Targeting v-ATPase mutations and activated autophagic flux in follicular lymphoma
Sami Malek
MDRegents of the University of Michigan
Project Term: July 1, 2019 - June 30, 2022
In this proposal we seek a mechanistic understanding how mutations in ATP6V1B2 in FL activate autophagic flux and also maintain mTOR in an active state. Given that 25-30% of FL harbor mutations in various v-ATPase subunits and regulators (ATP6V1B2, APT6AP1, VMA21) we will extend our studies to these genes. We will clarify how and under what circumstances activated autophagy can be targeted in FL, why it works, and what the best molecular targets and drugs are.
Follicular lymphoma (FL) constitutes the second most common non-Hodgkin’s lymphoma (NHL) in the United States, with over 100,000 patients living with the disease. While survival rates at 10 years have been improved, almost all patients with FL need therapy within a few years from diagnosis, and most patients receive multiple chemo- or immunotherapies over their lifetimes. Consequently, the psychological and physical strain on individual patients and the societal burden from this disease are substantial. Unfortunately, the development of targeted therapy in FL lags behind the substantial progress made for other blood cancers, and future advances in this area requires identification and validation of novel drug targets and treatment approaches. One of the surprising findings from recent research efforts in FL is the discovery of recurrent mutations in genes involved in a self-preserving response pathway to nutrient deprivation called autophagy (self-eating). The autophagy self-eating pathway is activated in times of low nutrient availability and allows cells to self-digest a small portion of their internal organelles to generate novel building material for critically needed biomolecules. Central to this process is a molecular pump called v-ATPase, which creates the correct acidic milieu within cells for digestions of proteins. We and others have discovered novel mutations in various v-ATPase components and regulators (named ATP6V1B2, APT6AP1, VMA21 and others) in a combined 25-30% of FL cases. Recently, we have made the novel intriguing observation that recurrent mutations in ATP6V1B2 activate autophagy. Physiologically, presence of altered v-ATPase molecules allowed for survival of lymphoma cells under low nutrient conditions, and blocking the self-eating and self-preservation process with drugs killed mutated lymphoma cells. Based on these findings, we wish to clarify the mechanisms of autophagy activation by mutant ATP6V1B2. Further, we wish to define the properties of frequent but unstudied mutations in ATP6AP1 and VMA21 in FL, as we anticipate contributions to activated autophagy as well. Altogether, we will use knowledge gained from this project to define activated self-eating and self-preservation as new therapeutic vulnerabilities of Follicular Lymphoma. Our work aims at finding a novel way of targeting follicular lymphoma.