# The pathophysiology of type 1 versus type 2 mutant calreticulin-drivenmyeloproliferative neoplasms

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2023 · $474,785

## Abstract

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 determ...

## Key facts

- **NIH application ID:** 10691392
- **Project number:** 5R01HL165119-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Shannon Elisabeth Elf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $474,785
- **Award type:** 5
- **Project period:** 2022-09-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691392

## Citation

> US National Institutes of Health, RePORTER application 10691392, The pathophysiology of type 1 versus type 2 mutant calreticulin-drivenmyeloproliferative neoplasms (5R01HL165119-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10691392. Licensed CC0.

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