TitleHematopoietic stem cell origin of BRAFV600E mutations in hairy cell leukemia.
Publication TypeJournal Article
Year of Publication2014
AuthorsChung, Stephen S., Kim Eunhee, Park Jae H., Chung Young Rock, Lito Piro, Teruya-Feldstein Julie, Hu Wenhuo, B├ęguelin Wendy, Monette Sebastien, Duy Cihangir, Rampal Raajit, Telis Leon, Patel Minal, Kim Min Kyung, Huberman Kety, Bouvier Nancy, Berger Michael F., Melnick Ari M., Rosen Neal, Tallman Martin S., Park Christopher Y., and Abdel-Wahab Omar
JournalSci Transl Med
Date Published2014 May 28
KeywordsAnimals, Hematopoietic Stem Cells, Humans, Leukemia, Hairy Cell, Mice, Mutation, Proto-Oncogene Proteins B-raf

<p>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.</p>

Alternate JournalSci Transl Med
PubMed ID24871132
PubMed Central IDPMC4501573
Grant ListK08 CA160647 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States