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

被引：7

作者：

Brown, Derek W. ^{[1
,2
]}

Zhou, Weiyin ^{[1
,3
]}

Wang, Youjin ^{[1
]}

Jones, Kristine ^{[1
,3
]}

Luo, Wen ^{[1
,3
]}

Dagnall, Casey ^{[1
,3
]}

Teshome, Kedest ^{[1
,3
]}

Klein, Alyssa ^{[1
]}

Zhang, Tongwu ^{[1
]}

Lin, Shu-Hong ^{[1
]}

Lee, Olivia W. ^{[1
]}

Khan, Sairah ^{[1
]}

Vo, Jacqueline B. ^{[1
,2
]}

Hutchinson, Amy ^{[1
,3
]}

Liu, Jia ^{[1
,3
]}

Wang, Jiahui ^{[1
,3
]}

Zhu, Bin ^{[1
,3
]}

Hicks, Belynda ^{[1
,3
]}

St Martin, Andrew ^{[4
]}

Spellman, Stephen R. ^{[5
]}

Wang, Tao ^{[4
,6
]}

Deeg, H. Joachim ^{[7
]}

Gupta, Vikas ^{[8
]}

Lee, Stephanie J. ^{[4
,7
]}

Freedman, Neal D. ^{[1
]}

Yeager, Meredith ^{[1
,3
]}

Chanock, Stephen J. ^{[1
]}

Savage, Sharon A. ^{[1
]}

Saber, Wael ^{[4
]}

Gadalla, Shahinaz M. ^{[1
]}

Machiela, Mitchell J. ^{[1
]}

机构：

[1] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA

[2] NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Rockville, MD 20850 USA

[3] Frederick Natl Lab, Canc Genom Res Lab, Frederick, MD USA

[4] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA

[5] Natl Marrow Donor Program, Ctr Int Blood & Marrow Transplant Res, Minneapolis, MN USA

[6] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA

[7] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA

[8] Univ Toronto, Princess Margaret Canc Ctr, MPN Program, Toronto, ON, Canada

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

美国国家卫生研究院;

关键词：

POST-ESSENTIAL THROMBOCYTHEMIA; GENOME-WIDE ASSOCIATION; MYELOPROLIFERATIVE NEOPLASMS; POLYCYTHEMIA-VERA; HEMATOPOIETIC-CELLS; CLINICAL-RELEVANCE; JANUS KINASES; RISK-FACTOR; HAPLOTYPE; MUTATIONS;

D O I：

10.1038/s41467-022-32986-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. Myelofibrosis is a risk factor for the development of Acute Myeloid Leukaemia. Here, the authors carry out an integrated genomic investigation of 933 myelofibrosis patients, and identified interactions between germline and somatic variation in patients who required haematopoietic cell transplantation.

引用

页数：11

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