Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

• Verfasst von: Durham, Benjamin H. [VerfasserIn]
• Verfasst von: Dietrich, Sascha [VerfasserIn]
• Verfasst von: Hüllein, Jennifer [VerfasserIn]
• Verfasst von: Walther, Tatjana [VerfasserIn]
• Verfasst von: Zenz, Thorsten [VerfasserIn]
• Titel: Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations
• Verf.angabe: Benjamin H. Durham, Bartlomiej Getta, Sascha Dietrich, Justin Taylor, Helen Won, James M. Bogenberger, Sasinya Scott, Eunhee Kim, Young Rock Chung, Stephen S. Chung, Jennifer Hüllein, Tatjana Walther, Lu Wang, Sydney X. Lu, Christopher C. Oakes, Raoul Tibes, Torsten Haferlach, Barry S. Taylor, Martin S. Tallman, Michael F. Berger, Jae H. Park, Thorsten Zenz, and Omar Abdel-Wahab
• E-Jahr: 2017
• Jahr: 5 October 2017
• Umfang: 5 S.
• Fussnoten: Prepublished online 2017 Aug 11 ; Gesehen am 28.11.2018
• Titel Quelle: Enthalten in: Blood
• Ort Quelle: Washington, DC : American Society of Hematology, 1946
• Jahr Quelle: 2017
• Band/Heft Quelle: 130(2017), 14, Seite 1644-1648
• ISSN Quelle: 1528-0020
• DOI: doi:10.1182/blood-2017-01-765107
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 158460221X

Abstract

KMT2C mutations occur in 15% and 25% of patients with cHCL and vHCL, respectively, along with CCND3 and U2AF1 mutations each in 13% of vHCLs. NF1, NF2, N/KRAS, and IRS1 alterations contribute to clinical resistance to vemurafenib treatment in patients with cHCL., 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.