To Examine the Role of Cdk5 in T-cell Leukemia in Altering a Tumor's Ability to Seed CNS or Altering Immune Sensitivity to the Host's Immune System

Background

I will determine the potential role of Cdk5 during the transformation of Notch1-induced T-cell leukemia from hematopoietic progenitor cells and its role in granting the ability of the leukemic cells to seed in the central nervous system (CNS). My mentor's laboratory identified a novel role of Cdk5 in T cell activation and function. We hypothesize that Cdk5 will also play a crucial role in regulating Notch1-induced transcriptome.

I will transduce the intracellular portion of Notch1 (ICN1) into hematopoietic cells that are wild type, deficient in Cdk5 or its co-activator, p35/p39 and observe the potency and timing of T-cell leukemia transformation in vivo. I will also learn the CRISPR/Cas9 approach to delete Cdk5 gene in fully transformed T-ALL cell lines to study the effect on T-ALL seeding in the CNS.

Project Goal

Ultimately, the goal is to provide new targets for the treatment of the aggressive T-ALL which affects both pediatric and adolescent populations. There are currently Cdk5 inhibitors being tried against adult cancers in clinical trials. The results of my research would provide scientific rationale for using the same drugs as potential therapies against T-ALL.