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 JAK2V617F mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2V617F 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 08, 2022
- Source ID
- 10.1038/s41467-022-32986-7
Entities
People
- Alyssa Klein
- Amy Hutchinson
- Andrew St. Martin
- Belynda Hicks
- Bin Zhu
- Casey Dagnall
- Derek W Brown
- H. Joachim Deeg
- Jacqueline B. Vo
- Jia Liu
- Jiahui Wang
- Kedest Teshome
- Kristine Jones
- Meredith Yeager
- Mitchell Machiela
- Neal D. Freedman
- Olivia W. Lee
- Sairah Khan
- Shahinaz Gadalla
- Sharon A. Savage
- Shu-hong Lin
- Stephanie J. Lee
- Stephen Chanock
- Stephen R. Spellman
- Tao Wang
- Tongwu Zhang
- Vikas Gupta
- Wael Saber
- Weiyin Zhou
- Wen Luo
- Youjin Wang
Organizations
- Division of Cancer Epidemiology and Genetics, National Cancer Institute
- Federal Office of Rural Health Policy
- National Cancer Institute
- Office of Naval Research
- United States Public Health Service