Journal Article

DKFZ-2017-04694

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations.

Durham, B. H. ; Getta, B. ; Dietrich, S.DKFZ* ; Taylor, J. ; Won, H. ; Bogenberger, J. M. ; Scott, S. ; Kim, E. ; Chung, Y. R. ; Chung, S. S. ; Hüllein, J.DKFZ* ; Walther, T.DKFZ* ; Wang, L. ; Lu, S. X. ; Oakes, C. C. ; Tibes, R. ; Haferlach, T. ; Taylor, B. S. ; Tallman, M. S. ; Berger, M. F. ; Park, J. H. ; Zenz, T.DKFZ* ; Abdel-Wahab, O.

2017
HighWire Press Stanford, Calif.

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Please use a persistent id in citations: doi:10.1182/blood-2017-01-765107

Abstract: Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutation, whereas ∼30% of variant HCLs (vHCLs) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 wild-type vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n = 53) and vHCL (n = 8). The most common genetic alteration in cHCL apart from BRAFV600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wild-type BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation. In addition to CDKN1B mutations in cHCL, recurrent inactivating mutations in KMT2C (MLL3) were identified in 15% and 25% of cHCLs and vHCLs, respectively. Moreover, 13% of vHCLs harbored predicted activating mutations in CCND3 A change-of-function mutation in the splicing factor U2AF1 was also present in 13% of vHCLs. Genomic analysis of de novo vemurafenib-resistant cHCL identified a novel gain-of-function mutation in IRS1 and losses of NF1 and NF2, each of which contributed to resistance. These data provide further insight into the genetic bases of cHCL and vHCL and mechanisms of RAF inhibitor resistance encountered clinically.

Keyword(s): Antineoplastic Agents ; CCND3 protein, human ; CDKN1B protein, human ; Cyclin D3 ; DNA-Binding Proteins ; Indoles ; MLL3 protein, human ; Splicing Factor U2AF ; Sulfonamides ; U2AF1 protein, human ; Cyclin-Dependent Kinase Inhibitor p27 ; vemurafenib ; Proto-Oncogene Proteins B-raf ; MAP Kinase Kinase 1 ; MAP2K1 protein, human

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Contributing Institute(s):

1. Molekulare Therapie in der Hämatologie und Onkologie (G250)

Research Program(s):

1. 317 - Translational cancer research (POF3-317) (POF3-317)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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