BME PhD Preliminary Exam Announcement for Christopher Schorr (K. Lee, X. Bao and S. Harbin, advisors) Everyone is invited to attend the public presentation beginning at 1:00 pm. Title: Elucidating the Kinase-Independent Regulation of PIM2 in Multiple Myeloma Date: April 16th, 2025 Time: 1:00 pm Zoom link: https://iu.zoom.us/j/82335784398<https://nam04.safelinks.protection.outlook.com/?url=https%3A%2F%2Fiu.zoom.us%2Fj%2F82335784398&data=05%7C02%7Cbmeroundtable-list%40ecn.purdue.edu%7Ce88ddf97a51a4ddbb6fe08dd73744165%7C4130bd397c53419cb1e58758d6d63f21%7C0%7C0%7C638793665330872770%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=oWT89Ebbv%2BWgTrx2R%2BxLLPJCptb2ZSptQhNyvxD8M4E%3D&reserved=0> Committee: Dr. Kelvin Lee, Dr. Xiaoping Bao, Dr. Sherry Harbin, Dr. Michael Heinz Abstract: Multiple myeloma (MM) remains an incurable hematologic malignancy with poor prognosis due to the inevitable development of drug resistance. A key driver of MM progression and therapeutic failure is the overexpression of the oncogenic kinase PIM2, which promotes cancer cell survival through both kinase-dependent and kinase-independent mechanisms. Despite significant overexpression in MM and association with poor outcomes, ATP-competitive PIM2 inhibitors have shown limited efficacy in clinical trials. In contrast, our laboratory's non-ATP competitive inhibitor JP11646 demonstrates superior efficacy by downregulating PIM2 gene expression, suggesting mechanisms beyond simple kinase inhibition. This research investigates the hypothesis that PIM2 maintains its constitutive overexpression in MM through a kinase-independent autoregulatory feedback loop involving the oncogenic transcription factors MYC and SP1. Through chromatin immunoprecipitation, protein interaction studies, and luciferase reporter assays, we demonstrate that both wild-type and kinase-dead PIM2 localize to the nucleus, associate with MYC and SP1, and bind to the PIM2 promoter. We identify critical SP1 binding sites in the PIM2 promoter region essential for this regulation, with mutation of these sites significantly reducing PIM2 expression. Disruption of the PIM2-MYC-SP1 complex through JP11646 treatment, but not through ATP-competitive inhibition, significantly reduces PIM2 expression and MM cell viability. These findings reveal a novel kinase-independent autoregulatory mechanism that maintains high PIM2 levels in MM cells and provides a potential explanation for the limited efficacy of conventional PIM2 kinase inhibitors. This work identifies a previously uncharacterized vulnerability that could be exploited to develop more effective targeted therapies for MM patients. -- Bmeroundtable-list mailing list Bmeroundtable-list@ecn.purdue.edu https://engineering.purdue.edu/ECN/mailman/listinfo/bmeroundtable-list