16 Genetic Variation in CH progression
Genetic variation can protect 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?
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?
To identify protective effects, we conducted a GWAS meta-analysis of CH across population biobanks. Sankaran Lab (Agarwal et al. 2025) 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.
We dug deeper, uncovering rs17834140 as the likely causal variant at 17q22 – located in a regulatory element selectively active in HSCs – the cell type of origin in CH!
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 microdeletion, showing natural germline variation protects from CH by reducing MSI2 levels in human HSCs.
MSI2 is an RNA-binding protein regulating 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.
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 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.
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 CH clones, implicating MSI2 levels as a modifier of HSC fitness.
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.
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.
Excitingly our work provides human genetic evidence supporting inhibition of MSI2 (or its downstream targets) as rational approaches to enable blood cancer prevention. More broadly, we hope this will inspire further efforts to decode and leverage natural cancer resilience.