2002 – GENETIC PREDISPOSITION TO MYELOPROLIFERATIVE NEOPLASMS IMPLICATES HEMATOPOIETIC STEM CELL BIOLOGY

Inherited genetic variants substantially contribute to the risk of myeloproliferative neoplasms (MPNs), a type of blood cancer that arise in the hematopoietic stem cell (HSC) compartment. To identify the germline genetic factors and underlying mechanisms predisposing to MPNs, we conducted a genome-wide association study involving 3,797 MPN cases and 1,152,977 controls and identified 17 genome-wide significant loci. We find an enrichment for risk variants mapping to accessible chromatin in HSCs, an association between MPN risk and multi-lineage blood cell traits, an association with longer leukocyte telomere length, and a significant genetic correlation with predisposition to clonal hematopoiesis of indeterminate potential. Collectively, all of these findings implicate HSC function and self-renewal. In addition to these global studies, we performed in depth mechanistic studies at one locus located ∼12kb downstream of the transcription factor GFI1B. Fine-mapping analyses and reporter assays identified rs524137 as the likely causal variant with the risk allele decreasing hematopoietic reporter activity. Endogenous deletion of the 1.6 kb enhancer region harboring this variant with Cas9 ribonucleoproteins in adult human hematopoietic stem and progenitor cells (HSPCs) resulted in ∼65% editing with a 36% reduction in GFI1B expression. Furthermore, deletion of GFI1B enhancer improved the maintenance of phenotypic HSCs during a 7-day HSPC culture and increased progenitor self-renewal capacity in colony replating assays. Interestingly, deletion of this enhancer only affected HSPC function without disruption of erythropoiesis, an independent effect observed with GFI1B coding perturbation. These results and our ongoing studies demonstrate that the GFI1B MPN risk locus expands HSPCs and reinforces this general mechanism as a risk factor for MPN acquisition.