| 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 5 53) and vHCL (n 5 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. © 2017 by The American Society of Hematology. |
| Keywords: |
mitogen activated protein kinase; protein kinase b; cancer chemotherapy; controlled study; protein phosphorylation; unclassified drug; dna binding protein; gene mutation; human cell; major clinical study; gene deletion; genetics; mutation; dna-binding proteins; cancer recurrence; antineoplastic agents; antineoplastic agent; mitogen activated protein kinase kinase 1; cyclin dependent kinase 8; drug resistance; drug resistance, neoplasm; chemosensitivity; mutational analysis; brca2 protein; heterozygote; tumor marker; cancer resistance; cancer genetics; genome analysis; sulfonamide; sulfonamides; cyclin dependent kinase inhibitor 1b; cdkn1b protein, human; cyclin-dependent kinase inhibitor p27; gene loss; genomics; androgen receptor; heterozygosity loss; indoles; retinoblastoma protein; indole derivative; smoothened protein; b raf kinase; map kinase kinase 1; vasculotropin receptor 1; proto-oncogene proteins b-raf; mutant; notch1 receptor; chromosome 7q; scatter factor receptor; hairy cell leukemia; notch2 receptor; cyclin dependent kinase 6; transcription factor runx1; cyclin d3; copy number variation; transcription factor ezh2; ccaat enhancer binding protein beta; cd135 antigen; e1a associated p300 protein; peptides and proteins; vemurafenib; zygosity; map2k1 protein, human; ccaat enhancer binding protein alpha; gain of function mutation; leukemia, hairy cell; n methyl dextro aspartic acid receptor 2a; brd4 protein; humans; human; priority journal; article; ephrin receptor b4; ephrin receptor b6; histone methyltransferase kmt2c; splicing factor u2af; splicing factor u2af1; ccnd3 protein, human; mll3 protein, human; u2af1 protein, human; change of function mutation; classical hairy cell leukemia; hemizygous; variant hairy cell leukemia
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