Trib2 in the Pathogenesis of T-ALL
T-ALL occurs in ~20% of children with acute lymphoblast leukemia (ALL). T-ALL incidence peaks in adolescence but occurs throughout life. Intensified chemotherapy is now able to cure ~75% of children with T-ALL; however, relapsed disease responds poorly to treatment. Furthermore, the intensive chemotherapy required for cure is quite toxic with multiple side effects. Thus, there is a need for new therapeutic approaches in T-ALL that are effective in relapsed disease and/or decrease the toxicity of current therapies.
We originally identified Trib2 as a direct Notch1 target gene in T-ALL that was highly expressed in a subset of biphenotypic ETP-like leukemias with poor outcomes. More recent data show that Trib2 is highly expressed in T-ALL.
Significantly, Trib2 is required for growth and survival of human T-ALL cell lines. These data suggest that Trib2 may be a therapeutic target in T-ALL. Importantly, Trib2 knockout mice show no developmental defects and are healthy as adults, suggesting that targeting Trib2 in leukemia may have a high therapeutic index.
In this proposal, we will investigate the in vivo requirement for persistent Trib2 expression in T-ALL pathogenesis. We will also determine the mechanism by which Trib2 maintains the T-ALL transformation and the precise regions of Trib2 to therapeutically target. These preclinical studies will show the feasibility of targeting Trib2 in T-ALL and have the potential to be extended to other Tribbles-associated malignancies. Thus, the results of our studies have the potential to identify a new class of anti-cancer drugs that will directly impact pediatric leukemia.
“Relapsed T-cell acute lymphoblastic leukemia (T-ALL) is extremely difficult to successfully treat. Thus, identifying new therapeutic targets is a high priority. We identified an evolutionarily
conserved protein, Tribbles homologue 2 (Trib2), that is important for growth and survival of TALL cell lines. The ALSF funding will allow us to test the importance of Trib2 in animal models of
T-ALL and determine how it functions. It is our ultimate goal to use these basic studies as a stepping stone to develop a successful therapy for relapsed T-ALL.” 8/2014