Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis
© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Nature communications - 13(2022), 1 vom: 08. Sept., Seite 5284 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Brown, Derek W [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 13.09.2022 Date Revised 02.08.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-022-32986-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM345930126 |
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| 100 | 1 | |a Brown, Derek W |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Intramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
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| 700 | 1 | |a Zhou, Weiyin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Youjin |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Kristine |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Dagnall, Casey |e verfasserin |4 aut | |
| 700 | 1 | |a Teshome, Kedest |e verfasserin |4 aut | |
| 700 | 1 | |a Klein, Alyssa |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Tongwu |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Shu-Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Olivia W |e verfasserin |4 aut | |
| 700 | 1 | |a Khan, Sairah |e verfasserin |4 aut | |
| 700 | 1 | |a Vo, Jacqueline B |e verfasserin |4 aut | |
| 700 | 1 | |a Hutchinson, Amy |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jiahui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Hicks, Belynda |e verfasserin |4 aut | |
| 700 | 1 | |a Martin, Andrew St |e verfasserin |4 aut | |
| 700 | 1 | |a Spellman, Stephen R |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Deeg, H Joachim |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Vikas |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Stephanie J |e verfasserin |4 aut | |
| 700 | 1 | |a Freedman, Neal D |e verfasserin |4 aut | |
| 700 | 1 | |a Yeager, Meredith |e verfasserin |4 aut | |
| 700 | 1 | |a Chanock, Stephen J |e verfasserin |4 aut | |
| 700 | 1 | |a Savage, Sharon A |e verfasserin |4 aut | |
| 700 | 1 | |a Saber, Wael |e verfasserin |4 aut | |
| 700 | 1 | |a Gadalla, Shahinaz M |e verfasserin |4 aut | |
| 700 | 1 | |a Machiela, Mitchell J |e verfasserin |4 aut | |
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