What protects individuals from developing blood cancers? Thrilled to share my work in @bloodgenes.bsky.social lab, describing inherited resilience protecting blood stem cells from clonal hematopoiesis by modifying RNA regulation. 🧵👇 (1/n) www.biorxiv.org/content/10.1... - ThreadSky

g-agarwal.bsky.social • 27 days ago

What protects individuals from developing blood cancers?

Thrilled to share my work in @bloodgenes.bsky.social lab, describing inherited resilience protecting blood stem cells from clonal hematopoiesis by modifying RNA regulation. 🧵👇 (1/n)
https://www.biorxiv.org/content/10.1101/2025.03.24.645017v1

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g-agarwal.bsky.social•27 days ago

Genetic variation protects some individuals from disease. Understanding natural resilience has enabled therapeutic development – e.g., BCL11A suppression for sickle cell disease and PCSK9 inhibition to reduce cardiovascular risk. Are there such opportunities for blood cancers? (2/n)

g-agarwal.bsky.social•27 days ago

Blood cancers are preceded by somatic mutations that drive expansion of hematopoietic stem cells (HSCs) – termed “clonal hematopoiesis” (CH). But CH also occurs ubiquitously in adults – so why do some progress to blood cancers, and others remain protected? (3/n)

g-agarwal.bsky.social•27 days ago

To identify protective effects, we conducted a GWAS meta-analysis of CH across population biobanks. We identified germline variation at the 17q22 locus associated with robust resilience to CH [OR=0.84] and myeloid malignancies [OR=0.80] in the population. (4/n)

g-agarwal.bsky.social•27 days ago

We dug deeper, uncovering rs17834140 as the likely causal variant at this locus – located in a regulatory element active selectively in HSCs – the cell type of origin in CH! We set out to mechanistically understand how rs17834140 modulates HSCs to confer blood cancer resilience. (5/n)

g-agarwal.bsky.social•27 days ago

Through variant-to-function mapping, we show that rs17834140-T protects from CH through loss-of-function at an MSI2 enhancer. We model variant effect through CRISPR microdeletions, showing natural germline variation can protect from CH through reducing MSI2 levels in human HSCs. (6/n)

g-agarwal.bsky.social•27 days ago

MSI2 is an RNA-binding protein that regulates stem cells – but can downtuning its levels alter HSCs functionally? Yes! Genetic variation-driven loss of the MSI2 enhancer partially phenocopies complete MSI2-KO, reducing HSC maintenance and multilineage engraftment in xenografts. (7/n)

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