High-dimensional Biochemical CyTOF Analysis of Pediatric T cell Leukemias

Background:

Pediatric T cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive blood cancer and children are currently treated with chemotherapy but its non-specific and toxic aspect is problematic. More specific therapies are desired but T-ALL's differ from patient to patient and even within one patient there are cell subsets within the leukemia (called heterogeneity). It is therefore challenging to implement or analyze the effects of precision medicine that inhibit abnormally functioning proteins in T-ALL.

Project Goal:

Here we will utilize a groundbreaking analysis method, termed CyTOF, which allows for simultaneous analysis of 60 markers on single T-ALL cells. Using CyTOF we can now resolve the heterogeneity and can analyze abnormally functioning proteins that send signals in T-ALL with high resolution. Our previous work established that T-ALL often signal abnormally to the "Ras protein" and can do so in two distinct manners. 65% of pediatric T-ALL patient signal to Ras abnormally and to a critical Ras-connection named PI3kinase. There are excellent inhibitors of PI3kinase that are currently in many clinical trials. We have developed mouse models of the two T-ALL Ras signals and a mouse model with transplanted pediatric T-ALL samples. Here we will use these mouse models in preclinical trial studies with the PI3kinase inhibitor GDC0941. We will utilize CyTOF analysis to generate high-resolution data to assess how effective PI3kinase inhibition is as therapy for T-ALL, how heterogeneity may result in resistant T-ALL cells, and to determine the precise identity of resistant cells to understand how to eradicate these with future therapy.