Regulation and Function of Very Long Chain Fatty Acid Biosynthesis in Multiple Myeloma

Multiple Myeloma (MM) is a plasma cell disorder that accounts for ~10% of all hematologic malignancies. Due to high production of IgG in endoplasmic reticulum (ER), MM cells continuously undergo ER stress which is considered an “Achille’s heel” of the disease. This feature makes MM susceptible to the agents that exacerbate ER stress, such as proteasome inhibitor bortezomib. Yet, currently MM is incurable for most patients due to rapidly emerging resistance to proteasome inhibitors. Therefore, identification of novel anti-MM drugs and targets is of high importance. Conversely, an increase in protein export from ER is a part of the adaptive response to ER stress. In the current application, we propose a novel clinically relevant pathway controlling ER homeostasis and resistance to bortezomib in MM via modulation of sphingolipid composition of the ER membrane. Our preliminary data suggest that such modulation affects ER-to-Golgi transport, ER homeostasis and ultimately MM cell viability. Furthermore, we identified 3-hydroxyacyl-CoA dehydratases (HACD3), an enzyme involved in the biosynthesis of very long fatty acids (VLCFA), as an important regulator of ER-to-Golgi export and ER homeostasis. Importantly, HACD3 mRNA levels were increased during MM progression and in MM cells from MM patients refractory to bortezomib-containing therapy. Therefore, in Specific Aim 1, we will functionally characterize mechanisms underlying VLCFA-dependent regulation of ER homeostasis and characterize enzymes upstream and downstream of HACD3 responsible for such regulation. In Specific Aim 2, we will identify mechanisms regulating HACD3 mRNA expression in MM cells. In Specific Aim 3, we will evaluate the efficacy of pharmacological suppression of VLCFAs in MM mouse models.