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Functional and Molecular Dissection of Mutant Calreticulin in Myeloproliferative Neoplasms

Award Number: R01HL131835
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/20/2024
PERIOD OF PERFORMANCE END DATE: 09/30/2026

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Functional and Molecular Dissection of Mutant Calreticulin in Myeloproliferative Neoplasms - PROJECT SUMMARY Although the mechanism by which calreticulin (CALR) mutations cause myeloproliferative neoplasms (MPN) has been elucidated, there is currently a fundamental gap in translating this knowledge into innovative therapeutic strategies. The long-term goal is to advance the treatment of CALR-mutant MPN, in particular to develop new therapies with disease-modifying activity and curative potential. The overall objective in this application is to exploit the insights we have gained from understanding the altered biochemical properties and unique molecular dependencies of mutant CALR-driven MPN, to identify novel therapeutic vulnerabilities, including in the context of CALR/ASXL1 co-mutation. The central hypothesis is that CALR-mutant hematopoietic stem cells (HSC) have unique properties, which arise as a consequence of the mechanism of oncogenicity of mutant CALR, which we have previously elucidated. The specific properties, which we hypothesize that CALR-mutant HSC possess, include altered protein homeostasis and a differential dependency on key cellular pathways (e.g. N-glycosylation and protein secretion) for survival. We further hypothesize that co-operating genetic events (e.g. concomitant ASXL1 mutation) alter the chromatin state of CALR-mutant HSC to drive disease progression in MPN. The rationale for the proposed research is that, once we develop novel therapeutic strategies to target the unique properties of CALR-mutant HSC, we will be able to preferentially target CALR-mutant MPN cells in patients. This has the potential to alter the natural history of CALR-mutant MPN, including in the context of ASXL1 co-mutation, which confers a negative prognostic impact on CALR-mutant MPN. Guided by strong preliminary data, the hypothesis will be tested by pursuing three specific aims: 1) Determine protein homeostasis and sensitivity to proteasome inhibition in Calr-mutant HSC; 2) Determine the molecular vulnerabilities of mutant CALR-driven MPN; and 3) Determine the impact of mutant Asxl1 on Calr-mutant MPN in vivo. Under the first aim, a mutant CALR knockin (KI) mouse model that closely recapitulates the features of human CALR-mutant MPN will be employed to measure protein synthesis and proteasome activity in Calr-mutant HSC and to determine if Calr- mutant HSC are differentially sensitive to in vivo proteasome inhibition. Under the second aim, key cellular pathways we have found to be uniquely required for the survival of mutant CALR-expressing hematopoietic cells in an in vitro whole genome CRISPR knockout screen, will be inhibited using functional genetic and pharmacological approaches in mutant CALR KI mice. Under the third aim, the impact of mutant Asxl1 on histone modifications, chromatin state and the transcriptome of Calr-mutant HSC, will be determined using a mutant Asxl1 KI mouse. The approach is innovative through the application of novel murine models, in vitro and in vivo CRISPR/Cas9 gene editing, chemical screening and mass spectrometry (MS)-based quantitative proteomics. The proposed research is significant because it will uncover novel therapeutic vulnerabilities in CALR-mutant MPN. Ultimately, such knowledge has the potential to be transformative in the treatment of this disease.


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	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Blood Diseases and Resources Research	001	9	3/28/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$41,388
2025	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	8	3/28/2025	NON-COMPETING CONTINUATION	-$41,388
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $355,000 )
2024	2024	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Blood Diseases and Resources Research	001	9	9/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$355,000
2024	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	8	9/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $355,000

Issue Date FY: 2023 ( Subtotal = $401,996 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	8	7/17/2023	NON-COMPETING CONTINUATION	$401,996
														Subtotal = $401,996

Issue Date FY: 2022 ( Subtotal = $401,996 )
2022	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	002	7	8/16/2022	NON-COMPETING CONTINUATION	$401,996
2022	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	6	5/11/2022	COMPETING CONTINUATION	$89
2022	2020	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	5	5/11/2022	NON-COMPETING CONTINUATION	-$89
														Subtotal = $401,996

Issue Date FY: 2021 ( Subtotal = $401,996 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	6	6/22/2021	COMPETING CONTINUATION	$401,996
2021	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	001	5	8/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $401,996

Issue Date FY: 2020 ( Subtotal = $436,000 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	5	5/28/2020	NON-COMPETING CONTINUATION	$436,000
														Subtotal = $436,000

Issue Date FY: 2019 ( Subtotal = $436,000 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	4	5/28/2019	NON-COMPETING CONTINUATION	$436,000
														Subtotal = $436,000

Issue Date FY: 2018 ( Subtotal = $436,000 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	3	5/11/2018	NON-COMPETING CONTINUATION	$436,000
														Subtotal = $436,000

Issue Date FY: 2017 ( Subtotal = $436,000 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Blood Diseases and Resources Research	000	2	5/8/2017	NON-COMPETING CONTINUATION	$436,000
														Subtotal = $436,000

Issue Date FY: 2016 ( Subtotal = $436,000 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	7/15/2016	NEW	$436,000
														Subtotal = $436,000

Grand Total All Awards = $3,740,988

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Functional and Molecular Dissection of Mutant Calreticulin in Myeloproliferative Neoplasms

Award Number: R01HL131835

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/20/2024

PERIOD OF PERFORMANCE END DATE: 09/30/2026

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