Hematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia Journal Article


Authors: Chung, S. S.; Kim, E.; Park, J. H.; Chung, Y. R.; Lito, P.; Teruya-Feldstein, J.; Hu, W.; B├ęguelin, W.; Monette, S.; Duy, C.; Rampal, R.; Telis, L.; Patel, M.; Kim, M. K.; Huberman, K.; Bouvier, N.; Berger, M. F.; Melnick, A. M.; Rosen, N.; Tallman, M. S.; Park, C. Y.; Abdel-Wahab, O.
Article Title: Hematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia
Abstract: Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder characterized by somatic BRAFV600E mutations. The malignant cell in HCL has immunophenotypic features of a mature B cell, but no normal counterpart along the continuum of developing B lymphocytes has been delineated as the cell of origin. We find that the BRAFV600E mutation is present in hematopoietic stem cells (HSCs) in HCL patients, and that these patients exhibit marked alterations in hematopoietic stem/progenitor cell (HSPC) frequencies. Quantitative sequencing analysis revealed a mean BRAFV600E-mutant allele frequency of 4.97% in HSCs from HCL patients. Moreover, transplantation of BRAFV600E-mutant HSCs from an HCL patient into immunodeficient mice resulted in stable engraftment of BRAFV600E-mutant human hematopoietic cells, revealing the functional self-renewal capacity of HCL HSCs. Consistent with the human genetic data, expression of BRaf V600E in murine HSPCs resulted in a lethal hematopoietic disorder characterized by splenomegaly, anemia, thrombocytopenia, increased circulating soluble CD25, and increased clonogenic capacity of B lineage cells - all classic features of human HCL. In contrast, restricting expression of BRafV600E to the mature B cell compartment did not result in disease. Treatment of HCL patients with vemurafenib, an inhibitor of mutated BRAF, resulted in normalization of HSPC frequencies and increased myeloid and erythroid output from HSPCs. These findings link the pathogenesis of HCL to somatic mutations that arise in HSPCs and further suggest that chronic lymphoid malignancies may be initiated by aberrant HSCs.
Keywords: controlled study; human cell; sequence analysis; somatic mutation; clinical feature; nonhuman; mouse; gene; gene expression; anemia; thrombocytopenia; animal experiment; animal model; gene frequency; cell renewal; cell differentiation; mutational analysis; b lymphocyte; carcinogenesis; germinal center; engraftment; quantitative analysis; splenomegaly; hematopoietic stem cell; alloantigen; interleukin 2 receptor alpha; clonogenesis; braf gene; hairy cell leukemia; phase 2 clinical trial (topic); cell composition; vemurafenib; human; priority journal; article
Journal Title: Science Translational Medicine
Volume: 6
Issue: 238
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2014-05-28
Start Page: 238ra71
Language: English
DOI: 10.1126/scitranslmed.3008004
PROVIDER: scopus
PUBMED: 24871132
PMCID: PMC4501573
DOI/URL:
Notes: Cited By (since 1996):1 -- Export Date: 1 August 2014 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    364 Rosen
  2. Julie T Feldstein
    288 Feldstein
  3. Piro Lito
    15 Lito
  4. Martin Stuart Tallman
    439 Tallman
  5. Jae Hong Park
    145 Park
  6. Stephen Shiu-Wah Chung
    58 Chung
  7. Raajit Kumar Rampal
    137 Rampal
  8. Sebastien Monette
    76 Monette
  9. Wenhuo Hu
    29 Hu
  10. Nancy Bouvier
    30 Bouvier
  11. Michael Forman Berger
    386 Berger
  12. Christopher Yongchul Park
    89 Park
  13. Minal A Patel
    37 Patel
  14. Young Rock Chung
    46 Chung
  15. Eunhee Kim
    28 Kim
  16. Min Kyung Kim
    6 Kim
  17. Leonid   Telis
    5 Telis