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 Solary & 7 others Koichi Akashi, William Vainchenker, Thomas Mercher, Nathalie Droin, Seishi Ogawa, Florence Nguyen-Khac, Olivier A. Bernard

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1088-1101
Number of pages14
JournalCancer Discovery
Volume4
Issue number9
DOIs
Publication statusPublished - Jan 1 2014

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B-Cell Chronic Lymphocytic Leukemia
Mutation
B-Lymphocytes
Cell Differentiation
Pre-B Cell Receptors
Clonal Evolution
High-Throughput Nucleotide Sequencing
Oncogenes
Survival

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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

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

In: Cancer Discovery, Vol. 4, No. 9, 01.01.2014, p. 1088-1101.

Research output: Contribution to journalArticle

Damm, F, Mylonas, E, Cosson, A, Yoshida, K, Della Valle, V, Mouly, E, Diop, M, Scourzic, L, Shiraishi, Y, Chiba, K, Tanaka, H, Miyano, S, Kikushige, Y, Davi, F, Lambert, J, Gautheret, D, Merle-Béral, H, Sutton, L, Dessen, P, Solary, E, Akashi, K, Vainchenker, W, Mercher, T, Droin, N, Ogawa, S, Nguyen-Khac, F & Bernard, OA 2014, 'Acquired initiating mutations in early hematopoietic cells of CLL patients', Cancer Discovery, vol. 4, no. 9, pp. 1088-1101. https://doi.org/10.1158/2159-8290.CD-14-0104
Damm F, Mylonas E, Cosson A, Yoshida K, Della Valle V, Mouly E et al. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discovery. 2014 Jan 1;4(9):1088-1101. https://doi.org/10.1158/2159-8290.CD-14-0104
Damm, Frederik ; Mylonas, Elena ; Cosson, Adrien ; Yoshida, Kenichi ; Della Valle, Véronique ; Mouly, Enguerran ; Diop, M'boyba ; Scourzic, Laurianne ; Shiraishi, Yuichi ; Chiba, Kenichi ; Tanaka, Hiroko ; Miyano, Satoru ; Kikushige, Yoshikane ; Davi, Frederick ; Lambert, Jérôme ; Gautheret, Daniel ; Merle-Béral, Hélène ; Sutton, Laurent ; Dessen, Philippe ; Solary, Eric ; Akashi, Koichi ; Vainchenker, William ; Mercher, Thomas ; Droin, Nathalie ; Ogawa, Seishi ; Nguyen-Khac, Florence ; Bernard, Olivier A. / Acquired initiating mutations in early hematopoietic cells of CLL patients. In: Cancer Discovery. 2014 ; Vol. 4, No. 9. pp. 1088-1101.
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AU - Scourzic, Laurianne

AU - Shiraishi, Yuichi

AU - Chiba, Kenichi

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AU - Lambert, Jérôme

AU - Gautheret, Daniel

AU - Merle-Béral, Hélène

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AU - Dessen, Philippe

AU - Solary, Eric

AU - Akashi, Koichi

AU - Vainchenker, William

AU - Mercher, Thomas

AU - Droin, Nathalie

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