Acquired initiating mutations in early hematopoietic cells of CLL patients
Menée sur 168 patients atteints d'une leucémie lymphocytaire chronique, cette étude identifie, dans les progéniteurs hématopoïétiques multipotents, des mutations acquises de plusieurs gènes
Appropriate cancer care requires thorough understanding of the natural history of the disease, including the cell of origin, the clonal organization of the proliferation and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from chronic lymphocytic leukemia (CLL) patients, we established the presence of acquired mutations in multipotent hematopoietic progenitors of CLL patients. Mutations affected known lymphoid oncogenes including BRAF, NOTCH1 and SF3B1. NFKBIE and EGR2 mutations were observed at unexpected 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 mutation suggest they affect deregulation of BCR intracellular signaling. Our data propose deregulation of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic convergence of CLL mutations and show that CLL develops from a pre-leukemic phase.