Preprint Watch: December

 

Read the last monthly trawl for 2024! We have one preprint, straight from our Community, plus no less than 17 other preprints! Remember, if you want your preprint highlighted here, send it to us using this form!

From the Simply Blood Community:

A rare HSC-derived megakaryocyte progenitor accumulates via enhanced survival and contributes to exacerbated thrombopoiesis upon aging
https://www.biorxiv.org/content/10.1101/2024.11.04.621964v1 

This study identifies an age-dependent, non-canonical pathway for megakaryocyte progenitor (MkP) and platelet production directly from hematopoietic stem cells (HSCs), generating hyperactive platelets linked to age-related thrombotic risks. Single-cell analyses reveal that these non-canonical MkPs exist in both young and aged mice, but aged MkPs exhibit enhanced survival and platelet production, highlighting functional and aging-dependent heterogeneity in megakaryopoiesis.

Learn more about this preprint by contacting Bryce Manso at bmanso@ucsc.edu.

STEM AND PROGENITOR CELLS BIOLOGY

Developmental regulation of endothelial-to-hematopoietic transition from induced pluripotent stem cells
https://www.biorxiv.org/content/10.1101/2024.09.24.612755v1

This study maps single-cell EHT dynamics and identifies that inhibiting FGF signaling during EHT improves hematopoietic output in both zebrafish and iPSC systems. Those increased numbers are obtained through the repression of endothelial genes.

Differential responses and recovery dynamics of HSPC populations following Plasmodium chabaudi infection
https://www.biorxiv.org/content/10.1101/2024.09.25.614952v1

Severe infections like malaria deplete the most functional HSPCs during the acute phase, while expanding multipotent progenitors and reducing oligopotent progenitors. The authors observed that upon pathogen clearance, HSPCs recover through distinct patterns, with more restricted proliferative capacity as cells differentiate, highlighting their adaptive response to infection.

No evidence of immunosurveillance in mutation-hotspot driven clonal haematopoiesis
https://www.biorxiv.org/content/10.1101/2024.09.27.615394v1

This study investigates whether T-cell immunosurveillance imposes selective pressure on pre-cancerous clones in clonal hematopoiesis (CH) by analyzing the association between MHC variant binding and the CH risk. Despite predicting MHC binding affinity for 40 known CH hotspot variants in a large UK Biobank cohort, the research found no significant associations between MHC binding and CH prevalence or clone size, indicating that immunosurveillance may have a limited role in influencing the genetic diversity of blood cell mutations.

Loss of Ing4 enhances hematopoietic regeneration in multipotent progenitor cells
https://www.biorxiv.org/content/10.1101/2024.09.27.615522v1

This study identifies the tumor suppressor Inhibitor of Growth 4 (Ing4) as a crucial regulator of multipotent progenitor (MPP) homeostasis in hematopoiesis. In the absence of Ing4, MPPs exhibit a transcriptional activation program while remaining quiescent, demonstrating enhanced regeneration capacity after competitive bone marrow transplantation.

Medium-dose irradiation impairs long-term hematopoietic stem cell functionality and hematopoietic recovery to cytotoxic stress
https://www.biorxiv.org/content/10.1101/2024.10.29.620607v1?rss=1
Irradiation and 5-fluorouracil (5-FU) treatment are classic cytotoxic stress used in experimental hematology. This study examined the long-term impacts of medium-dose ionizing radiation (MDIR) and 5-FU on hematopoietic stem cells (HSCs), finding that MDIR, unlike 5-FU, causes lasting impairments in HSC function and depletes a high self-renewal HSC subset. Additionally, MDIR significantly weakens hematopoietic recovery after subsequent 5-FU treatment, emphasizing key differences in their effects on the hematopoietic system.

LEUKEMIA AND PATHOLOGICAL HEMATOPOIESIS

Genomic Discovery of EF-24 Targets Unveils Antitumorigenic Mechanisms in Leukemia Cells
https://www.biorxiv.org/content/10.1101/2024.10.14.618197v1?rss=1

Authors report that curcumin analog EF-24 shows enhanced anticancer properties, significantly reducing leukemia cell viability by upregulating genes associated with decreased proliferation. Whole-transcriptome profiling reveals that EF-24 activates pathways like STAT1 and S100 family signaling, suggesting its potential as an effective therapeutic agent in targeting survival and immune response mechanisms in myeloid leukemia cells.

The long non-coding RNA FAM30A regulates the Musashi2-RUNX1 axis and is required for LSC function in AML cells
https://www.biorxiv.org/content/10.1101/2024.10.13.618058v1?rss=1

This study describes how the long non-coding RNA (lncRNA) FAM30A promotes leukemic stem cell activity in AML, by interacting with MSI2 and enhancing RUNX1 expression, contributing to stemness, chemoresistance, and xenograft engraftment. Targeting the FAM30A-MSI2-RUNX1 pathway could offer therapeutic potential for eliminating LSCs and improving outcomes in AML patients.

The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia
https://www.biorxiv.org/content/10.1101/2024.09.24.614781v1

Oncogenic growth in AML is resistant to proteasome inhibitors due to the activation of alternative proteostasis pathways. By inactivating HSF1 or combining autophagy and proteasome inhibition, AML cells can be sensitized, reducing proliferation and survival, slowing disease progression, and selectively targeting AML stem cells without affecting normal hematopoietic cells.

Dual Specificity Phosphatase 3 knockdown drives myeloid leukemia cells to differentiate into macrophages and polarize
https://www.biorxiv.org/content/10.1101/2024.09.30.615030v1

This study explores the role of dual-specificity phosphatase 3 (DUSP3) in the differentiation of acute myeloid leukemia (AML) cell lines lacking p53, highlighting its interaction with nucleophosmin (NPM). 

Metabolic vulnerabilities in Down syndrome B-cell acute lymphoblastic leukemia can be targeted using Venetoclax
https://www.biorxiv.org/content/10.1101/2024.09.30.615872v1

Children with Down syndrome (DS) and B-cell acute lymphoblastic leukemia (B-ALL) exhibit altered metabolism and mitochondrial function, making them more responsive to Venetoclax treatment compared to non-DS and Philadelphia chromosome-like B-ALL. Venetoclax, especially when combined with Trametinib or glucose metabolism inhibitors, shows promise in treating DS B-ALL.

Mutant IDH uncouples p53 from target gene regulation to disable tumor suppression

https://www.biorxiv.org/content/10.1101/2024.09.30.615916v1

(from the Authors): We find that chromatin states altered by cancer-associated IDH mutations intersect with transcriptional regulation of p53 target genes. This reversible interaction may represent a strategy to reinvigorate latent tumor suppression in IDH mutant, p53 wild-type tumors.

Heterogeneity in chromatin structure drives core regulatory pathways in B-cell Acute Lymphoblastic Leukemia

https://www.biorxiv.org/content/10.1101/2024.10.04.616668v1

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, classified into distinct subtypes based on gene expression, which correlate with different disease outcomes. This study reveals that B-ALL’s 3D genome organization mirrors arrested B-cell developmental stages, with chromatin interactions influencing gene expression and driving disease progression.

MOLECULAR HEMATOPOIESIS

RNA Binding Protein Khdrbs1 Regulates Hematopoietic Stem and Progenitor Cell Emergence via Splicing
https://www.biorxiv.org/content/10.1101/2024.11.01.621494v1?rss=1

This study reveals that alternative splicing, regulated by Khdrbs1 RNA-binding proteins, is critical for endothelial-to-hematopoietic transition (EHT) and definitive hematopoietic stem and progenitor cell (HSPC) formation in zebrafish. Mutagenesis of khdrbs1a/b disrupted HSPCs and lineage differentiation, while splicing modulation restored HSPC levels, highlighting splicing regulation as a key mechanism in EHT and cell fate determination.

HIRA-SETDB1-H3K9me3 axis regulate chromatin architecture in chronic myeloid leukemia cells
https://www.biorxiv.org/content/10.1101/2024.11.01.621462v1?rss=1

The authors identify a key role for the HIRA-SETDB1-H3K9me3 axis in regulating chromatin architecture and cellular behavior in Chronic Myeloid Leukemia (CML) cells. Downregulation of HIRA in CML cells leads to increased chromatin compaction, mediated by elevated SETDB1 expression and H3K9me3 levels, resulting in reduced proliferation and enhanced differentiation, offering potential targets for therapeutic intervention.

IKAROS facilitates antigen escape in the face of CD19- and CD22-targeted therapies for B-cell acute lymphoblastic leukemia
https://www.biorxiv.org/content/10.1101/2024.11.01.621347v1?rss=1

Here the authors describe how IKAROSlow B-ALL cells, resembling progenitor cells with lower B-cell commitment, are associated with CD19-negative relapse and exhibit resistance to CD19- and CD22-targeted therapies. IKAROS modulates CD19 and CD22 surface expression in a dose-dependent and reversible manner, influencing therapeutic outcomes.

TECH WATCH AND MODELING
Reconstructing signaling history of single cells with imaging-based molecular recording
https://www.biorxiv.org/content/10.1101/2024.10.11.617908v1

The authors present a method called INSCRIBE: a new approach that reconstructs signaling history in single cells using endpoint fluorescence images by linking CRISPR base editing to signaling activity. This study demonstrated that INSCRIBE accurately captures the intensity and duration of WNT and BMP pathway activity, revealing persistent memory in the BMP pathway where the progeny of cells with higher response levels retain stronger responses to subsequent stimulation weeks later.

Single-Nuclei Analysis of the Unfolded Protein Response (SNUPR): A Novel Method revealing bortezomib resistance mechanisms in Multiple Myeloma
https://www.biorxiv.org/content/10.1101/2024.10.22.617161v1?rss=1

The unfolded protein response (UPR) is a stress pathway linked to cancer chemotherapy efficacy, but its complex, cell-specific activation patterns are challenging to track. In this study, Arguello and colleagues developed SNUPR, a method for profiling UPR dynamics at the single-cell level, revealing that specific UPR branches like IRE-1/XBP1s can influence chemotherapy resistance. This method can offer insights for targeted cancer treatments.

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.