Preprint Watch: October
This month, we're excited to introduce a new series on Simply Blood, where we'll highlight preprints relevant to the ISEH community. We hope you find it engaging, and we welcome any feedback you'd like to share! If there's a specific preprint you enjoyed and would like to see featured, please send it to us using this form!
STEM AND PROGENITOR CELLS BIOLOGY
Fetal Liver-like Organoids Recapitulate Blood-Liver Niche Development and Multipotent Hematopoiesis from Human Pluripotent Stem Cells
https://www.biorxiv.org/content/10.1101/2024.10.11.617794v1?rss=1
Human Fetal Liver-like Organoids (FLOs) recreate the hepato-hematopoietic interactions of fetal liver development, establishing a niche that supports hematopoietic progenitor differentiation without external factors. In this paper, Rezvani and colleagues show that FLOs can model the integration of hematopoietic and hepatic lineages, showcasing multipotent progenitors with myeloid lineage bias and the potential for fetal B and T cell differentiation.
Single-cell and in situ spatial analyses reveal the diversity of newly born hematopoietic stem cells and of their niches
https://www.biorxiv.org/content/10.1101/2024.10.14.618250v1?rss=1
Using zebrafish embryos, this study identified at least two distinct EHT cell types from the aorta, each giving rise to differently fated hematopoietic cells, with variations in thymus colonization and T-lymphoid lineage commitment. Transcriptomic profiling of these cells uncovered diverse progeny, including NK-like cells and eosinophils, and revealed a previously unknown niche, from which the author can isolate HSPCs with adult HSC signatures.
Type 1 interferon perturbates clonal competition by reshaping human blood development
https://www.biorxiv.org/content/10.1101/2022.09.28.509751v2
Inflammation influences HSC clonal dynamics in myeloproliferative neoplasms (MPN), with IFN⍺ treatment inducing polarized HSC states: one supporting lymphoid progenitor expansion and another creating inflammatory granulocytic progenitors (IGPs). The authors demonstrate that in essential thrombocythemia (ET), one type of MPN, this lymphoid shift counteracts myeloid bias, though clonal stem cells resist differentiation into IGPs, highlighting inflammation’s role in altering clonal evolution.
LEUKEMIA AND PATHOLOGICAL HEMATOPOIESIS
The fetal specific gene LIN28B is essential for human fetal B-lymphopoiesis and initiation of KMT2A::AFF1 infant leukemia
https://www.biorxiv.org/content/10.1101/2024.09.18.613730v1.full.pdf+html
This study identifies LIN28B as a crucial factor in fetal hematopoietic stem/progenitor cells that promotes leukemic transformation and aggressiveness. Additional work suggest that LIN28B could be a potential therapeutic target in LIN28B-expressing iALL (infant Acute Lymphoblastic Leukemia)
Loss of the Inv(16) Oncogene CBFB::MYH11 Eliminates Leukemia from the Blood and Spleen, but not the Bone Marrow
https://www.biorxiv.org/content/10.1101/2024.10.06.616896v1
Using a knock-in mouse model, this work focused on the CBFB::MYH11 fusion gene (CM, resulting from chromosome 16 inversion). The authors showed that chromosome 16 inversion is essential for leukemia cell survival in blood and spleen, but not in bone marrow, where cells can persist and cause relapse without it. Experimental knockdown showed that while CM loss reduces leukemia cells in peripheral sites, bone marrow cells can survive and re-establish the disease independently.
A Distinct Alternative mRNA Splicing Profile Identifies the Oncogenic CD44 Transcript Variant 3 in KMT2A-Rearranged Pediatric T-cell Acute Lymphoblastic Leukemia Cells
https://www.biorxiv.org/content/10.1101/2024.09.05.611385v1
In pediatric T-ALL, KMT2A rearrangements are linked to poor prognosis and are associated with distinct gene and splice variant patterns, including upregulated pro-survival BCL2 variants and an oncogenic transcript of CD44, called CD44v3. This work suggests that CD44v3 could be a potential marker for risk stratification and a therapeutic target in KMT2A-rearranged T-ALL.
Leukemia-derived apelin selects endothelial niche clones to promote tumorigenesis
https://www.biorxiv.org/content/10.1101/2024.09.09.612077v1
This study reveals that leukemic cells expand niche endothelial and stromal cell clones in the Zebrafish bone marrow by secreting the pro-angiogenic peptide apelin, which promotes clonal selection and transcriptional changes in endothelial cells. Knocking out apelin significantly reduces disease progression, indicating that targeting apelin could serve as a potential target.
MOLECULAR HEMATOPOIESIS
Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors
https://www.biorxiv.org/content/10.1101/2024.09.16.613227v2
In this work, Karatepe and colleagues describe how linker histone H1.0 regulates HSPC differentiation by promoting lymphoid over myeloid fate, reducing chromatin accessibility at myeloid gene regions. Interferon alpha signaling decreases H1.0 in HSPCs through aspartyl protease activity, but inhibiting these proteases preserves H1.0 and supports lymphoid differentiation, offering a potential strategy to counter myeloid skewing.
Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q
https://www.biorxiv.org/content/10.1101/2024.09.11.611224v1
(from the preprint) Statement of significance This study examines the consequences of structural alterations and demonstrates that proto-oncogene activation by enhancer hijacking is an overlooked pathomechanism in AML. MNX1 overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency, but also to activation of oncogenes by enhancer hijacking, providing a novel leukemogenic mechanism.
RPS19 and RPL5, the most commonly mutated genes in Diamond Blackfan anemia, impact DNA double-strand break repair
https://www.biorxiv.org/content/10.1101/2024.10.10.617668v1
Diamond Blackfan anemia (DBA), caused by pathogenic variants in ribosomal protein genes like RPS19 and RPL5, increases cancer risk, though the mechanisms are unclear. Here the authors show that defects in DNA double-strand break repair in DBA cells, influenced by RPS19 and RPL5, likely contribute to this cancer predisposition, with these proteins playing distinct roles in DNA repair pathways.
TECH WATCH AND MODELING
Quantitative phase imaging with temporal kinetics predicts hematopoietic stem cell diversity
https://www.biorxiv.org/content/10.1101/2024.09.29.615639v1?rss=1
Advances in hematopoietic stem cell (HSC) identification have been limited by single snapshot analyses, missing temporal dynamics. This study introduces a Quantitative Phase Imaging (QPI)-driven machine learning approach, able to predict HSC diversity and stemness in real-time and capturing temporal heterogeneity for improved accuracy.
Advancing Variant Phenotyping in Myelodysplastic Syndromes via Computational Genomics of Mitochondrial Enzyme Complexes
https://www.biorxiv.org/content/10.1101/2024.09.04.611279v1
Recurrent mitochondrial DNA mutations in myelodysplastic syndromes (MDS) are linked to patient outcomes post-transplant, though their mechanisms remain unclear. This study uses computational structural genomics to analyze these mutations, revealing enhanced insights into their pathogenicity and setting the stage for translating mitochondrial biology into clinical applications.
Merging logical models: An application in Acute Myeloid Leukemia modeling
https://www.biorxiv.org/content/10.1101/2024.09.13.612961v1
This study integrates individual gene regulatory network (GRN) models into comprehensive models, to enhance the understanding of Acute Myeloid Leukemia (AML). By merging these models, the approach maintains accuracy while improving coverage of biological processes, providing insights into the underlying pathological mechanism.
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