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The Pathophysiology of Type 1 Versus Type 2 Mutant Calreticulin-Drivenmyeloproliferative Neoplasms

Award Number: R01HL165119
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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The Pathophysiology of Type 1 Versus Type 2 Mutant Calreticulin-Drivenmyeloproliferative Neoplasms - Project Summary Myeloproliferative neoplasms (MPNs) include primary myelofibrosis (PMF; characterized by the over- proliferation of megakaryocytes and granulocytes with abnormal collagen deposition in the bone marrow stroma), essential thrombocythemia (ET; increased megakaryocyte and platelet production), and polycythemia vera (PV; increased red cell production, hemoglobin, and hematocrit). Although all MPN driver mutations lead to constitutive activation of JAK/STAT signaling, targeted JAK inhibitors are not curative and fail to alter disease progression. Therefore, there is a great unmet need to identify novel curative therapies for MPNs. Mutations in calreticulin (CALR) represent the second most common genetic abnormality in MPN. The CALR gene encodes a calcium (Ca2+)-binding chaperone protein that primarily resides in the endoplasmic reticulum (ER). All CALR mutations share an identical neomorphic C-terminal peptide, which permits binding to the thrombopoietin receptor MPL and the subsequent activation of pathogenic JAK/STAT signaling. The majority of CALR mutations are classified as either type 1 or type 2 based on the extent of homology to the wild type protein, where type 1 proteins exhibit complete loss of C-terminal Ca2+ binding sites that are retained in type 2. Despite their shared mutant C-terminus and ability to bind and activate MPL, type 1 and 2 CALR mutations engender significant phenotypic and prognostic differences. Type 1 mutations are more common in PMF, and are associated with increased risk of myelofibrotic transformation from ET. Conversely, type 2 mutations are primarily associated with ET, exhibit low incidence of myelofibrotic transformation, and are rarely found in PMF. The mechanisms underlying these divergent clinical phenotypes remain unknown. We discovered that the IRE1a/XBP1 pathway of the unfolded protein response (UPR) is differentially activated in type 1 versus type 2 mutant CALR cells, and that type 1 mutant CALR cells are dependent on this pathway for survival and to drive ET. We found that IRE1a/XBP1 is activated only by type 1 and not type 2 mutant CALR due to a loss of calcium binding function specific to the type 1 protein. More recently, we found that the ATF6 pathway of the UPR is differentially up- regulated in type 2 compared to type 1 mutant CALR cells, and that type 2 mutant proteins exhibit loss of molecular chaperone function. These data support the central hypothesis that type 1 and type 2 CALR mutations activate and depend on different arms of the UPR based on their respective losses of function, and that these pathways promote distinct disease phenotypes. Thus, targeting different arms of the UPR based on mutation type may represent a novel, individualized treatment strategy for type 1 versus type 2 CALR+ MPN patients. To test this hypothesis, we will dissect the role of the UPR in type 1 mutant CALR-driven fibrosis (Specific Aim 1) and type 2 mutant CALR-driven ET (Specific Aim 2), and determine if each is uniquely sensitive to therapeutic targeting of different arms of the UPR (Specific Aim 3).


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 = $463,672 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Blood Diseases and Resources Research	002	4	8/14/2025	NON-COMPETING CONTINUATION	$463,672
2025	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Blood Diseases and Resources Research	001	3	3/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$151,131
2025	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	000	2	3/18/2025	NON-COMPETING CONTINUATION	-$151,131
														Subtotal = $463,672

Issue Date FY: 2024 ( Subtotal = $422,510 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Blood Diseases and Resources Research	001	3	9/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$422,510
2024	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	000	2	9/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $422,510

Issue Date FY: 2023 ( Subtotal = $474,785 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	000	2	8/15/2023	NON-COMPETING CONTINUATION	$474,785
														Subtotal = $474,785

Issue Date FY: 2022 ( Subtotal = $496,110 )
2022	2022	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	000	1	8/26/2022	NEW	$496,110
														Subtotal = $496,110

Grand Total All Awards = $1,857,077

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The Pathophysiology of Type 1 Versus Type 2 Mutant Calreticulin-Drivenmyeloproliferative Neoplasms

Award Number: R01HL165119

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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