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Synergestic roles of SRF2 and RUNX1 in blood cell development and pathology

Award Number: R01DK098808
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2013
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Synergestic roles of SRF2 and RUNX1 in blood cell development and pathology - Summary Myelodysplastic Syndromes (MDS) are chronic hematopoietic disorders characterized by dysplasia, inefficient hematopoiesis, and the propensity to transform into acute myeloid leukemia (AML). Recent advances in genomic sequencing revealed a large number of mutations associated with the disease, which can be roughly grouped into three classes: (1) genes involved in signaling (i.e. FLT3, JAK2, KRAS), (2) genes functioning at the levels of chromatin and pre-mRNA splicing (i.e. RUNX1, ASXL1, SRSF2, U2AF1), and (3) genes responsible for establishing/maintaining the genome methylome (i.e. DNMT3a, TET2, IDH1/2). Given MDS is highly heterogeneous in its clinical features, a fundamental question is whether individual mutations cause the disease via distinct mechanisms or whether many mutations function in some converging pathways. Support of the latter possibility is the co-occurrence of many of these causal mutations in MDS patients. As disease-oriented (Zhang) and mechanism-central (Fu) labs, we have been taking advantage of our combined expertise to work together under this funded R01 to attack some pressing questions in the field, focusing on RUNX1 and SRSF2. In the past funding cycle (9/2013-present), we have made two conceptual breakthroughs. First, by linking specific mutations to splicing responses in MDS patients, we found that non- overlapping responses induced by splicing factor mutations are converged to the common pathways of cell cycle and DNA damage response. Second, we unexpectedly uncovered that, besides their traditional roles in splicing, all causal mutations in key splicing factors trigger excessive R-loop formation, leading to replication stress and cell cycle checkpoint activation. These findings point to dysregulation of the DNA damage response as a common ground for MDS etiology. Importantly, such elucidated common ground has laid a critical foundation for our next phase of investigation, which is to understand the contribution of individual mutations to MDS and potential synergy among them, despite their diverse roles in regulating gene expression. Building upon both our published and unpublished results, we propose to pursue the following specific aims in the next phase: Aim 1. Function of RUNX1 and its synergy with SRSF2 in preventing DNA damage; Aim 2. Mutant SRSF2 and epigenetic regulators to synergistically drive aberrant gene expression; Aim 3. Potential mechanism for bypassing R-loop-induced cell cycle checkpoint activation.


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	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	9/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $620,251 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	6/13/2022	NON-COMPETING CONTINUATION	$620,251
														Subtotal = $620,251

Issue Date FY: 2021 ( Subtotal = $632,046 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/30/2021	NON-COMPETING CONTINUATION	$632,046
														Subtotal = $632,046

Issue Date FY: 2020 ( Subtotal = $641,790 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	4/17/2020	NON-COMPETING CONTINUATION	$641,790
2020	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/17/2020	COMPETING CONTINUATION	$0
														Subtotal = $641,790

Issue Date FY: 2019 ( Subtotal = $582,127 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	4/29/2019	COMPETING CONTINUATION	$650,270
2019	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/10/2019	NON-COMPETING CONTINUATION	-$68,143
														Subtotal = $582,127

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	9/13/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $424,003 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/10/2017	NON-COMPETING CONTINUATION	$424,003
2017	2015	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/17/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $424,003

Issue Date FY: 2016 ( Subtotal = $439,348 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/4/2016	EXTENSION WITH OR WITHOUT FUNDS	$439,348
														Subtotal = $439,348

Issue Date FY: 2015 ( Subtotal = $451,324 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/5/2015	NON-COMPETING CONTINUATION	$451,324
														Subtotal = $451,324

Issue Date FY: 2014 ( Subtotal = $460,948 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/20/2014	NON-COMPETING CONTINUATION	$460,948
														Subtotal = $460,948

Issue Date FY: 2013 ( Subtotal = $470,572 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/13/2013	NEW	$470,572
														Subtotal = $470,572

Grand Total All Awards = $4,722,409

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Synergestic roles of SRF2 and RUNX1 in blood cell development and pathology

Award Number: R01DK098808

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/16/2013

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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