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 BRafV600E 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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Chung
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jae H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Young Rock
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Piro
authors.initials: P
authors.lastname: Lito
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Wenhuo
authors.initials: W
authors.lastname: Hu
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Beguelin
authors.affiliation: Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, Rockefeller University, New York, NY 10065, USA.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Monette
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Cihangir
authors.initials: C
authors.lastname: Duy
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Telis
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Minal
authors.initials: M
authors.lastname: Patel
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kety
authors.initials: K
authors.lastname: Huberman
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Bouvier
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.affiliation: Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
mesh_terms: D000818:Animals; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf