Department of Biochemistry - University of Iowa
Host: Dipali Sashital

“Interrupting Double Negative Feedback Loops to increase Glucocorticoid Potency in Leukemia Treatment”

The glucocorticoid receptor (GR) is expressed in every tissue of the body, yet has diverse roles in each, ranging from suppressing inflammation to inducing cell death. To determine the signals that impinge on GR, and how they change its structure and activity, we study their function lymphoid malignancies, specifically B-cell precursor acute lymphoblastic leukemia (B-ALL). Glucocorticoids are a critical component of combination chemotherapy, and are normally highly effective in treatment of B-ALL, but their use is hampered by resistance and life-threatening side-effects in patients. Upon binding to glucocorticoids GR translocates from the cytoplasm to the nucleus and directly regulates genes. By taking a functional genomics approach were able to identify genes and pathways, including the B-cell receptor pathway, that restrain GR function specifically in B-cells.  By inhibiting components of these pathways, we can alter the modification of GR or its cofactors and increase glucocorticoid potency in B-ALL. 

In the course of these studies we found a surprising new role for GR: regulating B-cell development.  Our current model is that endogenous glucocorticoids (e.g. cortisol) have an influence on lymphoid specification and B-cell selection. This regulation is both direct, through repression of other developmental transcription factors, and indirect by altering the gene splicing.

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