Is SIRT5 a Therapy Target in Acute Lymphoblastic Leukemia?
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.
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.