Faculty Collaboration Database

Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis. Nat Commun 2022 Sep 08;13(1):5284

Date

09/09/2022

Pubmed ID

36075929

Pubmed Central ID

PMC9458655

DOI

10.1038/s41467-022-32986-7

Scopus ID

2-s2.0-85137561737 (requires institutional sign-in at Scopus site)   5 Citations

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^V617F mutations. Germline variation associated with longer telomeres is associated with increased myelofibrosis risk. Myelofibrosis cases with high-frequency JAK2 mCAs have marked reductions in measured telomere length - suggesting a relationship between telomere biology and myelofibrosis clonal expansion. Our results advance understanding of the germline-somatic interaction at JAK2 and implicate mCAs involving JAK2 as strong promoters of clonal expansion of those mutated clones.

Author List

Brown DW, Zhou W, Wang Y, Jones K, Luo W, Dagnall C, Teshome K, Klein A, Zhang T, Lin SH, Lee OW, Khan S, Vo JB, Hutchinson A, Liu J, Wang J, Zhu B, Hicks B, Martin AS, Spellman SR, Wang T, Deeg HJ, Gupta V, Lee SJ, Freedman ND, Yeager M, Chanock SJ, Savage SA, Saber W, Gadalla SM, Machiela MJ

Authors

Wael Saber MD, MS Professor in the Medicine department at Medical College of Wisconsin
Tao Wang PhD Associate Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Germ Cells
Haplotypes
Humans
Janus Kinase 2
Mutation
Myeloproliferative Disorders
Primary Myelofibrosis