Purinergic Receptors in Myeloma

Project summary The purpose of this project is to identify novel regulators of ER homeostasis in malignant plasma cells that can be targeted to induce the death of these cells and/or prevent upstream events that foster plasma cell malignancy. Our focus is multiple myeloma (MM), a deadly malignancy of antibody-secreting plasma cells that typically reside in and disrupt the bone marrow. Though current therapies often reduce tumor burden in MM, life- threatening relapse remains the norm. Therefore, new therapies targeting the unique biology and biochemistry of myeloma cells are needed. This project centers on the hypothesis that myeloma cells in the bone marrow and their premalignant precursors obtain requisite signals to avoid cell death by sensing extracellular ATP with receptors belonging to the purinergic family of gated cation channels. We further hypothesize that eATP is produced locally in the bone marrow for myeloma cells by osteoblastic cells via a gap junction protein known as Panx3. Thus, consistent with our preliminary data, inhibition of P2rX receptor signaling or Panx3 function is predicted to cause myeloma cell depletion. We will leverage several experimental systems including a novel patient-derived xenograft model to achieve the following objectives or answer the following questions: 1) Poison P2rX function in premalignant and malignant plasma cells, 2) Identify key ER regulatory nodes controlled by P2rX function, 3) Tie P2rX function in MM cells to Panx3 regulation of the BM PC niche. These studies will provide unique and needed insights into the specialized survival mechanisms employed by malignant plasma cells needed for new therapy development.