The overall goal of this research proposal is to further define the role of the Abcg2 transporter in hematopoietic stem cells (HSCs), in stem cells from other non-hematopoietic organs, and in cancer stem cells. Work in the prior funding period has shown that: 1) Abcg2 expression is required for the side population (SP) phenotype in HSCs and serves as a prospective molecular marker for isolating HSCs, 2) Abcg2-expressing SP cells exist in skeletal muscle, and as demonstrated by other labs, in many other non-hematopoietic organs, 3) a majority of human AML samples contain a small subpopulation of ABCG2-expressing cells that could represent a leukemia stem cell population, and 4) expression of Abcg2 protects HSCs from mitoxantrone, a xenobiotic drug. Experiments are now planned that will unequivocally determine whether Abcg2-expressing cells have stem cell activity in skeletal muscle and in other organ systems. By using a novel genetic approach, we will track the progeny of Abcg2-expressing cells in mice at different stages of development in order to evaluate candidate organ systems for the presence of Abcg2-expressing stem cells.
A second aim i s to use monoclonal antibodies to isolate hematopoietic stem cells from human and non-human primates. Using a panel of monoclonal antibodies that recognize external epitopes on ABCG2 that are present on living cells, we will isolate cells expressing ABCG2 and test them for hematopoietic stem cell function, with the ultimate goal defining a new stem cell population for use in transplantation protocols. Lastly, we will evaluate whether Abcg2 expression can identify cancer stem cells in myelogenous leukemia and in neuroblastoma. Both tumors contain a subpopulation of cells that express the side population phenotype and ABCG2, and therefore may represent a cancer stem cell population. We have and will develop novel genetic mouse models that should allow us to test this hypothesis in an unequivocal fashion. Not only could this provide a new marker for cancer stem cells, but it would have prognostic and therapeutic significance for these human cancers. Altogether, these studies should further elucidate the role of the Abcg2 transporter in normal and malignant stem cells, and should further increase our understanding of the role of ABC transporters in stem cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067366-08
Application #
7479086
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2005-08-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
8
Fiscal Year
2008
Total Cost
$355,568
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Fatima, Soghra; Zhou, Sheng; Sorrentino, Brian P (2018) Marking of definitive HSC precursors in E7.5-E8.5 embryos using an Abcg2-CreER lineage-tracing mouse model. Exp Hematol 65:29-33
Fatima, Soghra; Zhou, Sheng; Sorrentino, Brian P (2012) Abcg2 expression marks tissue-specific stem cells in multiple organs in a mouse progeny tracking model. Stem Cells 30:210-21
Nagai, Shinjiro; Takenaka, Kazumasa; Nachagari, Deepa et al. (2011) Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity. Cancer Res 71:1781-91
Campbell, Patrick K; Zong, Yang; Yang, Shengping et al. (2011) Identification of a novel, tissue-specific ABCG2 promoter expressed in pediatric acute megakaryoblastic leukemia. Leuk Res 35:1321-9
Takenaka, Kazumasa; Morgan, Jessica A; Scheffer, George L et al. (2007) Substrate overlap between Mrp4 and Abcg2/Bcrp affects purine analogue drug cytotoxicity and tissue distribution. Cancer Res 67:6965-72
Zong, Yang; Zhou, Sheng; Fatima, Soghra et al. (2006) Expression of mouse Abcg2 mRNA during hematopoiesis is regulated by alternative use of multiple leader exons and promoters. J Biol Chem 281:29625-32
Tadjali, Mehrdad; Zhou, Sheng; Rehg, Jerold et al. (2006) Prospective isolation of murine hematopoietic stem cells by expression of an Abcg2/GFP allele. Stem Cells 24:1556-63
Zhou, Sheng; Zong, Yang; Ney, Paul A et al. (2005) Increased expression of the Abcg2 transporter during erythroid maturation plays a role in decreasing cellular protoporphyrin IX levels. Blood 105:2571-6
Krishnamurthy, Partha; Schuetz, John D (2005) The ABC transporter Abcg2/Bcrp: role in hypoxia mediated survival. Biometals 18:349-58
Zong, Y; Zhou, S; Sorrentino, B P (2005) Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia 19:1590-6

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