Ulf Klein, Ph.D. Herbert Irving Comprehensive Cancer Center, Columbia University

GENETICS

The role of IRF4 in the pathogenesis of CLL

Grant Awarded in 2011

Abstract:

CLL results from an accumulation of B-cells that have defects in controlling cell death and proliferation. Our previous research helped to demonstrate that there are a series of mechanisms which keep CLL cells alive (pro-survival mechanisms) and signal the cells to continue multiplying (pro-proliferative mechanisms). This was shown in CLL cases with abnormalities of chromosome 13. Our present research efforts are directed at revealing an additional mechanism that is potentially involved in the multistep development of CLL.

There is increasing evidence that CLL cells become incapable of following the normal route of B-cell differentiation - the process of becoming a more specialized cell. It was recently found that Interferon Regulatory Factor 4 (IRF4), a gene which is part of the multistep process of normal B-cell differentiation, is associated with CLL development. We hypothesize that CLL cells fail to produce enough IRF4 needed to function normally. This subsequently arrests the CLL cells in their current developmental stage. This developmental block further exacerbates the cellular imbalance created by the loss of control of cell death and proliferation, resulting in tumor cell accumulation.

Our present proposal is aimed at understanding the biological consequences and mechanisms of reduced IRF4 expression in CLL. By deleting the IRF4 gene in mouse models, we can better understand the gene’s role in CLL cells and determine the extent to which IRF4-deletion accelerates CLL development. Clarifying the mechanisms that disrupt the normal differentiation path of the CLL cells is expected to guide the development of innovative therapeutic strategies for CLL treatment.