Preprint Watch: June

 

Welcome to the Preprint Watch, where we highlight some of the latest and most interesting preprints for the ISEH community. In this issue, we’re highlighting preprints of note from June. If you'd like to submit your preprint, please complete this brief form. 

STEM AND PROGENITOR CELLS BIOLOGY 

Hematopoietic stem cells undergo bidirectional fate transitions in vivo
https://www.biorxiv.org/content/10.1101/2025.02.23.639689v2

From the authors: Sequential introduction of DNA barcodes in vivo was developed to assess time-dependent changes in cell fate. Clonal phylogenetic tracer (CP-tracer) enabled high-resolution phylogenetic analysis of ∼100,000 subclones derived from ∼500 individual hematopoietic stem cells (HSC). Bidirectional fate transitions between myeloid-biased haematopoietic stem cells (My-HSCs) and lineage-balanced haematopoietic stem cells (balanced-HSCs) were observed. Hhex was identified as a molecular driver of HSC lymphoid competence.

GATA2 Mediates Macrophage Proliferation During Atherosclerosis
https://www.biorxiv.org/content/10.1101/2025.02.18.638845v1?rss=1

In this study, the authors identified a subset of proliferating macrophages in human atherosclerotic plaques that express the transcription factor GATA2. These cells showed a gene expression profile intermediate between monocytes and mature macrophages, with upregulation of proliferation and survival pathways. GATA2 was both necessary and sufficient for macrophage proliferation, acting through MYB induction and reduced apoptosis sensitivity, linking atherogenic stimuli to transcriptional control of cell proliferation.

Divergent granulopoiesis at extramedullary sites safeguards host defense
https://www.biorxiv.org/content/10.1101/2025.02.25.638781v1?rss=1

The authors show that during persistent inflammation, the spleen engages in stress-induced granulopoiesis, producing neutrophils along distinct and accelerated differentiation pathways. Despite their immature phenotype, these splenic neutrophils are functionally competent and essential for controlling bacterial infections. Type I interferon signaling is critical for this process, highlighting the spleen's role as a site of rapid, functional neutrophil production under inflammatory stress.

Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, fitness, and clonal structure
https://www.biorxiv.org/content/10.1101/2025.02.28.640879v2

The authors explored how clonal fitness shapes the clinical impact of clonal hematopoiesis (CH). By analyzing over 2,000 observations from three longitudinal cohorts, they revealed that clonal dynamics are influenced by mutation timing, pathway-specific fitness, and clonal composition. They developed MACS120, a predictive metric that integrates these factors, outperforming traditional measures in forecasting clonal growth and associated health risks, thereby offering a standardized framework for understanding and potentially managing CH-related diseases.

Stathmin 1 regulates mitophagy and cellular function in hematopoietic stem cells
https://www.biorxiv.org/content/10.1101/2025.03.10.642434v1?rss=1

From the authors: The microtubule-regulating protein Stathmin 1 is highly expressed in HSPCs and promotes normal microtubule architecture. Loss of Stathmin 1 in HSPCs leads to impaired autophagy with abnormal mitochondrial morphology, decreased respiratory capacity, and impaired cellular function.

Coordinated changes in thymic stromal and hematopoietic cells that define the perinatal to juvenile transition
https://www.biorxiv.org/content/10.1101/2025.03.04.641047v1?rss=1

To understand how the thymic microenvironment shapes T cell development in early life, the authors profiled stromal cell populations in the mouse thymus from birth to one month of age. Using single-cell transcriptomics, flow cytometry, and histology, they uncovered age-specific shifts in thymic epithelial, mesenchymal, endothelial, and antigen-presenting cell compartments, mirrored in human samples. These changes included reduced IGF2 expression, RB pathway activation, and increased type I interferon signaling.


PATHOLOGICAL HEMATOPOIESIS 

CCRL2 promotes the interferon-γ signaling response in myeloid neoplasms with erythroid differentiation and mutated TP53
https://www.biorxiv.org/content/10.1101/2025.02.21.639304v1?rss=1

From the authors: CCRL2 is overexpressed in AML with loss-of-function TP53 mutations and erythroid differentiation and promotes IFN-γ signaling response via a cell-intrinsic mechanism.

Computational investigation unveils pathogenic LIG3 non-synonymous mutations and therapeutic targets in acute myeloid leukemia
https://www.biorxiv.org/content/10.1101/2025.02.22.639676v1?rss=1

The authors used in-silico approaches to identify and characterize deleterious non-synonymous SNPs (nsSNPs) in the LIG3 gene, which is implicated in genomic instability and cancer, particularly AML. Among 132 coding-region nsSNPs, 18 were found to significantly impact protein function, with mutations like R528C showing altered stability and ligand interactions. Molecular docking and dynamics highlighted DM-BFC as a promising compound targeting both wild-type and mutant LIG3.

Systemic MIF facilitates chronic lymphocytic leukemia development independent of its cellular source
https://www.biorxiv.org/content/10.1101/2025.02.22.639632v1?rss=1

From the authors: CLL cells failed to establish disease in Mif-deficient hosts due to impaired tissue homing. Conditional deletion of Mif in B lymphoid- or myeloid cells did not significantly impact CLL progression in vivo. Systemic MIF is critical for CLL pathogenesis, independent of its cellular source

Single-cell profiling of human bone marrow reveals multiple myeloma progression is accompanied by an increase in CD56bright bone marrow resident NK cells
https://www.biorxiv.org/content/10.1101/2025.02.26.640356v1?rss=1

The authors investigated how natural killer (NK) cells evolve during multiple myeloma (MM) progression, focusing on their role in immune surveillance. Analysis of patient bone marrow samples revealed an expansion of CD56bright NK cells correlated with tumor burden. Single-cell RNA sequencing further identified a bone marrow–specific CD56bright-like NK cell population enriched in MM patients, suggesting these cells may contribute to immune evasion through reduced cytotoxic function.

Hierarchical Lineage Tracing Reveals Diverse Pathways of AML Treatment Resistance
https://www.biorxiv.org/content/10.1101/2025.02.27.640600v2

The authors introduce FLARE, a dynamic lineage tracing method designed to map how cancer cell populations evolve under treatment pressure. Applying FLARE to AML models exposed to Cytarabine, they uncover resistant lineages marked by enhanced adhesion, motility, and heritable expression of immunoproteasome subunits that support survival and immune evasion. These resistance signatures were validated in patient data.

Targeting CD38 effectively prevents myelofibrosis in myeloproliferative neoplasms
https://www.biorxiv.org/content/10.1101/2025.03.02.639410v1?rss=1

From the authors: CD38-overexpressing monocytes are increased in MF murine models and MPN patients progressing to fibrotic-phase disease. Restoring intracellular NAD+ levels using the CD38 inhibitor 78c prevented the development of fibrotic-phase disease in MPN murine models.

Lactate dehydrogenase A-coupled NAD+ regeneration is critical for acute myeloid leukemia cell survival
https://www.biorxiv.org/content/10.1101/2025.03.03.641255v1?rss=1

The authors investigated the glycolytic dependency of acute myeloid leukemia (AML) cells, focusing on the role of lactate dehydrogenase A (LDHA). They found that LDHA levels strongly correlate with glycolytic activity in AML, and its inhibition selectively impairs leukemic cell survival by disrupting NAD⁺ recycling and metabolic homeostasis. Restoring NAD⁺ balance rescued AML cells from LDHA inhibition, underscoring LDHA’s role in sustaining glycolysis.

Granulocyte-derived Resistin Inhibits Monocyte Maturation and Induces Immune Suppression in CMML
https://www.biorxiv.org/content/10.1101/2025.03.03.640303v1?rss=1

The authors investigated the role of granulocytes in chronic myelomonocytic leukemia (CMML) and uncovered their contribution to disease progression through the production of the inflammatory mediator resistin (RETN). CMML granulocytes showed impaired maturation and function, alongside strong upregulation of RETN, leading to elevated plasma levels associated with poor prognosis. Functionally, RETN impaired monocyte maturation, promoted immunosuppressive phenotypes, and altered T cell polarization via SEMA4A.

Novel Pan-ALDH Inhibitor KS100 Effectively Targets ALDH+/CD138⁻ Stem-like Cells to Overcome Relapse in Multiple Myeloma
https://www.biorxiv.org/content/10.1101/2025.03.06.641909v1?rss=1

The authors investigated relapse in multiple myeloma (MM), focusing on stem-like ALDH⁺/CD138⁻ cells suspected to drive treatment resistance. They tested KS100, a novel pan-ALDH inhibitor, and found it effectively reduced ALDH expression, viability, and stemness-associated proteins in both regular and bortezomib-resistant MM cells. 

DNA replication stress-induced transcriptome of Human Burkitt’s lymphoma identifies MBD1 as a novel suppressor of BCL6 rearrangements in germinal center derived B-lymphomagenesis
https://www.biorxiv.org/content/10.1101/2025.03.13.643172v1?rss=1

From the authors: MBD1 suppresses BCL6 expression under the DNA replication stress. MBD1 suppresses genomic instability at BCL6 translocation hotspots. MBD1 depletion is associated with reduced tumorigenicity in mouse xenograft and sensitivity to DNA replication inhibitors.


MOLECULAR HEMATOPOIESIS 

SUGP1 loss is the sole driver of SF3B1 hotspot mutant missplicing in cancer
https://www.biorxiv.org/content/10.1101/2025.02.17.638713v1?rss=1

The authors investigated how oncogenic SF3B1 mutations induce splicing defects by computationally screening 600 splicing-related proteins. They identified that loss of SUGP1, a G-patch protein, replicates nearly all splicing abnormalities seen in SF3B1-mutant cells, while  RNA helicase Aquarius (AQR) knockdown mimics only a subset, and indirectly, as it destabilizes SUGP1. These findings clarify the mechanistic basis of SF3B1-driven missplicing and underscore the central role of SUGP1 in this process.

Precursor RNA structural patterns at SF3B1 mutation sensitive cryptic 3’ splice sites
https://www.biorxiv.org/content/10.1101/2025.02.19.638873v1?rss=1

This study identifies 192 core splice junctions mis-spliced due to the common SF3B1 K700E mutation, distinguishing them from SF3B1-resistant cryptic sites by sequence and structural features. SF3B1-sensitive cryptic 3’ splice sites tend to lie within extended polypyrimidine tracts, have weaker splice site strength scores, and exhibit greater structural flexibility and less distinction from canonical sites. These unique sequence and RNA structural properties likely underlie altered 3’ splice site recognition caused by SF3B1 mutation, advancing understanding of splicing dysregulation in blood disorders.

TET dioxygenases localize at splicing speckles and promote RNA splicing
https://www.biorxiv.org/content/10.1101/2025.03.07.641893v1?rss=1

From the authors: TET1 localizes in splicing speckles in an RNA-dependent manner. TET proteins, especially TET1, interact with the splicing factors U2AF1 and U2AF2. TET proteins increase splicing efficiency, independent of their catalytic activity. RNA 5-methylcytosine (m5C) oxidation to 5-hydroxymethylcytosine (hm5C) restores splicing efficiently in vitro.


TECH WATCH AND MODELING  

comBO: A combined human bone and lympho-myeloid bone marrow organoid for pre-clinical modelling of haematopoietic disorders
https://www.biorxiv.org/content/10.1101/2025.02.16.638505v1?rss=1

The authors present comBOs, a next-generation human bone marrow organoid model that integrates osteolineage, vascular, lymphoid, and myeloid components derived from iPSCs. Cultured in a granular microgel scaffold under physiologically relevant conditions, comBOs support the creation of “chimeroids” that incorporate healthy or diseased adult cells, enabling faithful modeling of human hematopoietic microenvironments. 

Automatic computational classification of bone marrow cells for B-cell pediatric leukemia using UMAP
https://www.biorxiv.org/content/10.1101/2025.03.03.641130v1

The authors applied Uniform Manifold Approximation and Projection (UMAP) to flow cytometry data from 75 pediatric B-ALL patients to improve disease monitoring and prognosis. By analyzing 234 samples across diagnosis and treatment timepoints, UMAP enabled automated classification of B cell maturation states and detection of distinct bone marrow regeneration patterns between relapsed and non-relapsed cases. This study demonstrates the potential of UMAP to enhance flow cytometry analysis, offering a standardized, data-driven approach for tracking B-ALL progression and relapse risk.

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.