Oncotarget

Research Papers:

Role of mir-15a/16-1 in early B cell development in a mouse model of chronic lymphocytic leukemia

Chingiz Underbayev, Siddha Kasar, William Ruezinsky, Heba Degheidy, Joel Solomon Schneider, Gerald Marti, Steven R. Bauer, Diego Fraidenraich, Marilyn M. Lightfoote, Vijay Parashar, Elizabeth Raveche and Mona Batish _

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Oncotarget. 2016; 7:60986-60999. https://doi.org/10.18632/oncotarget.11290

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Abstract

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

Correspondence to:

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

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.


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