Acquired initiating mutations in early hematopoietic cells of CLL patients

Frederik Damm, Elena Mylonas, Adrien Cosson, Kenichi Yoshida, Véronique Della Valle, Enguerran Mouly, M'boyba Diop, Laurianne Scourzic, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Yoshikane Kikushige, Frederick Davi, Jérôme Lambert, Daniel Gautheret, Hélène Merle-Béral, Laurent Sutton, Philippe Dessen, Eric SolaryKoichi Akashi, William Vainchenker, Thomas Mercher, Nathalie Droin, Seishi Ogawa, Florence Nguyen-Khac, Olivier A. Bernard

研究成果: ジャーナルへの寄稿記事

131 引用 (Scopus)

抜粋

Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. SIGNIFICANCE: The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL.

元の言語英語
ページ(範囲)1088-1101
ページ数14
ジャーナルCancer Discovery
4
発行部数9
DOI
出版物ステータス出版済み - 9 2014

    フィンガープリント

All Science Journal Classification (ASJC) codes

  • Oncology

これを引用

Damm, F., Mylonas, E., Cosson, A., Yoshida, K., Della Valle, V., Mouly, E., ... Bernard, O. A. (2014). Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discovery, 4(9), 1088-1101. https://doi.org/10.1158/2159-8290.CD-14-0104