Is SIRT5 a Therapy Target in Acute Lymphoblastic Leukemia?
Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thanks to aggressive chemotherapy regimens most children with the so-called B subtype of ALL do well, while prognosis in children with the T subtype (T-ALL) is less favorable, and poor if first-line therapy fails. Unfortunately, many surviving children suffer from long-term side effects of chemotherapy such as neuropathy and have to deal with life-long functional impairment. We have preliminary evidence that ALL cells, but not normal bone marrow cells, are dependent on SIRT5, a master regulator of energy metabolism, to maintain their growth and survival.
Project Goal: We propose to determine how widespread dependency on SIRT5 is in T-ALL, and which metabolic pathways are regulated by SIRT5. We will also use murine models to test whether T-ALL cells are dependent on SIRT5 when growing in vivo. SIRT5 is an enzyme with a unique structure that should allow the design of selective inhibitors. Murine models with a deletion of the SIRT5 gene are viable, suggesting that SIRT5 inhibitors would be tolerated. If successful, our work will firmly implicate SIRT5 as a therapeutic target in T-ALL and provide a rationale for the development of clinical SIRT5 inhibitors. This novel approach may lead to an improved and less-toxic therapy of children with T-ALL.
Project Update 2021: We have identified a protein called SIRT5 that appears to be necessary for T-ALL cells to survive, while normal healthy blood cells tolerate loss of SIRT5. We have used modern technologies to eliminate SIRT5 from cell lines derived from patients with T-ALL. We find that most of these cells lines are to some degree dependent on SIRT5, and they die when SIRT5 is eliminated from the cells. However, dependence is variable, ranging from extremely sensitive to mostly resistant to elimination of SIRT5. Future directions include validating our findings in a mouse model of aggressive T-ALL and to identify markers that can easily identify which T-ALL cells are dependent on SIRT5. Our ultimate goal is to develop a drug that neutralizes SIRT5. Once a clinical SIRT5 inhibitor is available, it will be critical to offer this trial to those T-ALL patients who would benefit from this new drug.
