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The MYC Transcription Factor Network and the Path to Cancer

Award Number: R35CA231989
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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The MYC Transcription Factor Network and the Path to Cancer - Myc proteins are essential for normal cellular growth and proliferation. However, when its normal regulation is compromised (i.e. deregulated) Myc promotes initiation and progression of a broad spectrum of human cancers. Myc has been long known to be a transcription factor that heterodimerizes with the Max protein in order to specifically recognize DNA. When deregulated, Myc-Max alters gene expression programs resulting in metabolic and growth related changes that in turn support tumor progression. Recent studies show Myc- Max does not function alone, but is part of a larger transcriptional “network” of related, yet functionally dis- tinct, factors that heterodimerize with either Max or the Max-like protein MLX, or both. In order to understand and control Myc's role in the etiology of cancer it will be essential to define how Myc both depends on and influences the extended network. This application builds on 3 broad aspects of our ongoing studies: Transcriptional reprogramming of metabolism: We had earlier uncovered a critical role for Mlx, and its hetero- dimeric partner MondoA, in the metabolism and survival of several Myc-driven tumors. Focusing on pancre- atic adenocarcinoma we will examine cross-talk and functional dependencies involving Myc in the context of its extended network that may be exploited to identify new therapeutic strategies. Moreover, Myc and the other network proteins are transcription factors and we will determine their shared target genes and their co- operative effects on chromatin modifications and higher order structure as well as gene expression. Tumor suppression mediated by Mga, a member of the Myc Network: Mga is a large and unusual transcrip- tion factor with two distinct DNA binding domains, one of which dimerizes with Max, binds DNA, and is fre- quently subject to deletion or mutation in a wide range of neoplasms. However, little is known about Mga's oncogenic functions. Our very recent findings that Mga loss of function results in altered cell motility in vitro, and rapid lung adenocarcinoma formation in mice provide a biological system to elucidate Mga's capacity to suppress cancer. We will define regions in Mga essential for DNA binding, identify transcriptional complexes associated with Mga, and assess how loss of Mga leads to tumor initiation, progression and metastasis. Molecular alterations driving Myc oncogenicity: we introduced a point mutation (T58A), associated with B cell lymphomas and AML, within the phosphodegron of the endogenous murine myc gene. In these mice, Myc- T58A is regulated normally with no overt changes in tissue growth or proliferation. Yet we find that myc-T58A mice display increased hematopoietic progenitor cell self-renewal and resistance to apoptosis, and develop long-latency AML or lymphoma. Our data show that the Myc-T58A mutation alters the association of Myc with a specific co-regulatory complex. We hypothesize that this altered binding modifies expression of a sub- population of Myc target genes during hematopoiesis, resulting in production of tumor initiating cells. We plan to elucidate the underlying molecular basis for the T58A phenotype in these tumor-prone mice.


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: 2026 ( Subtotal = $0 )
2026	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	8	11/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $899,999 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	8	7/29/2024	NON-COMPETING CONTINUATION	$899,999
														Subtotal = $899,999

Issue Date FY: 2023 ( Subtotal = $1,034,880 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	7	9/15/2023	NON-COMPETING CONTINUATION	$947,591
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	7	9/25/2023	NON-COMPETING CONTINUATION	$87,289
														Subtotal = $1,034,880

Issue Date FY: 2022 ( Subtotal = $1,034,880 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	005	6	8/15/2022	NON-COMPETING CONTINUATION	$1,034,880
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	004	5	7/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	003	4	7/12/2022	NON-COMPETING CONTINUATION	$0
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	4	3/11/2022	NON-COMPETING CONTINUATION	$0
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	007	5	8/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$56,835
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	006	4	8/17/2022	NON-COMPETING CONTINUATION	-$56,835
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	002	5	6/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$479,851
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	4	6/9/2022	NON-COMPETING CONTINUATION	-$479,851
														Subtotal = $1,034,880

Issue Date FY: 2021 ( Subtotal = $1,055,996 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	4	8/30/2021	NON-COMPETING CONTINUATION	$1,055,996
														Subtotal = $1,055,996

Issue Date FY: 2020 ( Subtotal = $1,056,000 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	3	8/3/2020	NON-COMPETING CONTINUATION	$1,056,000
														Subtotal = $1,056,000

Issue Date FY: 2019 ( Subtotal = $1,024,317 )
2019	2019	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	2	8/21/2019	NON-COMPETING CONTINUATION	$1,024,317
														Subtotal = $1,024,317

Issue Date FY: 2018 ( Subtotal = $155,936 )
2018	2018	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	1	8/13/2018	NEW	$155,936
														Subtotal = $155,936

Grand Total All Awards = $6,262,008

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The MYC Transcription Factor Network and the Path to Cancer

Award Number: R35CA231989

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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