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BASIS FOR LYMPHOMAGENESIS IN AKT2 TRANSGENIC MICE

Award Number: R01CA077429
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/1998
PERIOD OF PERFORMANCE END DATE: 11/30/2014

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BASIS FOR LYMPHOMAGENESIS IN AKT2 TRANSGENIC MICE - ABSTRACT AKT plays a central role in tumorigenesis and is frequently activated in human lymphoma. v-akt is an oncogene harbored by a retrovirus that induced thymic T-cell lymphomas in mice, and transgenic mice expressing constitutively active forms of Akt (Myr-Akt) specifically in immature T cells develop thymic lymphomas. Multiple thymic lymphomas from a Myr-Akt2 mouse model were found to harbor a novel inversion of chromosome 6, inv(6), with breakpoints in the T-cell receptor beta chain locus (Tcrb) and Dss1 gene. A fusion protein was not detected, but the rearrangement places the Tcrb enhancer near several genes and noncoding RNAs that are consistently up regulated. Up regulation of one of these candidate genes, encoding the transcription factor Dlx5, has recently been reported in several common human cancers, suggesting that this homeobox gene may be oncogenic when expressed aberrantly. The broad, long-term objective of this project is to improve our understanding of the role of Akt2 in lymphomagenesis and elucidate mechanisms by which up regulation of Dlx5 converges with Akt2 signaling to promote tumor formation. The specific aims are: 1) Assess the relevance of up-regulated Dlx5 to lymphoma formation. We will determine if cell proliferation and/or viability of thymic lymphoma cells with the inv(6) are inhibited by knock down of Dlx5. In addition, bone marrow chimera experiments will be carried out to determine if knock down of Dlx5 in non-malignant marrow cells from a founder line with high incidence of inv(6)-positive lymphomas inhibits tumor formation in recipient wild-type littermates. We will also examine if transgenic mice engineered to overexpress Dlx5 in the thymus develop spontaneous T-cell lymphomas. 2) Using a direct genetic approach, test whether Dlx5 cooperates with Akt2 in thymic tumor development. Myr-Akt2 mice will be crossed with Dlx5 transgenic mice or conditional Dlx5 knockout mice to determine if tumor development is accelerated or inhibited, respectively. We will also identify mechanisms by which Akt2 cooperates with Dlx5 in tumorigenesis by assessing cell growth, proliferation and survival in primary thymocytes from transgenic mice expressing Dlx5 or Myr-Akt2 alone versus in combination. 3) Determine if hyperactivation of Akt2 signaling is required for both lymphoma development and maintenance of established tumors. Fluorescence in situ hybridization, PCR, and magnetic resonance microimaging analyses will be employed to establish when the inv(6) arises during tumor development; then an early intervention strategy will be used to determine if inhibition of Akt2 signaling prevents or delays the development of lymphoma. In addition, an inducible Myr-Akt2 model will be developed to ascertain if inactivation of Akt2 in established thymic lymphomas results in tumor regression. This project will enhance our understanding of Akt2-mediated lymphomagenesis and cooperation between Akt2 and a novel putative oncogene, Dlx5, whose activation may also contribute to the pathogenesis of various human cancers.


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: 2013 ( Subtotal = $374,544 )
2013	2013	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	001	14	5/28/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$175,318
2013	2013	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	14	1/22/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$199,226
														Subtotal = $374,544

Issue Date FY: 2012 ( Subtotal = $410,451 )
2012	2012	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	001	13	4/20/2012	NON-COMPETING CONTINUATION	$33,657
2012	2012	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	13	11/16/2011	NON-COMPETING CONTINUATION	$376,794
														Subtotal = $410,451

Issue Date FY: 2011 ( Subtotal = $419,987 )
2011	2011	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	001	12	5/16/2011	NON-COMPETING CONTINUATION	$18,618
2011	2011	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	12	10/28/2010	NON-COMPETING CONTINUATION	$401,369
														Subtotal = $419,987

Issue Date FY: 2010 ( Subtotal = $452,084 )
2010	2010	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	11	11/10/2009	NON-COMPETING CONTINUATION	$410,865
2010	2010	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	001	11	1/26/2010	NON-COMPETING CONTINUATION	$41,219
														Subtotal = $452,084

Issue Date FY: 2009 ( Subtotal = $418,237 )
2009	2009	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	002	10	4/7/2009	COMPETING CONTINUATION	$52,789
2009	2009	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	001	10	11/26/2008	COMPETING CONTINUATION	$365,448
2009	2006	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	9	11/26/2008	NON-COMPETING CONTINUATION	$0
														Subtotal = $418,237

Issue Date FY: 2006 ( Subtotal = $392,240 )
2006	2006	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	9	2/6/2006	NON-COMPETING CONTINUATION	$392,240
														Subtotal = $392,240

Issue Date FY: 2005 ( Subtotal = $420,343 )
2005	2005	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	8	2/22/2005	NON-COMPETING CONTINUATION	$420,343
														Subtotal = $420,343

Issue Date FY: 2004 ( Subtotal = $462,064 )
2004	2004	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Cause and Prevention Research	000	7	2/3/2004	NON-COMPETING CONTINUATION	$462,064
														Subtotal = $462,064

Issue Date FY: 2003 ( Subtotal = $396,934 )
2003	2003	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	6		NON-COMPETING CONTINUATION	$396,934
														Subtotal = $396,934

Issue Date FY: 2002 ( Subtotal = $382,920 )
2002	2002	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	5	1/14/2002	COMPETING CONTINUATION	$382,920
														Subtotal = $382,920

Issue Date FY: 2001 ( Subtotal = $310,502 )
2001	2001	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	4	2/16/2001	NON-COMPETING CONTINUATION	$310,502
														Subtotal = $310,502

Issue Date FY: 2000 ( Subtotal = $297,470 )
2000	2000	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	3	2/16/2000	NON-COMPETING CONTINUATION	$297,470
														Subtotal = $297,470

Issue Date FY: 1999 ( Subtotal = $283,983 )
1999	1999	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	2	2/17/1999	NON-COMPETING CONTINUATION	$283,983
														Subtotal = $283,983

Issue Date FY: 1998 ( Subtotal = $269,393 )
1998	1998	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	1	5/29/1998	NEW	$269,393
														Subtotal = $269,393

Grand Total All Awards = $5,291,152

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BASIS FOR LYMPHOMAGENESIS IN AKT2 TRANSGENIC MICE

Award Number: R01CA077429

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/1998

PERIOD OF PERFORMANCE END DATE: 11/30/2014

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