T-cell acute lymphoblastic leukemia (T-ALL) results from malignant

transformation of thymocytes. We discovered PHF6 as a novel tui:nor

suppressor gene frequently affected in T-ALL, and mutations primarily occur

in the TLX1/3 subgroups. The function of PHF6 and interrelationship with

TLX1 remains elusive. Our in vitro data Indicate that TLX1 and PHF6 regulate

IL7R expression, a cru.cial component in T-cell development and T-ALL We

hypothesize that IL7R regulation is crucial for cooperative effects of PHF6

loss in TLX1 expressing T-ALLs. Zebrafish will be used as in vivo model to

study IL7R mediated interaction between PHF6 and TLX1. Global gene

expression levels will be evaluated in PHF6 deficient and TLX1 transgenic

fish. We will assess PHF6-TLX1 cooperativity in T-ALL oncogenesis in vivo

and characterize the resulting T-ALLs. Finally, we aim to model the TLX1-

PHF6/IL7R/JAK/STAT oncogenic pathway in zebrafish and test JAK/STAT

inh1bitors as a novel therapeutic approach for T-ALL