Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis.

ABSTRACT: Myelofibrosis is a rare myeloproliferative neoplasm (MPN) with high risk for progression to acute myeloid leukemia. Our integrated genomic analysis of up to 933 myelofibrosis cases identifies 6 germline susceptibility loci, 4 of which overlap with previously identified MPN loci. Virtual karyotyping identifies high frequencies of mosaic chromosomal alterations (mCAs), with enrichment at myelofibrosis GWAS susceptibility loci and recurrently somatically mutated MPN genes (e.g., JAK2). We replicate prior MPN associations showing germline variation at the 9p24.1 risk haplotype confers elevated risk of acquiring JAK2^V617F mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2

SUBMITTER: Brown DW 

PROVIDER: S-EPMC9458655 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature