Date

September 2005

UMMS Affiliation

Graduate School of Biomedical Sciences

Document Type

Dissertation, Doctoral

Subjects

Leukemia, T-Cell, Acute; Mutation; Transcription Factors; Helix-Loop-Helix Motifs; Receptors, Cell Surface; Academic Dissertations; Dissertations, UMMS

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

A sequential series of mutational events is necessary for the development of leukemia. The misexpression of TAL1, a basic helix-loop-helix (bHLH) transcription factor, is the most common mutation in T cell acute lymphoblastic leukemia (T-ALL). Tal1 transgenic mice develop leukemia with a long latency and incomplete penetrance indicating additional mutations are necessary to develop disease. To investigate additional mutational events that potentially contribute to TAL1-expressing T-ALL patients, we sought to identify cooperating mutations in Tal1 transgenic mice. Clinical studies implicated the loss of the INK4a/ARF locus, which encodes two tumor suppressors, p16INK4a and p14ARF, in the majority of T-ALL patients. We demonstrated disease acceleration in tal1/ink4a/arf+/-, tal1/pl6ink4a+/- and tal1/p19arf+/- mice, thereby providing genetic evidence that Tal1 cooperates with loss of either p16Ink4a or p19Arf in leukemogenesis. The cooperation of Tal1 with the loss of or p16Ink4a or p19Arf, is consistent with our observation that Tal1 alters cell cycle regulation in leukemia by promoting S phase induction and apoptosis in vivo.

An additional mutational event common in tal1 tumors is activation of the Notch1 signaling pathway. We provide evidence that the majority of tal1 tumors express increased levels of Notch1, and exhibit activating notch1 mutations. Additionally, tal1 tumors display sensitivity to the pharmacologic inhibition of γ-secretase activity in vitro, indicating that γ-secretase inhibitors may prove an efficacious treatment for TAL1-expressing T-ALL patients. Furthermore, we developed a doxycycline-regulated NotchIC T-ALL cell line, which will allow the identification of important Notch1IC target genes in leukemogenesis.