Monday, June 30, 2025 6/30/2025

Distinct roles of U2AF1 mutations in myelodysplastic syndrome pathogenesis

Award Number: K08HL159354
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/09/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Distinct roles of U2AF1 mutations in myelodysplastic syndrome pathogenesis - PROJECT SUMMARY/ABSTRACT This proposal outlines a 5-year training plan for the transition of the candidate to an independent investigator. The long-term goal of the candidate is to be a physician-scientist at an academic medical center studying the molecular basis of genetic mutations in myelodysplastic syndrome (MDS) pathogenesis, in addition to directing a molecular pathology laboratory. The training plan proposed will expand upon the candidate's clinical and scientific background and provide him access to a supportive environment that will prepare him for a career as an independent investigator. The applicant will be mentored by Dr. Matthew Walter, an expert in MDS genetics and biology and Director of the Edward P. Evans Center for MDS at Washington University (WU). An advisory committee consisting of basic science and clinical/translational MDS experts and pathologists will provide scientific and career advice. The applicant's laboratory is well equipped for these studies, and WU provides a rich environment for training and development as access to core facilities, scientific resources, and clinical samples is exceptional. The experiments outlined in this application aim to clarify the distinct roles of different U2AF1 mutants in MDS pathogenesis, as highly recurrent heterozygous mutations in splicing factor genes (e.g., U2AF1) occur in over half of MDS patients. Hotspot mutations in U2AF1 (encoding U2AF1S34 and U2AF1Q157 mutants) are associated with different clinical features, outcomes, dysregulated RNA splicing, and co-occurring gene mutations in patients with MDS. For example, truncating mutations in ASXL1 cooccur more frequently with U2AF1Q157 than with U2AF1S34 mutations in MDS patients. The candidate has observed U2af1S34F/+ and U2af1Q157R/+ conditional knock-in mice develop different hematopoietic phenotypes, including cytopenias, and have distinct gene expression patterns and aberrant RNA splicing in hematopoietic stem and progenitor cells (HSPC). This proposal aims to understand how the distinct molecular perturbations induced by U2AF1S34F and U2AF1Q157R mutants contribute to the divergent hematopoietic phenotypes observed in MDS patients by determining: (1) how activation of MYC and mTORC1 pathways leads to HSPC dysfunction and multilineage cytopenias in U2af1S34F/+ mice and whether U2AF1S34F-specific splicing alterations result in activation of these pathways, and (2) how mutant ASXL1 and U2AF1Q157 associated histone modification and RNA splicing aberrancies selectively cooperate in MDS pathogenesis. Deciphering the role of MYC and mTORC1 activation will allow these models to be used to test pathway-specific therapeutic strategies to alter cytopenias, and identification of cooperation between ASXL1 and U2AF1 mutations in vivo may reveal novel mechanisms by which RNA splicing and histone modifications synergize in MDS. In sum, the proposed studies and training environment will facilitate the candidate's success in becoming an independent investigator.


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 = $162,828 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	000	5	5/28/2025	NON-COMPETING CONTINUATION	$162,828
														Subtotal = $162,828

Issue Date FY: 2024 ( Subtotal = $162,828 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	000	4	6/14/2024	NON-COMPETING CONTINUATION	$162,828
2024	2021	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	001	1	7/18/2024	NEW	$0
														Subtotal = $162,828

Issue Date FY: 2023 ( Subtotal = $162,828 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	000	3	6/21/2023	NON-COMPETING CONTINUATION	$162,828
														Subtotal = $162,828

Issue Date FY: 2022 ( Subtotal = $162,828 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Blood Diseases and Resources Research	002	2	8/19/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$162,828
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	001	1	8/18/2022	NEW	$0
2022	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	000	1	10/14/2021	NEW	$0
														Subtotal = $162,828

Issue Date FY: 2021 ( Subtotal = $162,828 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	000	1	7/8/2021	NEW	$162,828
														Subtotal = $162,828

Grand Total All Awards = $814,140

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Distinct roles of U2AF1 mutations in myelodysplastic syndrome pathogenesis

Award Number: K08HL159354

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/09/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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