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Cancer Discov. 2014 Sep;4(9):1088-101. doi: 10.1158/2159-8290.CD-14-0104. Epub 2014 Jun 11.

Acquired initiating mutations in early hematopoietic cells of CLL patients.

Author information

1
Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif;
2
INSERM U1138; Université Pierre et Marie Curie-Paris 6;
3
Cancer Genomics Project, Graduate School of Medicine; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto;
4
Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif; Université Paris-Sud;
5
Laboratory of DNA Information Analysis and Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo;
6
Medicine and Biosystemic Science; and Center for Cellular and Molecular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
7
INSERM U1138; Université Pierre et Marie Curie-Paris 6; Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, APHP;
8
Université Paris Diderot, Hôpital Saint-Louis, SBIM;
9
Institut Gustave Roussy, Villejuif; Université Paris-Sud, Institut de Génétique et Microbiologie, CNRS UMR 8621, Orsay;
10
Service d'Hématologie Clinique, Centre Hospitalier Victor Dupouy, Argenteuil, France;
11
INSERM U1009; Institut Gustave Roussy, Villejuif; Ligue Nationale Contre le Cancer, Equipe labellisée, Paris; Université Paris-Sud;
12
INSERM U1009; Institut Gustave Roussy, Villejuif; Université Paris-Sud;
13
Cancer Genomics Project, Graduate School of Medicine; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto; olivier.bernard@inserm.fr florence.nguyen-khac@psl.aphp.fr sogawa-tky@umin.ac.jp.
14
INSERM U1138; Université Pierre et Marie Curie-Paris 6; Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, APHP; olivier.bernard@inserm.fr florence.nguyen-khac@psl.aphp.fr sogawa-tky@umin.ac.jp.
15
Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif; Ligue Nationale Contre le Cancer, Equipe labellisée, Paris; Université Paris-Sud; olivier.bernard@inserm.fr florence.nguyen-khac@psl.aphp.fr sogawa-tky@umin.ac.jp.

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.

Comment in

PMID:
24920063
DOI:
10.1158/2159-8290.CD-14-0104
[Indexed for MEDLINE]
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