ID: 63. Issue 1 (November 2015) - Kalvakolanu, Dhan V.
Abstract The molecular and genetic bases for the progression of chronic lymphocytic leukemia (CLL), an indolent disease, are poorly understood. The Death associated protein kinase 1 (DAPK1), an IFN-inducible calcium-calmodulin-dependent serine/threonine kinase, is a critical regulator of autophagy and apoptosis. Its expression is frequently suppressed in a wide variety of tumors including CLL. Recently, we have identified a novel non-STAT signaling pathway, where in an endoplasmic resident transcription factor ATF6, in association with the transcription factor C/EBP-β regulates the IFN-γ-induced expression of DAPK1. IFN-γ-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-β are obligatory for the formation of ATF6/C/EBP-β transcriptional complex that regulates DAPK1. Our studies show that in B-CLL, failure of IFN-γ activated functional collaboration between C/EBP-β and/or ATF6 contributes to a loss of growth control via autophagy. We also show a correlation between loss of DAPK1 levels and a failure of ATF6 and/or C/EBP-β activation primary CLL tumors. Restoration of ATF6 or C/EBP-β into respective defective-primary tumor cells, re-established DAPK1 expression. Furthermore, IFN-γ and chemotherapeutics failed to activate autophagy in CLL patient samples lacking ATF6 or C/EBP-β.Together, these results identify a mechanistic basis for the loss of DAPK1 expression, drug resistance and progression of CLL.