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STEM CELL MANIPULATION VIA HOX GENE REGULATION

Award Number: R01CA090833
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/16/2001
PERIOD OF PERFORMANCE END DATE: 07/31/2011

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STEM CELL MANIPULATION VIA HOX GENE REGULATION - DESCRIPTION (provided by applicant): 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2010 ( Subtotal = $280,779 )
2010	2010	HAVERFORD COLLEGE	370 Lancaster Ave	HAVERFORD	PA	19041	MONTGOMERY	USA	Cancer Biology Research	000	9	7/13/2010	NON-COMPETING CONTINUATION	$280,779
														Subtotal = $280,779

Issue Date FY: 2009 ( Subtotal = $280,779 )
2009	2009	HAVERFORD COLLEGE	370 Lancaster Ave	HAVERFORD	PA	19041	MONTGOMERY	USA	Cancer Biology Research	000	8	7/17/2009	NON-COMPETING CONTINUATION	$280,779
														Subtotal = $280,779

Issue Date FY: 2008 ( Subtotal = $280,779 )
2008	2008	HAVERFORD COLLEGE		HAVERFORD	PA	19041	MONTGOMERY	USA	Cancer Biology Research	000	7	8/1/2008	NON-COMPETING CONTINUATION	$280,779
														Subtotal = $280,779

Issue Date FY: 2007 ( Subtotal = $280,779 )
2007	2007	HAVERFORD COLLEGE		HAVERFORD	PA	19041	MONTGOMERY	USA	Cancer Biology Research	000	6	9/21/2007	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$280,779
														Subtotal = $280,779

Issue Date FY: 2006 ( Subtotal = $287,409 )
2006	2006	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	5	8/7/2006	COMPETING CONTINUATION	$287,409
														Subtotal = $287,409

Issue Date FY: 2004 ( Subtotal = $295,999 )
2004	2004	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	4	3/29/2004	NON-COMPETING CONTINUATION	$295,999
														Subtotal = $295,999

Issue Date FY: 2003 ( Subtotal = $295,999 )
2003	2003	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	3		NON-COMPETING CONTINUATION	$295,999
														Subtotal = $295,999

Issue Date FY: 2002 ( Subtotal = $295,999 )
2002	2002	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	2	3/25/2002	NON-COMPETING CONTINUATION	$295,999
														Subtotal = $295,999

Issue Date FY: 2001 ( Subtotal = $295,999 )
2001	2001	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	5/16/2001	NEW	$295,999
														Subtotal = $295,999

Grand Total All Awards = $2,594,521

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STEM CELL MANIPULATION VIA HOX GENE REGULATION

Award Number: R01CA090833

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/16/2001

PERIOD OF PERFORMANCE END DATE: 07/31/2011

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