Northwestern University

Feb
28
Thu 10:00 AM

BMG Seminar: Dissecting the molecular mechanisms and therapeutic vulnerabilities of mutant calreticulin in myeloproliferative neoplasms- Shannon Elf, PhD

When: Thursday, February 28, 2019
10:00 AM - 11:00 AM  

Where: Robert H Lurie Medical Research Center, Baldwin Auditorium, 303 E. Superior, Chicago, IL 60611 map it

Audience: Faculty/Staff - Student - Post Docs/Docs - Graduate Students

Contact: Vanessa Hughes   312.503.5229

Group: Biochemistry & Molecular Genetics Seminar Series

Category: Lectures & Meetings

Description:

The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents:

Shannon Elf, PhD
Assistant Professor
The University of Chicago

 

Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN). Our work has sought to dissect the molecular mechanism by which mutations in CALR function as phenotypic drivers in MPN pathogenesis, as well as to identify unique molecular vulnerabilities in CALR-mutated MPN cells. Our mechanistic studies have revealed the following key findings: i) mutant CALR binds to the thrombopoietin receptor (MPL) to activate JAK-STAT signaling and drive cellular transformation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition; ii) the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the mutant C-terminus, which is necessary for physical interaction between mutant CALR and MPL, and iii) mutant CALR binds directly to the extracellular domain of MPL via its N-glycosylation sites, and that the lectin-dependent function of CALR is required for this interaction. Together, this work has revealed important insight into the mechanism by which mutant CALR drives hematopoietic transformation in MPN. We next sought to exploit the insight gained through our mechanistic studies to identify new therapeutic targets in CALR-mutated MPN. Although CALR+ MPN patients experience reduced symptom burden in response to JAK inhibitor treatment, these agents have minimal disease-modifying activity and are not curative. This points to the importance of identifying novel targets for therapeutic intervention in CALR-mutated MPN. We performed RNA sequencing studies on cell lines expressing wild type CALR, mutant CALR, or JAK2 V617F, and found that the PERK-eIF2a-ATF4 axis of the unfolded protein response (UPR) is significantly up-regulated only in mutant CALR-expressing cells. Mechanistically, we found that activation of this pathway is due to loss of CALR chaperone activity in the mutant protein, and that the endoplasmic reticulum-associated degradation (ERAD) pathway, an ATF4 target and proteasomal degradation pathway, is up-regulated as a consequence. Accordingly, we found that inhibition of this pathway with the proteasome inhibitor bortezomib leads to increased cell death in mutant CALR-expressing cells, but not cells expressing wild type CALR or JAK2 V617F. This suggests that dependence on this UPR axis is specific to CALR-mutated cells. Together, our data suggests that the UPR may be exploited for therapeutic intervention in CALR-mutated MPN patients, either alone or in combination with JAK inhibition, with the hope of improving upon currently available therapies.

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