Our findings uncover a germline mechanism directly protecting HSCs from blood cancers, by altering a post-transcriptional RNA network through reduced MSI2 levels, which attenuates the fitness advantage of CH. (12/n)

Moreover, we show in experimental models that reducing MSI2 levels protects human HSCs from phenotypic expansion in ASXL1-mutant CH, whilst MSI2 overexpression cooperates with Asxl1-/- in mouse models to induce myelodysplastic syndrome. (11/n)

Can rs17834140 protect from CH? In collaboration with @AlexBickMDPhD @yash_pershad, we show in a longitudinal cohort that rs17834140-T is associated with slower CH expansion rates, and predicts transience of large CH clones, implicating MSI2 levels as a modifier of HSC fitness. (10/n)

… thereby uncovering a network of MSI2-regulated mRNAs that are highly translated in human HSCs, and downregulated with inherited CH resilience. Strikingly, these mRNAs are reciprocally upregulated in TET2-CH, and enriched expression predicts poor prognosis in AML. (9/n)

So how does reduced MSI2 protect HSCs from blood cancers? In collaboration with @KharasLab, we mapped direct mRNA binding targets of MSI2 in human HSCs. Remarkably, the majority of MSI2-bound mRNAs were downregulated in CH-resilient HSCs with reduced MSI2 levels… (8/n)

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)

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)

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)

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)

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)

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)

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...