MOLECULAR PATHOGENESIS OF MYELOID LEUKEMIA

Project: Research project

Project Details

Description

DESCRIPTION: (Adapted from Applicant's Abstract) The ultimate goal
of this revised proposal is to understand the molecular pathogenesis
of human acute myeloid leukemia (AML), using the AML-1/ETO chimeric
transcription factor as a model system. The t(8;21) translocation,
seen in the M2 subtype of AML, invariably generates AML-1/ETO
fusion transcript which results in the expression of a chimeric
transcription factor protein. The applicant has demonstrated that
the normal AML-1B protein, but not the normal AML-1A protein, can
transactivate the human GM-CSF promoter via a TGTGGT sequence
located between bp-57 and -52 and can transactivate the human IL-3
promoter via a similar sequence. The AML-1/ETO protein can inhibit
transcription from these promoters and can act as a dominant negative
regulator of the GM-CSF promoter. The Specific Aims of this proposal
are to 1) define the basis for the differential effects of the normal
AML-1A and AML-1B proteins and the AML- 1/ETO fusion protein on a) the
activity of the human GM-CSF and IL-3 promoters and b) the regulation
of bcl-2 expression in AML cell lines and the prevention of apoptosis;
2) identify cellular partners capable of interacting with AML- 1/ETO
using a) the yeast two-hybrid system and b) bacterially or mammalian
cell expressed AML-1/ETO fusion proteins; and 3) determine the
effects of introducing the AML-1/ETO fusion gene on the proliferation
and differentiation of normal hematopoietic progenitor cells and
acute myeloid leukemia cell lines. These studies will define the
interactions of AML-1/ETO with its DNA recognition sequences and with
other cellular proteins. This study will also demonstrate whether
AML-1/ETO generates anti-apoptotic signals and whether it has
transforming activity by itself. Understanding how the AML-1/ETO
fusion protein alters the cells' proliferation and differentiation
program may provide insights into the pathogenesis of AML.
StatusFinished
Effective start/end date9/1/903/31/01

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases

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