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"ROLE OF MIR-15A/16-1 IN EARLY B CELL DEVELOPMENT OF MOUSE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA:
THE QUEST FOR THE CELL OF ORIGIN"

by
Chingiz Underbayev
Molecular Pathology and Immunology Program
MD 2004, Siberian State Medical University, Russia


Thesis Advisor: Elizabeth S. Raveche, Ph.D.
Professor
Department of Pathology and Laboratory Medicine

Thursday, July 17, 2014
1:00 P.M., MSB C-555


Abstract

Chronic lymphocytic leukemia (CLL), a malignancy of the CD5+ B cell, is the most common leukemia to affect adults in the Western world and is characterized by chromosomal instability and deletions within the 13q14 chromosomal region containing mir15a/16 resulting in decreased miR15a/16 expression. New Zealand Black (NZB) mice are a model of CLL and have a germline T¡úA point mutation six bases downstream from pre¨Cmir-16-1 on chromosome 14 similar to the C¡úT point mutation seen in human CLL, which may affect structural stability of the stem loop and proper processing, resulting in decreased miR-15a and miR-16 expression levels (manuscript submitted). Similar to CLL, the disease in NZB mice is an age-associated malignant expansion of B-1 (IgM+, B220(CD45R)dull, and CD5dull) clones. In this thesis I employed NZB and DBA congenic mice with replaced mir15a/16 loci (referred to as DBA-/-) to study early progenitors¡¯ capacity to recapitulate the disease both in vitro and in vivo using OP9 system and immunodeficient mice. B1 progenitors from both NZB and DBA-/- mice are capable to repopulate irradiated recipients and produce significantly higher numbers of B1a cells as well as CD11b+ myeloid lineage cells compared to wild type counterparts and syngenic hematopoietic stem cells (HSC).. This data supports the hypothesis that miR-15a deficient B progenitors experience a maturation blockage and that B1 progenitors can be the cells of origin for CLL. In addition exogenously delivered miR-15a/16-1 into NZB derived B cell line led to downregulation of genes aberrantly overexpressed in NZB strain as well as upregulation of PU.1 gene expression which is known to be critical for B2 cell development. Furthermore iPS cells derived for the first time for the mouse model of CLL provided insights into the B cell differentiation roadblock inherent in the NZB strain. These iPS cells may be a powerful tool in both research and preclinical CLL applications.


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