T (12/21) FUSION PROTEIN AND LEUKEMOGENESIS

Project: Research project

Project Details

Description

The broad long-term objective of this proposal is to enhance our
understanding of the transcriptional mechanisms regulating leukemogenesis.
In up to 30% of B-ALL patients, t(12;21) creates a fusion product,
TEL/AML-1B, which converts AML-1B from an activator to repressor of
transcription. In the majority of these cases, the non-translocated TEL
allele is deleted. Therefore, we hypothesize that TEL plays a key role in
regulating transcription and leukemogenesis. The specific aims are to
determine the mechanisms of TEL/AML-1B- mediated repression of basal and
AML-1B-induced transcription and to investigate whether TEL is a tumor
suppressor. To determine the mechanism of transcriptional repression by
TEL/AML-1B, we will make point mutations within the TEL-encoded helix-
loop-helix domain and define the region required for transcriptional
repression and protein-protein interactions. We will also design promoter
constructs that will allow us to determine whether TEL/AML-1B is short- or
long-range repressor. Secondly, we will create conditional TEL knock-out
mice using the Cre-loxP recombination system. We will also cross TEL-
deficient mice with TEL/AML-1B transgenic mice to re-create the genotype
seen in B-ALL patients. These mice will be analyzed the development of
tumors. The data obtained from these studies will enhance our
understanding of the roles of TEL in transcriptional regulation and
leukemogenesis.
StatusActive
Effective start/end date12/18/97 → …

ASJC

  • Medicine(all)