title: Role of mir-15a/16-1 in early B cell development in a mouse model of chronic lymphocytic leukemia.
abstract: In both human chronic lymphocytic leukemia (CLL) and the New Zealand Black (NZB) murine model of CLL, decreased levels of microRNAs miR-15a/16 play an important role in the disease. Here we investigate the effects of this microRNA on early steps of B cell development and the capacity of miR-15a-deficient hematopoietic stem cells (HSC) and B1 progenitor cells (B1P) to reproduce CLL-like phenotype both in vitro and in vivo. Our results demonstrate that both miR-15a deficient HSC and B1P cells are capable of repopulating irradiated recipients and produce higher numbers of B1 cells than sources with normal miR-15a/16 levels. Furthermore, induced pluripotent stem (iPS) cells derived for the first time from NZB mice, provided insights into the B cell differentiation roadblock inherent in this strain. In addition, exogenously delivered miR-15a into the NZB derived B cell line provided valuable clues into novel targets such as Mmp10 and Mt2. Our data supports the hypothesis that miR-15a/16 deficient stem cells and B1Ps experience a maturation blockage, which contributes to B1 cells bias in development. This work will help understand the role of miR-15a in early events of CLL and points to B1P cells as potential cells of origin for this incurable disease.
authors.affiliation: New Jersey Medical School, Rutgers University, Newark, NJ, USA.|NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Chingiz
authors.initials: C
authors.lastname: Underbayev
authors.affiliation: New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Siddha
authors.initials: S
authors.lastname: Kasar
authors.affiliation: New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: William
authors.initials: W
authors.lastname: Ruezinsky
authors.affiliation: CBER/FDA, Silver Spring, MD, USA.|Faculty of Medicine, Mansoura University, Egypt.
authors.forename: Heba
authors.initials: H
authors.lastname: Degheidy
authors.affiliation: Solid Biosciences LLC, Cambridge, MA, USA.
authors.forename: Joel Solomon
authors.initials: JS
authors.lastname: Schneider
authors.affiliation: OSEL/CDRH/FDA, Silver Spring, MD, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Marti
authors.affiliation: CBER/FDA, Silver Spring, MD, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Bauer
authors.affiliation: New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Fraidenraich
authors.affiliation: CBER/FDA, Silver Spring, MD, USA.
authors.forename: Marilyn M
authors.initials: MM
authors.lastname: Lightfoote
authors.affiliation: Rutgers School of Dental Medicine, Rutgers University, Newark, NJ, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Parashar
authors.affiliation: New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Raveche
authors.affiliation: New Jersey Medical School, Rutgers University, Newark, NJ, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Batish
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002469:Cell Separation; D004195:Disease Models, Animal; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D035683:MicroRNAs / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse; C522604:Mirn16 microRNA, mouse
keywords: B1 progenitors; cancer stem cells; chronic lymphocytic leukemia; induced pluripotent stem cells; microRNAs