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Blood. 2017 Oct 5;130(14):1644-1648. doi: 10.1182/blood-2017-01-765107. Epub 2017 Aug 11.

Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations.

Author information

Department of Pathology and.
Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY.
Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
Department of Molecular Therapy in Hematology and Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
Human Oncology and Pathogenesis Program and.
Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY.
Division of Hematology and Medical Oncology, Mayo Clinic/Mayo Clinic Cancer Center, Scottsdale, AZ.
School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH.
MLL Munich Leukemia Laboratory, Munich, Germany; and.
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.


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.

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