Preprint Watch: April

Welcome to our monthly Preprint Watch, where we highlight some of the most relevant preprints for the ISEH community! This month we cover some exciting findings on immunotherapy, hematopoietic fetal development and erythropoiesis. If you would like to see your preprint highlighted here, complete this brief form.

We are also happy to chat with Dr. Jane Xu, she will tell us more about chromatin accessibility and leukemia development! 

From the Simply Blood Community:

Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia
https://www.biorxiv.org/content/10.1101/2025.03.19.643917v1

From the authors: We developed humanized models to investigate how the developmental origin of hematopoietic stem and progenitor cells influences leukemia initiation, lineage plasticity, and therapeutic response in pediatric leukemias driven by NUP98 fusion oncoproteins. Our study reveals fundamental developmental differences underlying lineage potential and drug sensitivities, providing a rationale for age-tailored precision oncology strategies in fusion-driven leukemias.
Contact address: Elvin.Wagenblast@mssm.edu - Bluesky @elvinwag.bsky.social

Enhanced FLI1 accessibility mediates Stag2-mutant leukemogenesis
https://www.biorxiv.org/content/10.1101/2025.04.01.646632v1

Do you know that cohesin ring controls how transcription factor access chromatin? Excited to share my first piece of postdoctoral work where we investigate how Stag2 cohesin contributes to leukemia!
Contact address: jx2462@cumc.columbia.edu - Bluesky @DrJaneXu

STEM AND PROGENITOR CELLS BIOLOGY 

PERK Signaling Maintains Hematopoietic Stem Cell Pool Integrity under Endoplasmic Reticulum Stress by Promoting Proliferation
https://www.biorxiv.org/content/10.1101/2024.12.13.628451v1?rss=1

From the authors: PERK is not required for steady-state hematopoiesis but preserves hematopoietic stem cell pool integrity in response to increased ER stress. Under ER stress induced by ERAD deficiency, PERK is activated to promote mTOR signaling and HSC hyper-proliferation, depleting damaged HSCs.

Injured endocardium obtains characteristics of haemogenic endothelium during adult zebrafish heart regeneration
https://www.biorxiv.org/content/10.1101/2024.12.18.629122v1?rss=1

Following cardiac injury in zebrafish, Runx1-expressing endocardial cells exhibit marked heterogeneity, giving rise to both myofibroblast-like and haemogenic identities. This study reveals that injury reactivates a dormant endocardial-to-haematopoietic transition (EHT) program, positioning Runx1 as a key regulator of endocardial cell fate during regeneration.

Histone H3.3 ensures cell proliferation and genomic stability during myeloid cell development
https://www.biorxiv.org/content/10.1101/2024.12.26.630087v1?rss=1

The authors reveal that H3.3 is essential for the proliferation and genomic stability of myeloid progenitor cells but is largely dispensable for their differentiation into bone marrow-derived macrophages (BMDMs). Loss of H3.3 in progenitors leads to replication defects, DNA damage, and apoptosis, while surviving cells exhibit persistent interferon-stimulated gene expression and maintain overall chromatin structure.

Single-cell transcriptome profiling of the myeloid cells repopulating after chemotherapy identifies a neutrophil-like monocyte subset with pro-tumor activities
https://www.biorxiv.org/content/10.1101/2024.12.28.630613v1?rss=1

Chemotherapy triggers emergency myelopoiesis, leading to the regeneration of heterogeneous monocytes, including a distinct subset of neutrophil-like monocytes (NeuMo) with immunosuppressive properties. The authors performed scRNA-seq, revealing that these NeuMo cells, marked by Cxcr4 and Cx3cr1, expand after treatment and can suppress T cell activity, potentially contributing to cancer progression.

Secreted Frizzled-Related Protein 1a regulates hematopoietic development in a dose-dependent manner
https://www.biorxiv.org/content/10.1101/2025.01.10.632371v1?rss=1

This work presents Secreted Frizzled-Related Protein 1a (Sfrp1a) as a regulator of HSPC development in zebrafish, by modulating canonical Wnt signaling in a dose-dependent manner. Both loss and high-dose overexpression of sfrp1a lead to increased HSPC numbers and impaired differentiation, underscoring the need for precise Sfrp1a regulation during hematopoietic development and its relevance to disease.

Distinct origin and fate for fetal hematopoietic progenitors
https://www.biorxiv.org/content/10.1101/2025.01.08.631951v1?rss=1

Two sequential waves of intraembryonic progenitors contribute to blood cell production, with embryonic multipotent progenitors (eMPPs) supporting late gestation hematopoiesis and establishing the adaptive immune system, while hematopoietic stem cells (HSCs) expand to maintain lifelong blood production. The authors used lineage tracing to reveal that eMPPs, distinct from HSCs, predominantly generate embryonic lymphocytes and lymphoid tissue inducer cells, highlighting their foundational role in shaping postnatal immunity.

Local delivery of SBRT and IL-12 to Murine PDAC Tumors Modulates Hematopoiesis
https://www.biorxiv.org/content/10.1101/2025.01.10.632406v1?rss=1

From the authors: Intratumoral delivery of stereotactic body radiation therapy (SBRT) and interleukin-12 (IL-12) augment hematopoiesis in the bone marrow soon after treatment and induce long-term alterations in the hematopoietic stem cells (HSCs). These effects are mainly a result of IL-12 that is transiently increased in the bone marrow after treatment.

Ontogeny drives stage-specific effects of a Gata1 mutation
https://www.biorxiv.org/content/10.1101/2025.01.15.633164v1?rss=1

From the authors: Fetal and adult megakaryopoiesis pass through distinct immunophenotypic stages, and their ontogeny dictates their transcriptional trajectory. Progenitor origin rather than the differentiation pathway determines the effect of mutant Gata1, which causes megakaryocyte maturation block and drives blast cell formation exclusively in yolk sac-derived lineages

PATHOLOGICAL HEMATOPOIESIS 

Stress Granules Underlie Acute Myeloid Leukemia Stem Cell Survival and Stress Adaptation
https://www.biorxiv.org/content/10.1101/2025.01.14.632811v1?rss=1

This study identifies stress granules (SGs) as key regulators of leukemic stem cell (LSC) maintenance in acute myeloid leukemia (AML). The SG nucleator G3BP1 is shown to support AML propagation by modulating immune signaling and apoptosis through selective RNA interactions, revealing SGs as a stress-adaptive vulnerability and a potential therapeutic target.

Fenretinide targets GATA1 to induce cytotoxicity in GATA1 positive Acute Erythroid and Acute Megakaryoblastic Leukemic cells
https://www.biorxiv.org/content/10.1101/2025.01.19.633759v1?rss=1

Fenretinide (4-HPR) targets the transcription factor GATA1, inducing its loss and contributing significantly to 4-HPR cytotoxicity in M6 OCIM1 cells. 4-HPR treatment overcomes chemotherapeutic resistance in M6 AML cells, synergizing with standard-of-care and outperforming it as a single agent.

Regulation of cell cycle by the novel GATA1/TAL1/Sphingomyelin Synthase 1 (SGMS1) transcriptional axis. Implications for anti-leukemic strategies
https://www.biorxiv.org/content/10.1101/2025.01.19.633812v1?rss=1

This study describes the Sphingomyelin Synthase 1 gene (SGMS1) as a novel direct target of GATA1 and TAL1. High SGMS1 levels are associated with high GATA1/TAL1 expression and regulate cell cycle progression through the G2/M checkpoint in GATA1-positive erythroleukemic AML cells. High SGMS1 is associated with lower AML patients survival.

Selection of pre-leukemic hematopoietic stem cells driven by distinct extracellular matrix molecules
https://www.biorxiv.org/content/10.1101/2025.01.20.633881v2

This study presents a multi-omic analysis of Tet2-deficient hematopoietic stem cells (HSCs), revealing that proteomic profiling surpasses transcriptomics in distinguishing mutant from wildtype cells. It uncovers extracellular matrix (ECM) dysregulation as a novel mechanism promoting self-renewal in pre-leukemic HSCs, highlighting ECM components as potential modulators of disease progression.

CD33KO-CD33-mesothelin loop CAR design avoids fratricide and improves efficacy of iNK cells against acute myeloid leukemia
https://www.biorxiv.org/content/10.1101/2025.01.23.634500v2

The authors developed a prospective immunotherapy for AML, by designing a novel CD33-mesothelin Loop CAR in NK cells derived from human pluripotent stem cells (hPSCs). By knocking out CD33 to prevent fratricide and enhancing endogenous CD16 expression, the engineered CAR-iNK cells show potent dual-antigen-specific cytotoxicity and prolonged survival in AML models.

Engineered CRO-CD7 CAR-NK cells derived from pluripotent stem cells avoid fratricide and efficiently suppress human T-cell malignancies
https://www.biorxiv.org/content/10.1101/2025.01.23.634617v1?rss=1

From the authors: Our study provides a reliable strategy for the large-scale generation of fratricide-resistant CD7 CAR-iNK cells with robust anti-tumor effects from hPSCs, offering a promising cell product to treat T-cell malignancy.

Single Cell Spatial Transcriptomics Reveals Immunotherapy-Driven Bone Marrow Niche Remodeling in AML
https://www.biorxiv.org/content/10.1101/2025.01.24.634753v1?rss=1

From the authors: Spatial transcriptomic analysis of R-AML bone marrow niches provides detailed information about intercellular interactions in the tumor microenvironment. Immunotherapy shifts the cell composition of the leukemia neighborhood.

Uridine Metabolism as a Targetable Metabolic Achilles’ Heel for chemo-resistant B-ALL
https://www.biorxiv.org/content/10.1101/2025.01.27.635108v1?rss=1

This study reveals that chemo-resistant B-cell Acute Lymphoblastic Leukemia (B-ALL) cells with active signaling (pS6⁺) are highly glucose-dependent due to their reliance on de novo uridine synthesis. These cells upregulate key enzymes like DHODH, linking metabolic reprogramming to relapse risk. Inhibiting DHODH selectively kills pS6⁺ cells and prolongs survival in vivo, highlighting uridine synthesis as a targetable vulnerability in relapsed B-ALL.

Therapeutic Potential of PRMT1 as a Critical Survival Dependency Target in Multiple Myeloma
https://www.biorxiv.org/content/10.1101/2025.01.29.635603v1?rss=1

The authors, using a targeted CRISPR/Cas9 screen of DNA damage response genes, identified PRMT1 as a key survival dependency in multiple myeloma (MM). Inhibition of this arginine methyltransferase with a small molecule impaired MM cell viability, disrupted cell cycle progression, and downregulated proliferation and DNA repair programs, positioning PRMT1 as a promising therapeutic target in drug-resistant MM.

Utilizing Genomics to Identify Novel Immunotherapeutic Targets in Multiple Myeloma High-Risk Subgroups
https://www.biorxiv.org/content/10.1101/2025.01.29.635544v1?rss=1

Leveraging large-scale genomic datasets, this study identifies novel and subgroup-specific cell surface targets in multiple myeloma, including ROBO3, CD109, CD20, GPRC5D, and ADAM28 across distinct cytogenetic profiles. The authors further validated the expression of those targets via flow cytometry and CRISPR knockout models.

MOLECULAR HEMATOPOIESIS  

Enhancer heterogeneity in acute lymphoblastic leukemia drives differential gene expression between patients
https://www.biorxiv.org/content/10.1101/2024.12.08.627394v1?rss=1

From the authors: Leukemia patients with the same driver mutations often display gene expression differences. Using chromatin profiling and high-resolution 3C methods we show that enhancer heterogeneity drives gene expression differences.

Degradation of LMO2 in T cell leukaemia results in collateral breakdown of transcription complex partners and causes LMO2-dependent apoptosis
https://www.biorxiv.org/content/10.1101/2024.12.09.627495v2

Targeting the intrinsically disordered transcription factor LMO2, a driver in T-ALL, this work develops intracellular antibody-based biodegraders and small-molecule PROTACs that induce selective LMO2 degradation. Loss of LMO2 disrupts associated bHLH partners, impairing leukemia cell growth and triggering apoptosis.

IL-17A primes an early progenitor compartment to tune the erythropoietic feedback circuit
https://www.biorxiv.org/content/10.1101/2024.12.16.628761v1?rss=1

This study looks at erythropoiesis and the role of IL-17A: it synergizes with erythropoietin (Epo) to accelerate red blood cell production in response to hypoxia. Through both modeling and in vivo data, IL-17A is shown to sensitize progenitors to Epo, enabling a rapid response with minimal steady-state burden—illustrating a cytokine-driven mechanism for adaptive homeostatic tuning.

Reactivation of developmentally silenced globin genes through genomic deletions reveals that enhancer distance matters
https://www.biorxiv.org/content/10.1101/2025.01.13.632719v1?rss=1

This study reveals that linear genomic distance from enhancers can actively contribute to gene silencing. Deletion or inversion of intervening sequences repositions distal globin enhancers closer to silenced embryonic promoters, reactivating HBG and HBZ expression in adult erythroid cells, and highlighting the functional importance of non-regulatory DNA in insulating genes from inappropriate enhancer activation.

In vivo deletion of a GWAS-identified Myb distal enhancer acts on Myb expression, globin switching, and clinical erythroid parameters in β-thalassemia
https://www.biorxiv.org/content/10.1101/2025.01.17.633540v1?rss=1

Focusing on GWAS variants linked to erythroid traits, this study validates the functional relevance of the conserved MYB -81kb enhancer using a knockout mouse model. Disruption of this enhancer alters MYB expression and modulates erythropoiesis and disease severity in beta-thalassemia, providing in vivo evidence that non-coding variants near MYB can influence globin switching and red cell phenotypes.

TECH WATCH AND MODELING  

Human mitochondrial transfer modeling reveals biased delivery from mesenchymal-to-hematopoietic stem cells
https://www.biorxiv.org/content/10.1101/2025.01.06.631461v1?rss=1

This study introduces iMSOD-mito, an immortalized human MSC line with an inducible mitochondrial tag, enabling the modeling of mesenchymal-to-hematopoietic mitochondrial transfer. The research demonstrates high transfer rates, preferentially to hematopoietic stem cells, and reveals functional impacts such as enhanced mitochondrial membrane potential and ROS production, suggesting a role in HSPC quiescence. 

A prime editing strategy to rewrite the γ-globin promoters and reactivate fetal hemoglobin for sickle cell disease
https://www.biorxiv.org/content/10.1101/2025.01.13.632780v1?rss=1

From the authors: Fetal hemoglobin (HbF) reactivation is a promising therapy for β-hemoglobinopathies. We developed a prime editing strategy that introduces multiple mutations in the fetal γ-globin promoters of patients’ HSPCs, boosting HbF expression and offering alternative therapeutic perspectives.

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.