Understanding the processes that regulate the developmental program of normal stem cells and how aberrations in this program initiate leukemic proliferation remain a major challenge in biology. Progress to address these major questions in the human hematopoietic system has been hampered, until recently, by the lack of in vivo assays for normal and leukemic stem cells. The only way to conclusively assay stem cells is to follow their repopulating capacity. The recent development of methods to transplant human hematopoietic cells into immune-deficient mice provides an important approach to characterize stem cells and to develop animal models for hematopoietic diseases including leukemia. The development of an in vivo model that replicates many aspects of human AML and allows the identification of a novel leukemic stem cell (termed the SCID-Leukemia Initiating Cell, SL-IC) based on the ability of that cell to initiate AML in NOD/SCID mice provides the foundation of an assay to define the biological and molecular properties of such new leukemic stem cells. The major long-term objectives of my research program are to further characterize human leukemic stem cells. The research project proposed here will focus on three objectives: 1) determine the existence of an heterogeneity at the leukemic stem cell level (both Lin-CD34+ and Lin-CD341o/- subfractions have leukemic stem cell properties); 2) evaluate the biological properties of the leukemic stem cell pool (i.e., self-renewal, proliferation and differentiation capacities, response to cytokines and/or stromal cell environment); 3) to study the gene expression pattern of six regulatory molecules (AML1, PU.1, GATA- 1, Hox A5, Hox B4 and SCL/tal-1), known to be involved in the early stage of hematopoietic development and/or in the physiopathology of leukemia, before and after induction of differentiation of the leukemic stem cell fraction. The information obtained from these studies will gave us a more complete understanding of the nature of the leukemic stem cells, their biological properties, and the early molecular factors involved in the maintenance and/or differentiation of such leukemic stem cells. Furthermore, the knowledge gained about leukemic stem cells will allow us to devise new therapeutic strategies such as cell purging strategy, gene suicide therapy, antisense therapy and others, targeted specifically to the leukemic stem cell pool.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL064856-02
Application #
6390727
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Thomas, John
Project Start
2000-06-01
Project End
2004-05-31
Budget Start
2001-09-20
Budget End
2002-05-31
Support Year
2
Fiscal Year
2001
Total Cost
$277,375
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Pearce, Daniel J; Taussig, David; Zibara, Kazem et al. (2006) AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML. Blood 107:1166-73
Bonnet, Dominique (2005) Normal and leukaemic stem cells. Br J Haematol 130:469-79
Bonnet, Dominique (2005) Leukemic stem cells show the way. Folia Histochem Cytobiol 43:183-6
Taussig, David C; Pearce, Daniel J; Simpson, Catherine et al. (2005) Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 106:4086-92
Iyer, Dinakar; Belaguli, Narasimhaswamy; Fluck, Martin et al. (2003) Novel phosphorylation target in the serum response factor MADS box regulates alpha-actin transcription. Biochemistry 42:7477-86
Bonnet, D (2003) Biology of human bone marrow stem cells. Clin Exp Med 3:140-9
Bonnet, Dominique (2003) Hematopoietic stem cells. Birth Defects Res C Embryo Today 69:219-29
Bonnet, D (2001) Normal and leukemic CD34-negative human hematopoietic stem cells. Rev Clin Exp Hematol 5:42-61