Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations Journal Article


Authors: Durham, B. H.; Getta, B.; Dietrich, S.; Taylor, J.; Won, H.; Bogenberger, J. M.; Scott, S.; Kim, E.; Chung, Y. R.; Chung, S. S.; Hüllein, J.; Walther, T.; 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.; Abdel-Wahab, O.
Article Title: Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations
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
Journal Title: Blood
Volume: 130
Issue: 14
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2017-10-05
Start Page: 1644
End Page: 1648
Language: English
DOI: 10.1182/blood-2017-01-765107
PUBMED: 28801450
PROVIDER: scopus
PMCID: PMC5630011
DOI/URL:
Notes: Article -- Export Date: 2 November 2017 -- Source: Scopus
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MSK Authors
  1. Martin Stuart Tallman
    395 Tallman
  2. Jae Hong Park
    127 Park
  3. Stephen Shiu-Wah Chung
    57 Chung
  4. Lu Wang
    139 Wang
  5. Michael Forman Berger
    373 Berger
  6. Sydney X Lu
    48 Lu
  7. Barry Stephen Taylor
    135 Taylor
  8. Helen Hyeong-Eun Won
    78 Won
  9. Young Rock Chung
    46 Chung
  10. Sasinya Neka Scott
    66 Scott
  11. Benjamin Heath Durham
    58 Durham
  12. Bartlomiej Marcin Getta
    21 Getta
  13. Justin   Taylor
    16 Taylor