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

Derek W. Brown (), Weiyin Zhou, Youjin Wang, Kristine Jones, Wen Luo, Casey Dagnall, Kedest Teshome, Alyssa Klein, Tongwu Zhang, Shu-Hong Lin, Olivia W. Lee, Sairah Khan, Jacqueline B. Vo, Amy Hutchinson, Jia Liu, Jiahui Wang, Bin Zhu, Belynda Hicks, Andrew St. Martin, Stephen R. Spellman, Tao Wang, H. Joachim Deeg, Vikas Gupta, Stephanie J. Lee, Neal D. Freedman, Meredith Yeager, Stephen J. Chanock, Sharon A. Savage, Wael Saber, Shahinaz M. Gadalla and Mitchell J. Machiela ()
Additional contact information
Derek W. Brown: National Cancer Institute
Weiyin Zhou: National Cancer Institute
Youjin Wang: National Cancer Institute
Kristine Jones: National Cancer Institute
Wen Luo: National Cancer Institute
Casey Dagnall: National Cancer Institute
Kedest Teshome: National Cancer Institute
Alyssa Klein: National Cancer Institute
Tongwu Zhang: National Cancer Institute
Shu-Hong Lin: National Cancer Institute
Olivia W. Lee: National Cancer Institute
Sairah Khan: National Cancer Institute
Jacqueline B. Vo: National Cancer Institute
Amy Hutchinson: National Cancer Institute
Jia Liu: National Cancer Institute
Jiahui Wang: National Cancer Institute
Bin Zhu: National Cancer Institute
Belynda Hicks: National Cancer Institute
Andrew St. Martin: Medical College of Wisconsin
Stephen R. Spellman: National Marrow Donor Program
Tao Wang: Medical College of Wisconsin
H. Joachim Deeg: Fred Hutchinson Cancer Research Center
Vikas Gupta: University of Toronto
Stephanie J. Lee: Medical College of Wisconsin
Neal D. Freedman: National Cancer Institute
Meredith Yeager: National Cancer Institute
Stephen J. Chanock: National Cancer Institute
Sharon A. Savage: National Cancer Institute
Wael Saber: Medical College of Wisconsin
Shahinaz M. Gadalla: National Cancer Institute
Mitchell J. Machiela: National Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32986-7

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