Project: Research project

Project Details


The long term objectives of the principal investigator's laboratory are to
extend our understanding of the pathogenesis of acute pro-myelocytic
leukemia (APL), and of the mechanisms by which the vitamin A derivative
all-trans retinoic acid (ATRA) contributes to the cure of this disease.
The specific theme of this proposal is the identification and functional
characterization of genes involved in APL, and of genes regulated by ATRA
in APL cells and PML-RARalpha-expressing cell lines. PML-RARalpha is the
fusion gene, created by the 15;17 translocation that is felt to cause APL
in humans (and exhibits leukemogenic activity in transgenic mice).

In specific aim 1, a cDNA substraction technique will be used to identify
genes that are downstream targets of PML-RARalpha. Candidate cDNAs will be
evaluated for differential expression in APL and other myeloid leukemias,
and assayed for their responsiveness to ATRA. Those which appear most
likely to be involved in APL pathogenesis will be cloned and further
characterized. In addition, cDNA microarray technology will be used to
define a gene expression profile in APL cells and in PML-RARalpha-positive
cell lines.

In specific aim 2, a novel gene isolated from PML-RARalpha-expressing
cells by subtractive hybridization, termed ARA-1 (ATRA-Regulated in APL),
will be completely characterized. Since ARA-1 appears to be induced by
ATRA specifically in PML-RARalpha-positive cells, the hypothesis that ARA-
1 is involved in the mechanism by which ATRA differentiates, and
ultimately kills, APL cells, will be tested.

Finally, in specific aim 3, the response of PML-RARalpha-expressing
hematopoietic cells to ATRA will be further characterized. PML-RARalpha
sensitizes TF1 erythroleukemia cells to ATRA-induced differentiation and
apoptosis, and the magnitude of this effect is dependent on PML-RARalpha
isoform type. These studies will be extended to identify regions within
the PML-RARalpha protein which mediate this pro-differentiative and pro-
apoptotic effect, and to further characterize the mechanism by which PML-
RARalpha, in conjunction with ATRA, leads to differentiation and death of
these cells. It is hoped that the research proposed here will lead to a
more complete understanding of the pathogenesis of APL, and to strategies
for transition of retinoid-based differentiation therapy from the
laboratory to the bedside.
StatusNot started


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