Role of mir-15a/16-1 in early B cell development in a mouse model of chronic lymphocytic leukemia
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Chingiz Underbayev1,6, Siddha Kasar1, William Ruezinsky1, Heba Degheidy3,7, Joel Solomon Schneider4, Gerald Marti2, Steven R. Bauer3, Diego Fraidenraich1, Marilyn M. Lightfoote3, Vijay Parashar5, Elizabeth Raveche1 and Mona Batish1
1 New Jersey Medical School, Rutgers University, Newark, NJ, USA
2 OSEL/CDRH/FDA, Silver Spring, MD, USA
3 CBER/FDA Silver Spring, MD, USA
4 Solid Biosciences LLC, Cambridge, MA, USA
5 Rutgers School of Dental Medicine, Rutgers University, Newark, NJ, USA
6 NHLBI, NIH, Bethesda, MD, USA
7 Faculty of Medicine, Mansoura University, Egypt
Mona Batish, email:
Keywords: chronic lymphocytic leukemia, microRNAs, B1 progenitors, induced pluripotent stem cells, cancer stem cells
Received: July 22, 2016 Accepted: August 01, 2016 Published: August 14, 2016
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.
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