.org/10.1182/blood.2026033236
  2. Blood. 2026 Sep 22. pii: blood.2026034001. [Epub ahead of print]
    Mutant ASXL1 Cooperates with MECOM and BRD4 to Drive Transcriptional Dysregulation in Human Hematopoiesis.
    Madison L Hall, Aliya Quintal, Sonia N Acharya, Samantha Worme, Thai T Nguyen, Zachary Schonrock, Mitsuhiro Tsuchiya, Hanqian L Carlson, Itallia V Pacentine, Shawn B Shrestha, Jommel Macaraeg, Randall Armstrong, Nicole Szczepanski, James Adler, James McGann, Sara Evans-Dutson, Theresa A Lusardi, Brendan L O'Connell, Andrew C Adey, Galip Gürkan Yardımcı, Julia E Maxson, Theodore P Braun.
      Mutations in the epigenetic regulator ASXL1 are common in myeloid malignancies and portend a near-universally poor prognosis. While multiple mechanisms for mutant ASXL1-dependent oncogenesis have been proposed, none have been functionally validated in the context of the human hematopoietic stem cell, where these mutations almost certainly arise. Here, we extensively characterized a CRISPR-engineered human hematopoietic stem and progenitor cell model of ASXL1 mutations. In this context, mutant ASXL1 expression decreases differentiation, increases clonogenicity in serial replating experiments, and improves engraftment in immunodeficient mice. We also show that endogenous truncating ASXL1 mutations stabilize the protein and confirm that mutant ASXL1 resists proteasomal degradation. At the transcriptional level, these phenotypes are driven by significant repression of immediate early genes and subtle global transcriptional upregulation, especially of genes repressed during normal differentiation. Using protein-interaction screens, genomic and functional approaches, we link the phenotypic changes in ASXL1-mutant cells to increased chromatin binding of RNAPII, BRD4, and the transcription factor MECOM. The association between ASXL1 and MECOM may reflect a direct or indirect interaction. We also observe aberrant RNA polymerase II pausing dynamics, especially at immediate early genes, in ASXL1-mutated cells. Finally, we demonstrate that ASXL1-mutant AML exhibits increased MECOM activity, consistent with our gene-editing models. Collectively, these studies highlight a highly reproducible model of mutant ASXL1 in the appropriate cell context. Further, they are the first to functionally describe the mutant ASXL1 interactome in the context of human HSCs, identifying MECOM and BRD4 as actionable dependencies with therapeutic potential for ASXL1-mutant myeloid malignancies.
    DOI:  https://doi.org/10.1182/blood.2026034001
  3. Br J Haematol. 2026 Sep 24.
    SLIT2 modulates leukaemic cell proliferation and stromal support in acute myeloid leukaemia models.
    Luise Albuquerque-Simões, Isabel Weinhäuser, Diego A Pereira-Martins, César Alexander Ortiz Rojas, Lúcio Henrique Sousa Pinheiro, Livia Bassani Lins de Miranda, Thiago Mantello Bianco, Rita de Cássia Cavaglieri, Mariane Cristina do Nascimento, Lynn Quek, Steffen Boettcher, Jan Jacob Schuringa, Eduardo Magalhães Rego.
      Acute myeloid leukaemia (AML) is supported by leukaemic stem cells (LSCs), whose continued existence and growth are dependent upon signals derived from their bone marrow (BM) microenvironment. Although the highly conserved glycoprotein slit guidance ligand 2 (SLIT2), implicated in axon guidance, has been proposed to support normal haematopoietic stem cell (HSC) function, its role in AML pathogenesis remains poorly defined. Here, we show that SLIT2 is downregulated in mesenchymal stem cells (MSCs) from AML patients. Patients with higher-than-normal SLIT2 protein levels had better outcomes, independently of classical risk factors. Functionally, knocking down (KD) SLIT2 in MSCs caused a reprogramming of the microenvironment. Specifically, SLIT2-KD in MSCs resulted in increased expression of LSC-supporting genes including C-X-C motif chemokne ligand 12 (CXCL12) and KIT proto-oncogene, receptor tyrosine kinase (KIT), and co-culture of primary AML cells on SLIT2-KD stromal cells prevented myeloid differentiation. Conversely, the addition of recombinant SLIT2 had cytostatic effects on AML cells, resulting in reduced proliferation and reduced clonogenicity in all tested models. Furthermore, in human xenograft models, systemic administration of recombinant SLIT2 resulted in a decrease in leukaemic burden in BM and spleen, delayed disease progression and improved survival. Overall, these data demonstrate that SLIT2 may act as a tumour suppressor, while SLIT2 loss impairs myeloid terminal differentiation, suggesting that SLIT2 signalling could serve as a potential therapeutic axis in AML.
    Keywords:  SLIT2; acute myeloid leukaemia; bone marrow niche
    DOI:  https://doi.org/10.1111/bjh.70785
  4. Blood Adv. 2026 Sep 24. pii: bloodadvances.2026019911. [Epub ahead of print]
    A CRISPR-Based Humanized Model Reveals Cooperative Role of STAG2 Loss in Familial GATA2-Deficient MDS Progression.
    Grace Freed, Miguel Quijada Álamo, Linda Lee, Ke Wang, Nikita Poddar, Subrina Autar, Saul Carcamo, Persephone Fiore, Emma K Kim, Isabella G Martinez, Mimi Zhang, Shayan Saniei, Clifford Chao, Levan Mekerishvili, Zayna Jinan Diaz, Sai Ma, Dan Hasson, Elvin Wagenblast.
      Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy driven by hematopoietic stem cell dysfunction, leading to ineffective hematopoiesis and cytopenias. Familial GATA2 deficiency is the most common cause of Myelodysplastic syndrome in adolescents, with progression often accelerated by co-occurring mutations, notably STAG2 loss-of-function. Using CRISPR/Cas9-mediated genome engineering in primary human fetal liver-derived hematopoietic stem cells and xenotransplantation in mice, we modeled GATA2-deficient Myelodysplastic syndrome with acquired STAG2 loss to investigate disease initiation and progression. While GATA2 deficiency alone had minimal short-term impact in our model, combined GATA2 and STAG2 loss increased hematopoietic stem cell maintenance and self-renewal, induced a myeloid-lineage bias, and expanded primitive progenitors. Single-cell transcriptional profiling revealed upregulation of stemness genes and inflammatory pathways. This humanized model faithfully recapitulates high-risk GATA2-deficient Myelodysplastic syndrome, providing mechanistic insight into how cooperative mutations drive stem cell expansion, inflammatory signaling, and myeloid skewing.
    DOI:  https://doi.org/10.1182/bloodadvances.2026019911
  5. Leuk Res. 2026 Sep 19. pii: S0145-2126(26)00166-9. [Epub ahead of print]171 108322
    Cladribine and low-dose cytarabine as first salvage after hypomethylating agent and venetoclax in acute myeloid leukemia.
    Ritika Dutta, Claire Schumann, Edna Cheung, Tian Yi Zhang, Asiri Ediriwickrema, Bita Fakhri, Jason Gotlib, Michaela Liedtke, William Shomali, Gabriel N Mannis.
      The combination of a hypomethylating agent (HMA) and venetoclax (Ven) is the standard frontline therapy for older adults with acute myeloid leukemia (AML) ineligible for intensive chemotherapy and is increasingly used in broader patient populations. However, the optimal approach for patients following progression on HMA/Ven remains undefined. Here, we retrospectively analyze 28 patients with AML who received cladribine plus low-dose cytarabine (Clad/LDAC)-based therapy as second-line treatment after frontline HMA/Ven failure. In this real-world cohort of older patients enriched for secondary AML features, Clad/LDAC-based therapy achieved an overall response rate (ORR) of 41% and composite complete remission (CR/CRi) rate of 33%. Median PFS (mPFS) in responders was 90 days compared to 30 days in non-responders (log-rank p < 0.001), and median OS (mOS) was 185 days versus 66 days (log-rank p = 0.056); for the overall cohort, mPFS was 45 days and mOS was 105 days. Prior HMA/Ven response did not predict Clad/LDAC outcomes, supporting this approach even in patients with primary refractory disease. Genetic risk stratification by ELN 2024 less-intensive-therapy classification was prognostic for both PFS (p = 0.028) and OS (p = 0.012), whereas ELN 2022 was not prognostic. TP53-mutated AML was uniformly refractory to both HMA/Ven and Clad/LDAC, with rapid disease progression and high early mortality following Clad/LDAC treatment. Serial molecular profiling identified heterogeneous patterns of clonal evolution across the treatment trajectory, including exploratory observations of high Clad/LDAC ORR in patients with emergent RAS-pathway clones at HMA/Ven failure. These findings highlight Clad/LDAC-based therapy as a salvage option with modest clinical activity following HMA/Ven.
    Keywords:  Acute Myeloid Leukemia; Cladribine; Cytarabine; Hypomethylating agent; Venetoclax
    DOI:  https://doi.org/10.1016/j.leukres.2026.108322
  6. Leukemia. 2026 Sep 24.
    Selective dependency of CALR-mutant myeloproliferative neoplasms on TYK2 signaling.
    Milena Kalmer, Chiara Wirths, Rebecca Lemanzyk, Alessia Piergentili, Mia Mönnig, Chunxiao Zhou, Bärbel Junge, Jonas Goßen, Siddharth Gupta, Laura Schulz, Anna Spitzer, Stefan Tillmann, Kim Kricheldorf, Joelle Schifflers, Kristina Pannen, Angela Galauner, Jacob Piehler, Christian Pecquet, Marcelo A S de Toledo, Stefan N Constantinescu, Giulia Rossetti, Steffen Koschmieder, Nicolas Chatain.
      Myeloproliferative neoplasms (MPN) are driven by the oncoproteins JAK2V617F, mutant calreticulin (CALR), and mutant thrombopoietin receptor (TPOR; MPL), all of which activate JAK/STAT signaling. While JAK2 signaling is engaged in all MPNs, TYK2 is dispensable for JAK2V617F-driven disease. Here, we hypothesized a distinct role for TYK2 in CALR-mutant driven MPN. We found constitutive TYK2 phosphorylation in CALRdel52/ins5- and MPLW515K- but not JAK2V617F-expressing cells. Structural modeling predicted similar TPOR-binding affinities for JAK2 and TYK2, while micropatterning experiments demonstrated that both JAK2WT and JAK2V617F displace TYK2 from the receptor. The TYK2 inhibitor deucravacitinib reduced viability and STAT3/5 phosphorylation in CALRdel52/ins5- and MPLW515K- but not JAK2V617F-mutant cells, with enhanced efficacy when combined with the JAK2-selective inhibitor fedratinib. Cellular response correlated with JAK2 protein abundance, as CALRins5 JAK2high clones outcompeted JAK2low clones upon TYK2 inhibition. In primary samples, deucravacitinib significantly suppressed colony growth in ET and PMF but not PV, and selectively reduced CALR- but not JAK2V617F-mutant allele burden. Similarly, CALR-mutant patient-specific iPSC-derived CD34+ progenitors showed increased TYK2 phosphorylation and were more sensitive to TYK2 inhibition than their JAK2V617F counterparts. These findings identify TYK2 as a selective vulnerability in CALR-mutant MPN and support combined TYK2/JAK2 inhibition strategies to overcome JAK2-dependent resistance.
    DOI:  https://doi.org/10.1038/s41375-026-03139-2
  7. Blood Neoplasia. 2026 Nov;3(4): 100279
    Tamibarotene with venetoclax and azacitidine in RARA+ acute myeloid leukemia: results from the SY-1425-202 study.
    Thomas Cluzeau, Uma Borate, Christine McMahon, Pierre Fenaux, Mael Heiblig, Pierre Peterlin, Brian Ball, Sylvain Chantepie, Alireza Eghtedar, Suman Kambhampati, Melhem Solh, Jose Torregrosa-Diaz, Thorsten Braun, James Dugan, Jonathan Feld, Marie-Pierre Gourin, Arnaud Pigneux, Jean-Baptiste Robin, Gary Schiller, Eytan Stein, David Roth, Michael Kelly, Daniel Pollyea, Stephane de Botton.
      RARA overexpression defines a molecularly distinct subset of acute myeloid leukemia (AML). Tamibarotene, an oral selective RARA agonist, synergizes with azacitidine (AZA) but its addition to venetoclax (VEN) with AZA has not been assessed. SY-1425-202 was a multicenter, open-label, randomized study evaluating tamibarotene combined to VEN/AZA (TAMI/VEN/AZA) vs VEN/AZA alone in newly diagnosed RARA-positive, unfit AML. Part 1 assessed the safety of TAMI/VEN/AZA, part 2 randomized participants to TAMI/VEN/AZA vs VEN/AZA, and part 3 explored salvage therapy with TAMI/VEN/AZA after VEN/AZA failure in part 2. TAMI 6 mg twice daily was administered. Randomization occurred after confirmation of RARA positivity by cycle 1, day 8. The primary end point was complete remission (CR) + CR with incomplete hematologic recovery (CRi) in part 2 and part 3, and safety in part 1. In part 1 (n=10), overall response rate (ORR) was 77.8% (5 CR, 2 CRi). In part 2 (n=51), CR/CRi was 60.0% for TAMI/VEN/AZA and 69.2% for VEN/AZA. Median CR/CRi duration was 293 vs 253 days. ORR was 80.0% vs 73.1%, respectively. In part 3, 2 of 5 patients responded (CR, morphologically leukemia-free state). Grade ≥3 treatment-emergent adverse event occurred in 76% of patients. Deaths were attributed mainly to disease progression or known complications of therapy; none were attributed to TAMI. The study met prespecified futility criteria and was discontinued early. The addition of TAMI to VEN/AZA was tolerable but did not improve efficacy over VEN/AZA. These results did not demonstrate clinical benefit of TAMI in the frontline unfit RARA-positive AML setting receiving VEN/AZA. This trial was registered at www.clinicaltrials.gov as #NCT04905407.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100279
  8. Blood. 2026 Sep 22. pii: blood.2025032501. [Epub ahead of print]
    How I Treat: MRD testing to personalize allogeneic HCT for adults with AML.
    Hatem A Ellaithy, Yi-Bin Chen, Christopher S Hourigan.
      Allogeneic hematopoietic cell transplantation (allo-HCT) is long established as the only curative option for many patients with acute myeloid leukemia (AML). Recent evidence demonstrates that measurable residual disease (MRD) testing, known to help stratify patients with AML in remission based on their risk for post-HCT relapse and mortality, can provide opportunities for patient-specific allo-HCT personalization. This includes patient selection for transplantation, guiding conditioning regimen intensity, surveillance for early identification of relapse during post-transplant remission, and, in some cases, selecting patients predicted to benefit from post-transplant maintenance or pre-emptive therapy. Just as therapy for AML is not yet perfected, MRD testing for AML currently still has many caveats but is emerging as a useful tool in specific contexts for the clinical management of those undergoing allo-HCT. As with all emerging technologies, physicians continue to face uncertainty regarding how to appropriately interpret or intervene upon such results. As we move forward, it will be important to distinguish promising translational research claims and theoretical aspirations from the practical testing realities in order to provide robust, reproducible, and actionable results to better guide therapeutic decisions. In four representative cases, we describe how we currently use MRD testing for adult patients with AML undergoing allo-HCT.
    DOI:  https://doi.org/10.1182/blood.2025032501
  9. Blood. 2026 Sep 25. pii: blood.2026033782. [Epub ahead of print]
    Multipotent Progenitor-3 Cells Are Reprogrammed by Bone-derived DKK1 to Drive Myelopoiesis in Breast Cancer.
    Emily Eul, Giulia Furesi, Wentao Han, Seunghyun Lee, Mark Watson, Rebecca Aft, Grant Challen, Roberta Faccio.
      The expansion of immunosuppressive myeloid cells drives tumor progression, yet clinical strategies aimed at depleting these populations have shown limited effects and high toxicity. Because myeloid cells arise from hematopoietic progenitors, we asked whether solid tumors durably reprogram hematopoietic stem and progenitor cells (HSPCs) to sustain pathological myeloid bias. Here, we show treatment-naïve stage-III breast cancer (BC) patients and murine models of primary BC exhibited expansion of bone marrow HSPCs with enhanced myeloid output. Transplantation assays further demonstrated that tumor-educated HSPCs retained durable myeloid bias following transfer into healthy recipients and promoted tumor progression upon secondary challenge, accompanied by selective expansion of multi-potent progenitors (MPPs) and mature myeloid cells. In contrast, transplantation of long-term HSCs did not confer durable hematopoietic changes or enhanced tumor growth, indicating that tumor-induced myeloid bias is mediated by downstream progenitors. Consistently, depletion of mature myeloid cells did not alter HSCs but triggered rapid MPP expansion and myeloid rebound in tumor-bearing mice compared to no-tumor controls. Among progenitor subsets, MPP3s emerged as the principal drivers of tumor-associated myelopoiesis. Single-cell RNA sequencing of BC patient bone marrow revealed reduced Wnt-β-catenin signaling in HSPCs and identified DKK1, a bone-derived Wnt inhibitor elevated during BC progression, as a mediator of MPP3 reprogramming. Targeting bone-derived DKK1 limited HSPC engraftment following transplantation into naïve mice, and reduced BC progression, MPP3 expansion, and myeloid output in tumor bearing mice. These findings highlight solid tumor-induced hematopoietic reprogramming and identify bone-derived DKK1 as a regulator of MPP3 fate.
    DOI:  https://doi.org/10.1182/blood.2026033782
  10. FASEB J. 2026 Oct 15. 40(19): e72341
    Nucleolin Alterations and ROS Production Associate With Sensitivity of AML Cells to Venetoclax.
    Kateřina Wolfová, Petra Otevřelová, Barbora Brodská.
      Acute myeloid leukemia (AML) is a heterogeneous disease with large spectrum of specific mutations and gene aberrations. Recently, the Bcl-2 inhibitor Venetoclax, in combination with hypomethylating agents (HMAs), was approved for older (> 65 years) AML patients, as well as for those unfit for intensive induction chemotherapy. In addition to Bcl-2 inhibition, Venetoclax also induces generation of reactive oxygen species (ROS). We demonstrated that distinct fraction exhibiting specific features arises during 24 h of sample exposure to Venetoclax. This fraction displays characteristic preapoptotic markers as mitochondria depolarization and partial Annexin V surface positivity. Moreover, monitoring of ROS showed negative correlation between signals detected using H2DCFDA and CellROX probes pointing to dynamic ROS changes induced by Venetoclax. The addition of HMA (Decitabine) had almost no effect on cell viability or ROS production but caused proliferation arrest in sensitive cells. In our panel of AML cell lines and primary AML samples we have found a correlation between ROS production, markers of apoptosis, and attenuation of Bcl-2 activity after Venetoclax treatment. Level of Mcl-1, another antiapoptotic protein from the Bcl-2 family, was reduced in sensitive cells, but increased in the resistant samples in response to Venetoclax. Moreover, the nucleolar protein nucleolin (NCL), which is frequently overexpressed in AML cells, was significantly deregulated in Venetoclax-treated cells. In particular, both NCL protein level and specific phosphorylation decreased in fractions sensitive to Venetoclax. Our findings suggest that Venetoclax targets distinct cell subpopulation, and that ability of a cell to follow increased ROS drives its response to Venetoclax.
    Keywords:  Bcl‐2; Decitabine; Doxorubicin; ROS; Venetoclax; acute myeloid leukemia; nucleolin
    DOI:  https://doi.org/10.1096/fj.202504934RR
  11. Haematologica. 2026 Sep 24.
    Search for leukemia-restricted targets: a new paradigm for precision immunotherapy in acute myeloid leukemia.
    Soheil Meshinchi, Franco Locatelli.
      Acute myeloid leukemia (AML) remains a major therapeutic challenge despite remarkable advances in genomic characterization. Although molecular profiling has transformed disease classification and risk stratification, treatment for most patients continues to rely on cytotoxic chemotherapy regimens developed more than 50 years ago. Numerous attempts to improve outcomes through treatment intensification, alternative chemotherapy approaches, and targeted agents have produced incremental benefits for selected patient populations, but have failed to fundamentally alter outcomes for many high-risk AML subtypes. A major obstacle to the broader application of immunotherapy in AML has been the absence of targets that clearly distinguish leukemic cells from normal hematopoietic tissues. Consequently, most immune-based therapies have focused on AML-associated antigens such as CD33, CD123, and CLEC12A, resulting in a narrow therapeutic window and significant hematopoietic toxicity. Recent advances in large-scale transcriptomic profiling, integrated genomic analyses, and immunopeptidomics have enabled systematic identification of AML-restricted biomarkers linked to leukemia-defining oncogenic programs. Rather than seeking a universal AML antigen, these approaches have uncovered subtype-specific targets, including FOLR1 in CBFA2T3::GLIS2 AML, CLEC2A in KMT2A-rearranged AML, mesothelin or CD7 in selected high-risk AML subsets, and intracellular targets such as WT1, PRAME, NPM1 neoantigens, and fusion-derived peptides. These discoveries have created opportunities for immunotherapeutic approaches capable of selectively targeting leukemic cells, while preserving normal hematopoiesis. This Spotlight Review discusses the evolution of AML biomarker discovery from prognostic classification to therapeutic target identification and highlights emerging AML-restricted biomarkers that may enable a new generation of biologically-precise immunotherapies for molecularly defined AML subsets.
    DOI:  https://doi.org/10.3324/haematol.2026.301517
  12. Blood. 2026 Sep 21. pii: blood.2026034660. [Epub ahead of print]
    Melatonin, circadian metabolism, mitochondrial remodeling, and cell size dynamics in primitive hematopoietic stem cells.
    Priyasmita Chakrabarti, Abhishek K Singh, Nicola K Wilson, Iwo Kucinski, Orit Kollet, Lizeth-Alejandra Ordonez Moreno, Arturo Simoni-Nieves, M S Vijayabaskar, Sarah J Kinston, Tzu-Hsuan Chang, Yi-Hao Wang, Montaser Haddad, Angelica Varesi, Ekaterina Petrovich-Kopitman, Ziv Porat, Tatiana Smirnova, Jiffin Paulose, Avik Choudhuri, John Hogenesch, You-Yang Zhao, Ping-Chih Ho, Amnon Buxboim, Leonard I Zon, Marie-Dominique Filippi, Regina P Markus, John E Dick, Stephanie Z Xie, Berthold Gottgens, Jose A Cancelas, Tsvee Lapidot.
      Primitive hematopoietic stem cells (pHSCs) sustain lifelong hematopoiesis through tightly regulated transitions between quiescence and activation. Circadian oscillations influence hematopoiesis; however, the mechanisms coordinating metabolic state and stem cell function daily remain incompletely defined. Here, we show that circadian cues coordinated a program of mitochondrial remodeling, metabolic reprogramming, and structural adaptation in pHSCs. At night, peak melatonin levels were associated with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species, and activation of DRP1 and PINK1 dependent mitophagy, resulting in enhanced long term repopulating capacity. In parallel, pHSCs exhibited increased glycolytic activity characterized by elevated glucose uptake, GLUT1 expression, AMPK phosphorylation, and HIF1α signaling. Mechanistically, mitochondrial remodeling was regulated in part by melatonin signaling, whereas glycolytic reprogramming was modulated by systemic circadian inputs, including feeding associated cues and Wnt/β-catenin signaling. FoxM1 and DRP1 contributed to mitochondrial quality control, while PGC1α dependent transcription supported compensatory mitochondrial biogenesis across the daily circadian cycle. These metabolic transitions were accompanied by dynamic changes in cell and nuclear size, linked to lamin A/C phosphorylation modulation. These coordinated processes defined a nocturnal state of enhanced stem cell fitness characterized by improved regenerative potential. Key features of glycolytic regulation were conserved in human HSCs, and in vitro melatonin treatment reduced the mitochondrial membrane potential and cell size of human pHSCs. Together, these findings establish a temporally regulated metabolic framework in which circadian cues partition mitochondrial and glycolytic programs to preserve stem cell maintenance and function, adding a new layer to pHSC metabolic physiology with clinical transplantation implications.
    DOI:  https://doi.org/10.1182/blood.2026034660
  13. Cell Stem Cell. 2026 Sep 24. pii: S1934-5909(26)00343-7. [Epub ahead of print]
    Systemic delivery of phagocytosis-shielded retroviral vectors enables in vivo HSC gene therapy for sickle cell disease.
    Denise Klatt, Adele Mucci, Boya Liu, Marie Peschers, Giulia Schiroli, Axel Schambach, John Manis, Myriam Armant, David T Scadden, Els Verhoeyen, Danilo Pellin, David A Williams, Christian Brendel.
      Ex vivo hematopoietic stem cell (HSC) gene therapy is effective for non-malignant blood disorders including sickle cell disease (SCD), but requires hospitalization, ex vivo cell manipulation, and conditioning. Direct in vivo gene delivery could remove these barriers and widen access. Here, we explore phagocytosis-shielded lentiviral and alpha-retroviral vectors pseudotyped with the baboon endogenous retrovirus glycoprotein variant BaEVRLess for in vivo HSC gene transfer. Vector injection into mobilized humanized mice yielded up to 8.8% gene marking in hCD45+ cells, which chemoselection enriched to 70% of hCD45+ cells and 54% of HSCs. Barcode analysis showed polyclonal reconstitution in over 90% of mice, which remained stable in secondary recipients. For SCD, we targeted BCL11A and ZNF410 selectively in erythroid cells using miRNA-embedded shRNAs to derepress gamma-globin, reaching therapeutically relevant levels of 61.5% of beta-like globins. In summary, BaEVRLess-pseudotyped lentiviral vectors enable clinically relevant in vivo gene transfer and fetal globin induction for SCD.
    Keywords:  BaEV; HSC; SCD; alpha-retroviral vector; baboon endogenous retrovirus glycoprotein; hematopoietic stem cell; in vivo gene therapy; lentiviral vector; sickle cell disease
    DOI:  https://doi.org/10.1016/j.stem.2026.09.001
  14. Mol Ther. 2026 Sep 22. pii: S1525-0016(26)00794-X. [Epub ahead of print]
    p38 MAPK inhibition safeguards genome integrity during gene editing of hematopoietic stem and progenitor cells.
    Roberta Vacca, Lucrezia Della Volpe, Nicolò Gualandi, Kohei Shiroshita, Edoardo Carsana, Kety Giannetti, Chiara Gaddoni, Fabrizio Benedicenti, Barbara Gega, Sergio Arévalo, Parinaz Zarghamian, Stefano Beretta, Maria Carmina Castiello, Chiara Brombin, Daniele Canarutto, Ivan Merelli, Toni Cathomen, Eugenio Montini, Anna Villa, Luigi Naldini, Raffaella Di Micco.
      Ex vivo genome editing of hematopoietic stem and progenitor cells (HSPCs) holds significant therapeutic potential but remains constrained by genotoxic risks associated with nuclease-induced DNA double-strand breaks, DNA donor template delivery and sensing, and proliferation-induced stress during ex vivo manipulation. These processes can lead to chromosomal instability, large on-target deletions, donor mis-integration, off-target events, and impaired long-term stem cell function, raising safety concerns for clinical translation. Here, we evaluate the impact of transient p38 MAPK inhibition on genomic integrity during clinically relevant CRISPR-Cas9 editing and show that this intervention attenuates ex vivo culture-associated stress without increasing detectable genotoxic outcomes. Comprehensive genotoxicity analyses, including quantification of large on-target deletions, adeno-associated viral vector mis-integration, and CAST-seq mapping of translocations, reveal no measurable differences in gene editing-associated structural alterations upon p38 MAPK inhibition, while micronuclei were significantly reduced. Importantly, long-term xenotransplantation followed by whole-exome sequencing shows that p38i-treated HSPCs display a reduced mutational burden without evidence of increased genomic alterations. Collectively, these findings identify transient p38 MAPK inhibition as a strategy to improve the quality and long-term fitness of gene-edited HSPCs without detectable adverse effects on the genome editing outcomes, supporting its further evaluation as a refinement to clinically relevant CRISPR-Cas9 editing workflows.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.09.024
  15. bioRxiv. 2026 Sep 18. pii: 2026.09.16.752145. [Epub ahead of print]
    Unbiased, systematic surfaceome profiling of Acute Leukemia to identify novel immunotherapy targets.
    Benson M George, Anna Rodriguez-Pöhnlein, Donavelle J DeCastro, Jennifer Porat, Benyu Zhou, Dinah M Abeja, Ryan J Lumpkin, Rebecca J Metivier, Anna Schmoker, Wencke Walter, Torsten Haferlach, Yana Pikman, Katherine A Donovan, Kimberly Stegmaier, Eric S Fischer, Franziska Wachter, Ryan A Flynn.
      Cell surface proteomics provides a direct topological assessment of the outer membrane of cells and enables the capture of low abundance proteins that may be missed by whole cell proteomics. Here we present an unbiased atlas of the whole cell and surface proteomes of 25 commonly used leukemic cell lines, encompassing both lymphoid and myeloid lineages, and a variety of driver mutations. Paired-wise analysis highlights recurrent surface proteins that are not detected by whole cell proteomics. Coupling this dataset to RNA-sequencing, we also discovered genes where protein and RNA abundances are discordant. In KMT2A -rearranged AML, CD70 expression was increased across cell lines and validated in primary patient samples, supporting CD70 as a candidate therapeutic target in this disease. Several proteins are enriched in the surface proteomes but lack surface annotation, adding to the growing list of potential non-canonical cell surface proteins. These findings reveal a substantial pool of proteins absent from conventional surface annotations, including RNA-binding proteins, an emerging class of candidate immunotherapeutic targets.
    Key Points: Direct surface proteomics identifies leukemia cell-surface proteins not reliably predicted by transcriptomic or whole-proteome profilingSurface profiling reveals genotype-specific therapeutic targets, including CD70 in KMT2A-rearranged AML.
    DOI:  https://doi.org/10.64898/2026.09.16.752145
  16. Cancer. 2026 Oct 01. 132(19): e70549
    Oral vitamin C supplementation in patients with clonal cytopenia of undetermined significance or lower-risk myeloid malignancies: Results from EVITA, a phase 2 randomized, placebo-controlled trial.
    Stine Ulrik Mikkelsen, Ali Al-Mousawi, Amalie Bach Puglisi, Anders Pommer Vallentin, Astrid Østergaard Mortensen, Zachary Madaj, Toshinori Hinoue, Heidi Naomi Ottesen, Jakob Schmidt Jespersen, Linn Gillberg, Morten Tulstrup, Niels Richard Hansen, Jakob Werner Hansen, Mette Klarskov Andersen, Stacey Lyn Thomas, Christine Isaguirre, Ryan Sheldon, Marie Adams, Ryan Burgos, Stephen Baylin, Bo Kok Mortensen, Casey Lee O'Connell, Marianne Tang Severinsen, Peter William Laird, Jens Lykkesfeldt, Peter Jones, Kirsten Grønbæk.
       BACKGROUND: Vitamin C (VitC) is a cofactor for TET enzymes involved in DNA demethylation and epigenetic regulation. Mutations in TET2 are common drivers of leukemia. Preclinical studies suggest that VitC may delay leukemia progression. This study aimed to evaluate the biological activity, safety, and clinical impact of oral VitC in patients with clonal cytopenia of undetermined significance (CCUS) or lower risk myeloid malignancies.
    METHODS: EVITA (Epigenetics, Vitamin C, and Abnormal Hematopoiesis) was a double-blind, randomized, placebo-controlled, phase 2 trial conducted in Denmark and the United States. Adults with CCUS or lower risk myeloid malignancies not receiving anticancer therapy were randomly assigned (1:1) to receive oral VitC (1000 mg/day) or placebo for 12 months, followed by long-term follow-up. The primary end point was the median clonal growth rate from baseline to end of treatment. EVITA was registered at ClinicalTrials.gov (NCT03682029), and is now completed.
    RESULTS: Between November 1, 2017, and September 28, 2022, 109 patients were enrolled (VitC, n = 55; placebo, n = 54). Although the primary end point, median clonal growth rate, did not differ between groups (-0.016; 95% CI, -0.096 to 0.064; p = .70), secondary outcomes included differences in inflammatory cytokine trajectories and fewer serious adverse events in the VitC group versus placebo (18 of 55 [33%] vs. 30 of 53 [57%]). In exploratory analyses, overall survival was significantly longer with VitC (hazard ratio, 0.35; 95% CI, 0.17 to 0.71; p = .0025).
    CONCLUSIONS: These findings suggest oral VitC as a safe, biologically active intervention in patients with early-stage myeloid malignancies and precursor conditions. A phase 3 trial is warranted.
    Keywords:  clonal cytopenia; interception; myeloid malignancies; precursor conditions; randomized controlled trial
    DOI:  https://doi.org/10.1002/cncr.70549
  17. Cell Genom. 2026 Sep 21. pii: S2666-979X(26)00227-2. [Epub ahead of print] 101365
    Concentrating cell-type-specific transcriptional signatures in bone marrow from interspecies comparisons.
    Lea C Wölbert, Veronica F Busa, Amy F Danson, Sonia Fernández Torices, Shubhankar Sood, Fritjof Lammers, Julia Knoch, Melanie Ball, Foteini Fotopoulou, Esther Rodríguez Correa, Anja Schneider, Francesca Coraggio, Andrea Kuck, Stefania Del Prete, Nina Claudino, Marie-Luise Koch, James P Cleland, Jeyan Jayarajan, Franziska Pilz, Helena Borgers, Adrien Jolly, Thomas Höfer, Michael D Milsom, Marieke A G Essers, Duncan T Odom.
      Cell-type definition is commonly achieved using marker genes. Because cell types are broadly conserved across evolution, marker genes are identifiable via interspecies comparisons. We generated single-cell RNA sequencing datasets of bone marrow niche and hematopoietic progenitor compartments from four mouse species. Using these data, we developed a strategy that adds conservation of transcriptional levels to existing approaches that identify marker genes using conserved cell-type specificity. The resulting "signature gene" lists contain both well-known and underexplored bone marrow markers. Signature genes capture cell identities and thus can robustly discern homologous cell types in diverse tissues of evolutionarily distant species. Unbiased benchmarking assessments demonstrated that our signature genes are comparable or superior to larger, less-conserved gene lists. Last, we confirm our framework's versatility and robustness using published datasets from another tissue and mammalian order. Thus, combining conserved cell-type specificity and transcriptional levels is a powerful, widely applicable strategy to distill profoundly descriptive signatures.
    Keywords:  bone marrow; cell-type identity; cell-type signatures; cross-species comparisons; hematopoietic niche; hematopoietic stem cells; marker genes; mesenchymal stromal cells; single-cell transcriptomics; transcriptomic conservation
    DOI:  https://doi.org/10.1016/j.xgen.2026.101365
  18. Curr Oncol. 2026 Aug 26. pii: 506. [Epub ahead of print]33(9):
    Lenalidomide Exposure and TP53-Mutated Myelodysplastic Syndromes/Neoplasms.
    Bahga Katamesh, Rory M Shallis.
      The benefits of lenalidomide, which leverages TP53-dependent apoptosis and promotion of megakaryocytic differentiation, in lower-risk MDS (LR-MDS) with del(5q) are well-established and drive its frequent use in clinical practice. In parallel, advances in molecular testing have elucidated the clear impact of TP53 mutations on response to therapies and prognosis, with diversity in the latter informed by variant allele frequency (VAF) and/or predicted allelic state. In this review, we discuss the converging pre-clinical and clinical evidence that implicates TP53 mutations not only as a driver of lenalidomide resistance in del(5q) LR-MDS, but as a source of selective clonal advantage under lenalidomide exposure. Lenalidomide-induced CK1α degradation triggers TP53-mediated apoptosis in wild-type clones, inadvertently favoring the survival and expansion of TP53-mutated cells. Clinically, this dynamic has been demonstrated across multiple studies, with rising TP53 variant allele frequency and clonal evolution observed following treatment. These findings underscore the importance of baseline molecular assessment in patients with MDS and, in select cases, serial monitoring during therapy. Investigational approaches for del(5q) LR-MDS with the TP53 mutation include GATA2-directed strategies aimed at restoring lenalidomide sensitivity, as well as immune-based therapies targeting the tumor microenvironment characteristic of TP53-mutated disease.
    Keywords:  MDS; Revlimid; TP53; lenalidomide; myelodysplastic syndrome
    DOI:  https://doi.org/10.3390/curroncol33090506
  19. N Engl J Med. 2026 Sep 24. 395(12): 1241-1244
    Cumulative Hematologic Morbidity and Outcomes in Shwachman-Diamond Syndrome.
    International SDS Research Consortium
      
    DOI:  https://doi.org/10.1056/NEJMc2605001
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