title: Acquired initiating mutations in early hematopoietic cells of CLL patients.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif;
authors.forename: Frederik
authors.initials: F
authors.lastname: Damm
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif;
authors.forename: Elena
authors.initials: E
authors.lastname: Mylonas
authors.affiliation: INSERM U1138; Université Pierre et Marie Curie-Paris 6;
authors.forename: Adrien
authors.initials: A
authors.lastname: Cosson
authors.affiliation: Cancer Genomics Project, Graduate School of Medicine; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto;
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif; Université Paris-Sud;
authors.forename: Véronique
authors.initials: V
authors.lastname: Della Valle
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif; Université Paris-Sud;
authors.forename: Enguerran
authors.initials: E
authors.lastname: Mouly
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif;
authors.forename: M'boyba
authors.initials: M
authors.lastname: Diop
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif; Université Paris-Sud;
authors.forename: Laurianne
authors.initials: L
authors.lastname: Scourzic
authors.affiliation: Laboratory of DNA Information Analysis and Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo;
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis and Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo;
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of DNA Information Analysis and Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Laboratory of DNA Information Analysis and Laboratory of Sequence Data Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo;
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Medicine and Biosystemic Science; and Center for Cellular and Molecular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Kikushige
authors.affiliation: INSERM U1138; Université Pierre et Marie Curie-Paris 6; Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, APHP;
authors.forename: Frederick
authors.initials: F
authors.lastname: Davi
authors.affiliation: Université Paris Diderot, Hôpital Saint-Louis, SBIM;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lambert
authors.affiliation: Institut Gustave Roussy, Villejuif; Université Paris-Sud, Institut de Génétique et Microbiologie, CNRS UMR 8621, Orsay;
authors.forename: Daniel
authors.initials: D
authors.lastname: Gautheret
authors.affiliation: INSERM U1138; Université Pierre et Marie Curie-Paris 6; Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, APHP;
authors.forename: Hélène
authors.initials: H
authors.lastname: Merle-Béral
authors.affiliation: Service d'Hématologie Clinique, Centre Hospitalier Victor Dupouy, Argenteuil, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Sutton
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif;
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.affiliation: INSERM U1009; Institut Gustave Roussy, Villejuif; Ligue Nationale Contre le Cancer, Equipe labellisée, Paris; Université Paris-Sud;
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: Medicine and Biosystemic Science; and Center for Cellular and Molecular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: INSERM U1009; Institut Gustave Roussy, Villejuif; Université Paris-Sud;
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: Institut National de la Santé et de la Recherche Medicale (INSERM) U985; Institut Gustave Roussy, Villejuif; Université Paris-Sud;
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
authors.affiliation: INSERM U1009; Institut Gustave Roussy, Villejuif; Université Paris-Sud;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Droin
authors.affiliation: 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.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: 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.
authors.forename: Florence
authors.initials: F
authors.lastname: Nguyen-Khac
authors.affiliation: 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.
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
mesh_terms: D016000:Cluster Analysis; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D039902:Multipotent Stem Cells / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D000072260:RNA Splicing Factors; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D015398:Signal Transduction
chemical_list: D007143:Immunoglobulin Heavy Chains; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D011947:Receptors, Antigen, B-Cell; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human