Preprint Watch: March
This month, we're featuring a special edition of the Preprint watch, focused exclusively on pathological and malignant hematopoiesis. If you want your research to be featured here, submit this brief form.
From the Simply Blood Community:
RUNX1::RUNX1T1 Depletion Eliminates Stemness and Induces Bidirectional Differentiation of Acute Myeloid Leukemia
https://www.biorxiv.org/content/10.1101/2025.02.13.637937v1
From the authors: “The relevance of continuing expression of fusion genes in primary leukaemic cells has remained unclear. Silencing RUNX1::RUNX1T1 expression in primary AML cells using siRNA-loaded lipid nanoparticles induces substantial changes in chromatin accessibility and therewith associated transcriptional networks linked with granulocytic and eosinophilic differentiation at the complete expense of LSC-enriched populations.”
Contact address: o.t.heidenreich@prinsesmaximacentrum.nl
Wnt-dependent spatiotemporal reprogramming of bone marrow niches drives fibrosis
https://www.biorxiv.org/content/10.1101/2025.02.12.637594v1
From the authors: “Bone marrow fibrosis involves extensive matrix remodeling, including osteosclerosis, driven by fibrosis-inducing hematopoietic cells that reprogram perivascular CAR progenitors, leading to loss of hematopoietic support and activation of osteogenic and apoptotic pathways. Peritrabecular osteolineage cells (OLCs) contribute to fibrosis through Wnt-dependent expansion and differentiation, with NCAM1 marking their spread, and Wnt inhibition emerging as a potential therapeutic strategy.”
PATHOLOGICAL HEMATOPOIESIS
Dona Flor and her two husbands: Discovery of novel HDAC6/AKT2 inhibitors for myeloid cancer treatment
https://www.biorxiv.org/content/10.1101/2024.11.30.626092v1?rss=1
Using curated IC50 datasets and Random Forest models, the authors identified, synthesized, and biologically validated a list of potent chemical inhibitors, demonstrating strong anticancer activity and HDAC6 inhibition. They validated some of those in multiple leukemic cell lines, confirming the ability of our models to predict drug candidates.
Effects of Hypomethylating Agents on Gene Modulation in the Leukemic Microenvironment and Disease Trajectory in a Mouse Model of AML
https://www.biorxiv.org/content/10.1101/2024.12.01.626276v1?rss=1
The authors investigated the effects of 5-azacytidine (AZA) on immune-related gene expression in non-leukemic blood cells and the spleen during leukemia treatment. Their findings reveal key pathways linked to adhesion, thrombosis, and angiogenesis and potential gene targets that could enhance HMA efficacy and mitigate relapse.
VEXAS anemia is a mosaic erythroblastopenia
In this study, the authors define VEXAS-associated anemia as a mosaic erythroblastopenia, where UBA1 mutations disrupt early erythroid differentiation but spare mature red cells. The observed defective ubiquitylation leads to TP53 overexpression and ribosome biogenesis anomalies, highlighting potential therapeutic targets for managing anemia severity.
Leukemia-mutated proteins PHF6 and PHIP form a chromatin complex that represses acute myeloid leukemia stemness
https://www.biorxiv.org/content/10.1101/2024.11.29.625909v3
The authors identify PHF6 as a transcriptional repressor that suppresses AML stemness and demonstrate its functional dependence on PHIP. Those findings establish PHF6 and PHIP as part of a common chromatin-associated complex, linking their mutations to leukemogenesis and potential therapeutic targeting.
Inflammatory Mesenchymal Stromal Cells and IFN-responsive T cells are key mediators of human bone marrow niche remodeling in CHIP and MDS
https://www.biorxiv.org/content/10.1101/2024.11.27.625734v1?rss=1
This study describes an inflammatory remodeling of the bone marrow niche in CHIP and MDS, characterized by the loss of HSPC-supportive CXCL12-abundant reticular cells and the emergence of inflammatory mesenchymal stromal cells (iMSCs). It proves the existence of niche-driven mechanisms that may contribute to disease progression and offer potential targets for early intervention in hematological malignancies.
Autophagy inhibition induces AML cell death and enhances the efficacy of chemotherapy under hypoxia
https://www.biorxiv.org/content/10.1101/2024.11.24.625107v1?rss=1
In this study, the authors demonstrate that AML cells enhance mitophagy to survive in the hypoxic bone marrow microenvironment, contributing to chemoresistance. Autophagy inhibitor Lys05 disrupts mitochondrial clearance, induces AML cell death under hypoxia, reduces CD34+CD38− cells in xenografted mice prolonging survival, and enhances the efficacy of cytarabine, venetoclax, and azacytidine ex vivo and in vivo.
PRMT1-Mediated Metabolic Reprogramming Promotes Leukemogenesis
https://www.biorxiv.org/content/10.1101/2024.12.12.628174v1?rss=1
The authors show that PRMT1 drives leukemia initiation and progression in a subset of AMKL (Acute Megakaryoblastic Leukemia) cells by enhancing glycolysis and suppressing fatty acid oxidation. They demonstrate that PRMT1 increases extracellular acidification, promotes glucose consumption, and induces lipid accumulation while downregulating CPT1A, a key regulator of fatty acid oxidation.
NK cells control the progression of myelodysplastic syndrome but become initial disease target in NUP98-HOXD13 mouse model
https://www.biorxiv.org/content/10.1101/2024.12.11.627924v1?rss=1
Using a transgenic mouse model (NUP98/HOXD13, or NHD13tg), the authors demonstrate that NK cells are crucial in controlling MDS progression in the mouse model. They show that NK cells are reduced before MDS onset, their depletion accelerates disease progression, and they exhibit impaired differentiation and IL-15/IL-2 responses, due to intrinsic defects affecting KLRG1+ mature NK cells.
DNMT/G9a Complex Inhibition Uncovers Epigenetic Vulnerabilities and Induces IFN-Response in Acute Myeloid Leukemia
https://www.biorxiv.org/content/10.1101/2024.12.11.627891v1?rss=1
The authors identify a specific epigenetic vulnerability in AMLs harboring DNMT3A and NPM1 mutations, driven by a DNMT/G9a complex that regulates oncogenic programs. They demonstrate that dual inhibition of DNMT and G9a restores differentiation, reduces tumor growth while sparing healthy progenitors, and activates viral mimicry pathways by modulating hypermethylated retrotransposons.
Leukaemia cell intrinsic and extrinsic factors cooperate to facilitate the survival and proliferation of KMT2A-rearranged B-ALL in the CNS niche
https://www.biorxiv.org/content/10.1101/2024.12.03.626602v1?rss=1
In this study, the authors investigate the mechanisms driving CNS involvement in KMT2A-rearranged infant B-ALL, using an immune-competent murine model. They demonstrate that CNS exposure alters leukemia propagating cell dynamics, suppresses T cell and macrophage activity, and promotes immune escape. The authors also identified the PI3K pathway activation as key drivers of CNS leukemia propagation, highlighting the microRNA miR-93 as a potential therapeutic target.
Translation Initiation Represents an Acute Myeloid Leukemia Cell Vulnerability That Can Be Co-Targeted With BCL-2 Inhibition
https://www.biorxiv.org/content/10.1101/2024.12.20.629809v1?rss=1
To improve the clinical efficacy of BCL-2 inhibition, the authors identify EIF4A1 as a potential target, as it acts as a key driver of oncogenic translation in AML stem- and progenitor-like cells. Inhibition of EIF4A1 via Zotatifin downregulates AKT, STAT-5, and MCL-1, synergizing with Venetoclax to induce apoptosis across AML genotypes while sparing healthy cells.
STAT5B leukemic mutations, altering SH2 tyrosine 665, have opposing impacts on immune gene programs
https://www.biorxiv.org/content/10.1101/2024.12.20.629685v1?rss=1
The authors investigate the functional impact of two STAT5B mutations found in human T-cell leukemias. They demonstrate that the Y665F mutation exhibits gain-of-function with enhanced phosphorylation, DNA binding, and transcriptional activity, while Y665H functions as a loss-of-function variant. These findings highlight the structural and mechanistic consequences of disease-associated STAT5B mutations and their effects on T-cell homeostasis.
Leukemia escapes immunity by imposing a Type-1 regulatory program on neoantigen-specific CD4+ T cells
https://www.biorxiv.org/content/10.1101/2024.12.21.629902v1?rss=1
From the authors: B-ALL induces neoantigen-specific CD4+ T cells to adopt Type-1 regulatory states, which protect leukemic cells from immune pressure. Repolarizing neoantigen-specific CD4+ T-cells towards Th1 states eradicates measurable residual disease.
T505A variant of ETV5 promotes proliferation of precursor B cells in a mouse model of acute lymphoblastic leukemia
https://www.biorxiv.org/content/10.1101/2024.12.19.629436v1?rss=1
Using a transgenic mouse model of pre-B-ALL, the authors sought to identify secondary mutations and characterize their functional impact on leukemia development. They found multiple recurrent mutations in Etv5, characterising them functionally and molecularly, highlighting ETV5 mutations as potential drivers of pre-B-ALL.
Base edited “universal” donor CAR T cell strategies for acute myeloid leukaemia
https://www.biorxiv.org/content/10.1101/2024.12.28.630573v1?rss=1
In this preclinical study, the authors explore using base-edited (BE) universal CAR T cells to overcome antigen heterogeneity in AML and facilitate bridging to stem cell transplantation. They demonstrate that monotherapy with BE-CAR33 (against CD33), BE-CARCLL-1 (against CLL1), or BE-CAR7 (against CD7) T cells effectively inhibits AML when antigen expression is homogeneous. Conversely, dual BE-CAR33 and BE-CARCLL-1 therapy is required for heterogeneous disease.
Targeting AML Resistance with LY3009120-Sapanisertib and Ruxolitinib-Ulixertinib Combinations Demonstrate Superior Efficacy in FLT3, TP53, and MUC4 mutations
https://www.biorxiv.org/content/10.1101/2024.12.31.630711v1?rss=1
The authors test the efficacy of two novel drug combinations, LY3009120+sapanisertib (LS) and ruxolitinib+ulixertinib (RU), in AML using cell lines and an in vivo zebrafish xenograft model. They demonstrate that both combinations outperform venetoclax-based treatments in reducing cell viability, while also identifying correlations between treatment response and specific genetic variants (TP53, FLT3, and MUC4 mutations).
Nucleophosmin mutations lead to abnormal, but reversible, nucleoli architecture and aggregate formation – Implications for NPM1-targeting therapies in AML
https://www.biorxiv.org/content/10.1101/2024.12.30.630786v1?rss=1
The authors demonstrate that NPM1 is essential for maintaining nucleolar architecture and that NPM1-mutated AML cells exhibit aberrant nucleoli structure, which can be reversed. Using high-resolution imaging, they identify distinct aggregates of mutant NPM1 protein and characterize them, a novel vulnerability that could be exploited for therapeutic intervention.
Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy
https://www.biorxiv.org/content/10.1101/2024.12.30.630700v1?rss=1
From the authors: Rapid selection of leukemic clones occurs within small populations with LSC potential, months or years prior to relapse. Rapid eradication of leukemic clones leads to sustained remission in the context of ivosidenib combination therapy.
Phosphoproteomics reveals novel BCR::ABL1-independent mechanisms of resistance in chronic myeloid leukemia
https://www.biorxiv.org/content/10.1101/2025.01.08.631869v1?rss=1
Using high-sensitivity phosphoproteomics and computational analysis, the authors map BCR::ABL1-dependent and independent signaling pathways in chronic myeloid leukemia (CML). Their approach identifies acquired FLT3 dependency as a key mechanism in TKI-resistant CML, repositioning FLT3 as a potential therapeutic target to overcome drug resistance.
Single-cell transcriptomics-guided development of flow cytometric tests predicting chronic myeloid leukemia blast crisis transformation at chronic phase diagnosis
https://www.biorxiv.org/content/10.1101/2025.01.09.632094v1?rss=1
The authors looked for early biomarkers predicting blast crisis (BC) progression in chronic myeloid leukemia (CML), analyzing single-cell gene expression data from imatinib-resistant cases. They find that aberrant CD42A+ megakaryocytic and CD10+CD19+ lymphoid progenitors, along with STAT1- and IFNγ-driven inflammatory programs, are present in patients at high risk of transformation. Using multi-color flow cytometry (MFC), they validate these biomarkers in a cohort of 28 CP patients.
Blog post contributed by Alessandro Donada, PhD (Bluesky: @alessandrodonada.bsky.social) of the ISEH Publications Committee.
Please note that the statements made by Simply Blood authors are their own views and not necessarily the views of ISEH. ISEH disclaims any or all liability arising from any author's statements or materials.
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