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Functional and molecular consequences of SF3B1 mutations in human hematopoietic stem cells

Award Number: R01HL151651
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Functional and molecular consequences of SF3B1 mutations in human hematopoietic stem cells - ABSTRACT The surprising discovery that RNA splicing alterations induced by recurrent and common change-of-function mutations in the spliceosome can perturb hematopoiesis and lead to disease has raised a number of fundamental questions. SF3B1 mutations are found ~30% of patients with myelodysplastic syndromes (MDS) and are common disease-initiating events that first arise in hematopoietic stem cells (HSCs) in premalignant clonal hematopoiesis, or CHIP. The finding of SF3B1 mutations in CHIP suggests that these mutations confer a clonal fitness advantage to HSCs. However, how SF3B1 mutations dysregulate HSC function to promote clonal expansion and subsequent MDS development has not been established. We lack an understanding of how these mutations “re-wire” RNA splicing in HSCs, which mis-spliced genes are critical for promoting clonal expansion and impaired differentiation of mutant stem cells, and how to target pathogenic mis-splicing while sparing alternative splicing that is essential for normal HSC function. Here, we propose to gain a fundamental understanding of how SF3B1 mutations promote CHIP and MDS and use this knowledge to develop new therapeutic approaches. Our team consists of a stem cell biologist with expertise in hematologic disease modeling (Doulatov), a basic scientist with expertise in RNA splicing and functional genomics (Bradley), and a physician-scientist with expertise in MDS pathophysiology (Abkowitz). In preliminary studies, we leveraged precise gene editing in human HSCs to define the molecular and functional RNA splicing alterations induced by mutant SF3B1 in the HSC context. These experiments uncovered novel HSC-specific mis-spliced isoforms, implicating an altered response to inflammatory signaling in pathophysiology; showed that SF3B1-mutant human HSCs display robust in vivo reconstitution in humanized mice, including a competitive advantage over their wild-type counterparts; and identified checkpoint kinase 1 (CHK1) inhibition as a promising therapeutic strategy for selectively targeting SF3B1-mutant HSCs. We propose to build on these preliminary studies as follows: Aim 1, Define the molecular consequences of SF3B1 mutations on RNA splicing in human HSCs and progenitors; Aim 2, Define the functional basis of clonal expansion and aberrant differentiation of SF3B1-mutated HSCs; Aim 3, Identify therapeutic vulnerabilities and preclinical efficacy created by coordinated mis-splicing of mitotic regulators. The significance of these studies is that they will directly connect RNA mis-splicing to HSC dysfunction and pathology in MDS. The health relevance is that the proposed work will directly test novel treatments for MDS with SF3B1 mutations.


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	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Blood Diseases and Resources Research	000	6	11/26/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $719,314 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Blood Diseases and Resources Research	000	6	7/24/2025	COMPETING CONTINUATION	$719,314
2025	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	5	9/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $719,314

Issue Date FY: 2023 ( Subtotal = $629,851 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	5	6/8/2023	NON-COMPETING CONTINUATION	$633,700
2023	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	2	5/15/2023	NON-COMPETING CONTINUATION	-$3,849
														Subtotal = $629,851

Issue Date FY: 2022 ( Subtotal = $636,097 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	002	4	7/8/2022	NON-COMPETING CONTINUATION	$636,097
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	3	6/23/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$174,777
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	003	3	8/3/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	005	3	8/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,338
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	004	2	8/31/2022	NON-COMPETING CONTINUATION	-$1,338
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	2	6/21/2022	NON-COMPETING CONTINUATION	-$174,777
														Subtotal = $636,097

Issue Date FY: 2021 ( Subtotal = $636,097 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	2	6/22/2021	NON-COMPETING CONTINUATION	$636,097
														Subtotal = $636,097

Issue Date FY: 2020 ( Subtotal = $654,938 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	1	5/20/2020	NEW	$654,938
														Subtotal = $654,938

Grand Total All Awards = $3,276,297

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Functional and molecular consequences of SF3B1 mutations in human hematopoietic stem cells

Award Number: R01HL151651

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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