Stem cell therapies play a major and increasing role in cancer therapies. The ability to expand stem cell numbers would have broad application in hematology and oncology. In addition, the ability to enforce stem cell differentiation could improve the therapy of many cancers, notably acute leukemias. Biochemical and genetic experiments in many systems indicate that homeobox proteins regulate the balance between stem cells and lineage-specific cells, in many tissues. We have recently found that the trimeric transcription factor NF-Y, which had been previously shown to regulate c-jun, p27 and CD34 transcription, is the key regulated transcription factor controlling the expression of HOXB4, as well as the paralogs HOXC4 and HOXD4. Enforced overexpression of NF-Ya, the inducible element of the trimer, in stem cells by retroviral gene transfer increases the expression of HOXB4, HOXC4, HOXD4, as well as hTERT, LEF-1 and several stem cell markers. NF-Ya overexpression in stem cells also increases stem cell numbers as assayed by competitive repopulation following stem cell transplantation, while inhibition of NF-Y activity decreases stem cell numbers and promotes terminal differentiation. Based upon these data, we hypothesize that NF-Y functions as a master switch, controlling the expression of several genes critical for stem cell cycling and proliferation, including homeobox and other genes. To explore and test this hypothesis, we propose to: 1) Measure the consequences of NF-Ya over/ and underexpression in hematopoietic stem cells, both in normal mice and mouse strains deficient in each of several candidate downstream NF-Y target genes; 2) test the ability of soluble TAT-NF-Ya protein to biochemically and reversibly activate NF-Y target genes and increase HSCs, as measured by transplantation in vivo; and 3) Test the ability of DN-NF-Ya, and TAT-DN- NF-Ya protein to differentiate primary AML blasts in vitro, and on NOD/SCID mice with human AML in vivo. These experiments will describe in detail the role of NF-Y in the biology of hematopoietic stem cells, and will develop two experimental therapies based directly on the biology of NF-Y, for both HSC expansion and HSC differentiation. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA090833-05A1
Application #
7097538
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Mccarthy, Susan A
Project Start
2001-05-16
Project End
2007-07-31
Budget Start
2006-08-07
Budget End
2007-07-31
Support Year
5
Fiscal Year
2006
Total Cost
$287,409
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

Showing the most recent 10 out of 44 publications