title: The chronic lymphocytic leukemia clone disrupts the bone marrow microenvironment.
abstract: The systematic localization of chronic lymphocytic leukemia (CLL) B-cells in the bone marrow (BM), together with the ex vivo protective effect of stromal cells on their spontaneous apoptosis, both indicate a specific role of the BM microenvironment. In vivo, the impact of CLL cells on mesenchymal stromal cells (MSCs) remains a source of debate. Here, we quantified and expanded colony forming unit-fibroblasts (CFU-Fs) from CLL-BM under standard conditions, analyzed the expression of selected genes, and studied secretion profiles. We observed failing of CLL-BM cultures in standard conditions (45.5% vs. <0.1%), and even after adding basic fibroblast growth factor (bFGF), there were fewer CFU-F than from normal BM (1.3 vs. 40/10(6) cells respectively; P<0.01). Furthermore, their polygonal aspect and low proliferative capacity, together with the expression of 384 selected genes and a secreted set of molecules related to senescence-associated secretory phenotype indicated a state of senescence, further confirmed by the higher proportion of senescence-associated β-galactosidase (SA-βGAL)-positive cells and p16INK4a overexpression. In our hands, hypoxic conditions (5% O2) did not rescue CFU-Fs. Given the role of MSC in BM tissue organization, we studied hematons that are generally considered to be elementary BM units. These structures were rare or had even disappeared completely. When hematons were present, we systematically observed nodular B-CLL cell invasion only. These data confirm that the B-CLL clone has a marked impact on MSC and disrupts BM organization in vivo, raising new questions about in vivo pathophysiology.
authors: 1 Hématologie Biologique, CHU (University Hospital Center) Clermont-Fd , Hopital Estaing, Clermont-Ferrand, France .
authors: Alexandre
authors: A
authors: Janel
authors: Frédérique
authors: F
authors: Dubois-Galopin
authors: Céline
authors: C
authors: Bourgne
authors: Juliette
authors: J
authors: Berger
authors: Karin
authors: K
authors: Tarte
authors: Nathalie
authors: N
authors: Boiret-Dupré
authors: Stéphane
authors: S
authors: Boisgard
authors: Pierre
authors: P
authors: Verrelle
authors: Pierre
authors: P
authors: Déchelotte
authors: Olivier
authors: O
authors: Tournilhac
authors: Marc G
authors: MG
authors: Berger
mesh_terms: D000368:Aged; D001402:B-Lymphocytes / Q000166:cytology*; D002478:Cells, Cultured; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D005089:Exocytosis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006410:Hematopoiesis; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008875:Middle Aged; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D055153:Stem Cell Niche; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D001616:beta-Galactosidase