The molecular controls governing commitment of hematopoietic stem cells to specific lineages have still not been fully elucidated. The importance of understanding such controls is underscored by the fact that a block in differentiation is a hallmark of acute leukemias. Acute myeloid leukemia (AML), involving the precursors of myeloid cells (granulocytes and monocytes/macrophages), accounts for over 90 percent of acute leukemias in adults. In this application, I propose to continue our study of the molecular basis of differentiation of myeloid cells, employing a detailed analysis of the transcription factor PU.1, which regulates nearly every myeloid gene, and is absolutely required for normal myeloid development. PU.1 is expressed in stem cells and upregulated early during myeloid and lymphoid commitment. The importance of understanding how PU.1 is regulated is underscored by studies indicating that altered expression of PU. 1 can induce changes in hematopoietic lineage development, and in some experimental cases misexpression leads to leukemia. Thus, the overall goal of this continuation proposal is to continue our studies of how PU.1 is regulated, and what its function is in adult hematopoiesis. These studies will further our understanding of (1) commitment of normal hematopoietic precursors to the myeloid lineage; and (2) the block in normal myeloid maturation from blasts to mature myeloid cells in AML. Therefore, the Specific Aims are: (1)To determine how PU.1 expression is regulated in hematopoietic cells, using transgenic and knockout studies; (2) To determine the role of PU.1 in adult hematopoiesis by studying a conditional knockout model; and (3) To determine whether different levels of PU. 1 expression play a role in directing hematopoietic lineage determination and development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA041456-20
Application #
6851682
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mufson, R Allan
Project Start
1986-01-01
Project End
2008-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
20
Fiscal Year
2005
Total Cost
$443,562
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Aikawa, Yukiko; Katsumoto, Takuo; Zhang, Pu et al. (2010) PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2. Nat Med 16:580-5, 1p following 585
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