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Molecular Mechanisms of eIF4E Mediated Transformation

Award Number: R01CA098571
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2003
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Molecular Mechanisms of eIF4E Mediated Transformation - Abstract This revised renewal application investigates novel mechanisms driving dysregulation of post- transcriptional control in cancer. Indeed, dysregulation of these events can drive the production of proteins that underpin proliferation, survival, invasion and metastases. Dysregulation can occur at many levels of RNA processing including splicing of RNAs, their nuclear export and translation. The eukaryotic translation initiation factor eIF4E, dysregulated in ~30% of cancers including in acute myeloid leukemia (AML), governs the RNA processing of networks of transcripts that ultimately underpin its oncogenic activities. Its ability to govern these regulons has been attributed to its well-established roles in nuclear export and translation of specific RNAs. Here, we discovered that eIF4E reprograms the splicing landscape of 1000s of transcripts both as a function of eIF4E dysregulation in AML patients as well as upon eIF4E overexpression in model systems. We compared alternative splicing (AS) events in high-eIF4E AML and upon eIF4E overexpression in cells, postulating those in common would represent pan-cancer targets of eIF4E-dependent splicing. We discovered a set of ~150 AS “core” transcripts, which encoded factors in the same biochemical networks. Importantly, these pathways also play roles in AML and in cancer more generally. Many of the AS events are predicted to produce proteins with different domain structures and thus altered functionalities. As to the mechanisms by which eIF4E modulates AS, our studies unearthed physical interactions between eIF4E and components of the spliceosome as well as revealed novel means to control the production of the splicing machinery i.e. via eIF4E. Three aims are proposed to dissect the mechanistic principles and biological impacts related to these novel findings: Aim 1. Explore eIF4E-dependent alterations to splicing where we will dissect the biochemical activities of eIF4E required for its AS activity, and assess the functional outcome of this activity; Aim 2. Elucidate the biochemical role that eIF4E plays in re-programming splicing by dissecting the physical interactions of eIF4E with components of the spliceosome and ascertain its relationship with active spliceosomes; and Aim 3. Determine the impact of dysregulated eIF4E-dependent splicing in AML where we will explore the impact of AS, and identify the splicing factors required for eIF4E’s activity. These studies will transform our view with regard to the impact of eIF4E dysregulation, which would now include altering the form of the transcript as well as regulating its protein-coding capacity.


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: 2025 ( Subtotal = $0 )
2025	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Biology Research	001	20	3/6/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$276,965
2025	2024	UNIVERSITE DE MONTREAL	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC			CAN	Cancer Biology Research	000	19	3/6/2025	NON-COMPETING CONTINUATION	-$276,965
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $276,966 )
2024	2024	UNIVERSITE DE MONTREAL	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC			CAN	Cancer Biology Research	000	19	6/3/2024	NON-COMPETING CONTINUATION	$276,966
														Subtotal = $276,966

Issue Date FY: 2023 ( Subtotal = $291,544 )
2023	2023	UNIVERSITE DE MONTREAL	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC			CAN	Cancer Biology Research	000	18	5/31/2023	NON-COMPETING CONTINUATION	$285,712
2023	2023	UNIVERSITE DE MONTREAL	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC			CAN	Cancer Biology Research	001	18	9/15/2023	NON-COMPETING CONTINUATION	$5,832
														Subtotal = $291,544

Issue Date FY: 2022 ( Subtotal = $285,712 )
2022	2022	UNIVERSITE DE MONTREAL, L'	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC			CAN	Cancer Biology Research	001	17	7/1/2022	NON-COMPETING CONTINUATION	$285,712
2022	2021	UNIVERSITE DE MONTREAL, L'	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC			CAN	Cancer Biology Research	000	16	12/21/2021	COMPETING CONTINUATION	$0
														Subtotal = $285,712

Issue Date FY: 2021 ( Subtotal = $293,545 )
2021	2021	UNIVERSITE DE MONTREAL, L'	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC			CAN	Cancer Biology Research	001	16	9/21/2021	COMPETING CONTINUATION	$293,545
2021	2019	UNIVERSITE DE MONTREAL, L'	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC			CAN	Cancer Biology Research	000	15	8/26/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $293,545

Issue Date FY: 2019 ( Subtotal = $220,245 )
2019	2019	UNIVERSITE DE MONTREAL, L'	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC	H3T 1J4		CAN	Cancer Biology Research	000	15	3/27/2019	NON-COMPETING CONTINUATION	$220,245
														Subtotal = $220,245

Issue Date FY: 2018 ( Subtotal = $227,057 )
2018	2018	UNIVERSITE DE MONTREAL, L'	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC	H3T 1J4		CAN	Cancer Biology Research	000	14	4/12/2018	NON-COMPETING CONTINUATION	$227,057
														Subtotal = $227,057

Issue Date FY: 2017 ( Subtotal = $256,369 )
2017	2017	UNIVERSITE DE MONTREAL, L'	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC	H3T 1J4		CAN	Cancer Biology Research	001	13	6/7/2017	NON-COMPETING CONTINUATION	$25,637
2017	2017	UNIVERSITE DE MONTREAL, L'	2900 BOUL EDOUARD-MONTPETIT	MONTREAL	QC	H3T 1J4		CAN	Cancer Biology Research	000	13	4/26/2017	NON-COMPETING CONTINUATION	$230,732
														Subtotal = $256,369

Issue Date FY: 2016 ( Subtotal = $227,057 )
2016	2016	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Cancer Biology Research	000	12	5/13/2016	NON-COMPETING CONTINUATION	$227,057
														Subtotal = $227,057

Issue Date FY: 2015 ( Subtotal = $227,057 )
2015	2015	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Cancer Biology Research	001	11	5/5/2015	COMPETING CONTINUATION	$215,107
2015	2015	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Cancer Biology Research	002	11	5/11/2015	COMPETING CONTINUATION	$11,950
2015	2013	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC		00000		CAN	Cancer Biology Research	000	10	4/29/2015	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $227,057

Issue Date FY: 2013 ( Subtotal = $202,079 )
2013	2013	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Cancer Biology Research	000	10	6/10/2013	EXTENSION WITH OR WITHOUT FUNDS	$202,079
														Subtotal = $202,079

Issue Date FY: 2012 ( Subtotal = $214,977 )
2012	2012	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Cancer Biology Research	000	9	5/3/2012	NON-COMPETING CONTINUATION	$214,977
														Subtotal = $214,977

Issue Date FY: 2011 ( Subtotal = $214,976 )
2011	2011	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Cancer Biology Research	001	8	5/17/2011	NON-COMPETING CONTINUATION	$9,530
2011	2011	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Cancer Biology Research	000	8	4/4/2011	NON-COMPETING CONTINUATION	$205,446
														Subtotal = $214,976

Issue Date FY: 2010 ( Subtotal = $221,625 )
2010	2010	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Cancer Biology Research	000	7	8/4/2010	NON-COMPETING CONTINUATION	$221,625
														Subtotal = $221,625

Issue Date FY: 2009 ( Subtotal = $217,280 )
2009	2009	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC				CAN	Cancer Biology Research	000	6	7/7/2009	COMPETING CONTINUATION	$217,280
														Subtotal = $217,280

Issue Date FY: 2007 ( Subtotal = $204,807 )
2007	2007	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC		00000		CAN	Cancer Biology Research	000	5	5/2/2007	NON-COMPETING CONTINUATION	$204,807
														Subtotal = $204,807

Issue Date FY: 2006 ( Subtotal = $210,924 )
2006	2006	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC		00000		CAN	Cancer Biology Research	000	4	4/24/2006	NON-COMPETING CONTINUATION	$210,924
														Subtotal = $210,924

Issue Date FY: 2005 ( Subtotal = $216,000 )
2005	2005	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC		00000		CAN	Cancer Biology Research	000	3	7/7/2005	NON-COMPETING CONTINUATION	$216,000
														Subtotal = $216,000

Issue Date FY: 2004 ( Subtotal = $216,000 )
2004	2004	UNIVERSITY OF MONTREAL	3850 RUE SAINT-URBAIN	MONTREAL, QUEBEC		00000		CAN	Cancer Biology Research	000	2	9/24/2004	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$216,000
														Subtotal = $216,000

Issue Date FY: 2003 ( Subtotal = $339,424 )
2003	2003	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Cancer Biology Research	000	1	7/25/2003	NEW	$339,424
														Subtotal = $339,424

Grand Total All Awards = $4,563,644

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Molecular Mechanisms of eIF4E Mediated Transformation

Award Number: R01CA098571

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2003

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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