Stem cell therapies play a major and increasing role in cancer therapies. If we were able to isolate repopulating stem cells, expand them in vitro and genetically manipulate them prior to reinfusion, we would be able to explore many avenues of protective therapies, including expansion of stem cells for multi-cycle chemotherapy, protection of stem cells with chemotherapy resistance genes, and improvement in stem cell quality with DNA repair genes. Published studies indicate that the homeobox gene HOXB4 is expressed in primitive hematopoietic cells, and that its enforced expression induces stem cell symmetric cycling. Our preliminary data indicates that we have isolated the human HOXB4 gene and its promoter, and that we have isolated at least two transcription factors that activate this promoter in both leukemic cells and normal CD34+ cells. In addition, we have found that CD34+ cells activating a HOXB4 expression construct are substantially enriched in long term culture initiating cells (LTCIC). This proposal seeks to identify and stimulate the fraction of stem cells that are capable of self-renewal, as illustrated by their ability to transcribe the homeobox gene HOXB4. In particular, we propose to: 1) Test the Ability of the Activated HOXB4 Promoter to NOD/SCID Repopulating Cells following Xenotransplantation; 2) Identify the Transcription Factors Activating the HOXB4 Promoter at the HxRE-1 (NF-1) Site; and 3) Identify Additional More Distant Genetic Elements That Enhance the Activity of the HOXB4 Promoter In Vivo. Integrated together, these aims will define a new paradigm for the molecular identification and manipulation of stem cells for hematopoietic support and genetic modification. If successful, this model should be directly translatable to clinical practice in the future.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA090833-01
Application #
6321190
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Mccarthy, Susan A
Project Start
2001-05-16
Project End
2005-03-31
Budget Start
2001-05-16
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$295,999
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
Zhao, Jin-Kou; Wu, Ming; Kim, Claire H et al. (2017) Jiangsu Four Cancers Study: a large case-control study of lung, liver, stomach, and esophageal cancers in Jiangsu Province, China. Eur J Cancer Prev 26:357-364
Meyers, Travis J; Chang, Shen-Chih; Chang, Po-Yin et al. (2017) Case-control study of cumulative cigarette tar exposure and lung and upper aerodigestive tract cancers. Int J Cancer 140:2040-2050
Miles, Fayth L; Chang, Shen-Chih; Morgenstern, Hal et al. (2016) Associations of red and processed meat with survival among patients with cancers of the upper aerodigestive tract and lung. Nutr Res 36:620-6
Miles, Fayth L; Chang, Shen-Chih; Morgenstern, Hal et al. (2016) Association of sugary beverages with survival among patients with cancers of the upper aerodigestive tract. Cancer Causes Control 27:1293-1300
Chen, Li-Shiun; Baker, Timothy; Hung, Rayjean J et al. (2016) Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis. EBioMedicine 11:219-226
Chen, Li-Shiun; Hung, Rayjean J; Baker, Timothy et al. (2015) CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis. J Natl Cancer Inst 107:
Zhang, Li Rita; Morgenstern, Hal; Greenland, Sander et al. (2015) Cannabis smoking and lung cancer risk: Pooled analysis in the International Lung Cancer Consortium. Int J Cancer 136:894-903
Huang, Ruyi; Wei, Yongyue; Hung, Rayjean J et al. (2015) Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium. EBioMedicine 2:1677-85
Kim, Claire H; Lee, Yuan-Chin Amy; Hung, Rayjean J et al. (2015) Secondhand Tobacco Smoke Exposure and Lung Adenocarcinoma In Situ/Minimally Invasive Adenocarcinoma (AIS/MIA). Cancer Epidemiol Biomarkers Prev 24:1902-6
Land, Ruben H; Rayne, Anna K; Vanderbeck, Ashley N et al. (2015) The orphan nuclear receptor NR4A1 specifies a distinct subpopulation of quiescent myeloid-biased long-term HSCs. Stem Cells 33:278-88

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