[Aug. 24] D5 Medical & Life Science Seminar-Dr. Shannon Elisabeth Elf (The University of Chicago)

August 10 2022

The "D5 Medical & Life Science Seminar" course will be offered by International Research Center for Medical Sciences (IRCMS). It will run from May 2022 to March 2023, with lectures given by scientists who are affiliated with IRCMS or in collaboration with researchers at IRCMS. The lectures will be given once a month, in English, and by leading scientists in the relevant research field. Students will be taught: 1) how normal physiological functions are maintained in the human body; 2) how these systems become abnormal under certain pathophysiologic conditions; 3) why stem cells are important in animal development and homeostasis; 4) how stem cell-based approaches can help us understand disease mechanisms and find potential cure for diseases related to stem cell malfunction (e.g., cancer, aging).

Anyone who wants to join is welcome.
For students who have registered for the course, please check your attendance in Moodle.

Date      : August 24, 2022 (Wednesday)

Time      : 10:00 -
              * Zoom online seminar

Speaker : Dr. Shannon Elisabeth Elf, Ph.D
                The University of Chicago

Title        : Type 1 and type 2 calreticulin mutations activate discrete unfolded protein response pathways to drive myeloproliferative neoplasms

Abstract :

Myeloproliferative neoplasms (MPNs) include primary myelofibrosis (PMF), essential thrombocythemia (ET), and polycythemia vera (PV).  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 (1, 2). 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 (3). 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 (4). 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 (4). More recently, we found that the ATF6 pathway of the UPR is differentially upregulated in type 2 compared to type 1 mutant CALR cells, and that type 2 mutant proteins exhibit loss of molecular chaperone function. Together, we show 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.

Selected publications

1. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'Antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013 Dec 19;369(25):2379-90. doi: 10.1056/NEJMoa1311347. Epub 2013 Dec 10. PMID: 24325356.
2. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O'Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJP, Harrison CN, Cross NCP, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013 Dec 19;369(25):2391-2405. doi: 10.1056/NEJMoa1312542. Epub 2013 Dec 10. PMID: 24325359; PMCID: PMC3966280.
3. Elf S, Abdelfattah NS, Chen E, Perales-Patón J, Rosen EA, Ko A, Peisker F, Florescu N, Giannini S, Wolach O, Morgan EA, Tothova Z, Losman JA, Schneider RK, Al-Shahrour F, Mullally A. Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation. Cancer Discov. 2016 Apr;6(4):368-81. doi: 10.1158/2159-8290.CD-15-1434. Epub 2016 Mar 7. PMID: 26951227; PMCID: PMC4851866.
4. Pietra D, Rumi E, Ferretti VV, Di Buduo CA, Milanesi C, Cavalloni C, Sant'Antonio E, Abbonante V, Moccia F, Casetti IC, Bellini M, Renna MC, Roncoroni E, Fugazza E, Astori C, Boveri E, Rosti V, Barosi G, Balduini A, Cazzola M. Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia. 2016 Feb;30(2):431-8. doi: 10.1038/leu.2015.277. Epub 2015 Oct 9. PMID: 26449662; PMCID: PMC4740452.
5. Ibarra J, Elbanna YA, Kurylowicz K, Ciboddo M, Greenbaum HS, Arellano NS, Rodriguez D, Evers M, Bock-Hughes A, Liu C, Smith Q, Lutze J, Baumeister J, Kalmer M, Olschok K, Nicholson B, Silva D, Maxwell L, Dowgielewicz J, Rumi E, Pietra D, Casetti IC, Catricala S, Koschmieder S, Gurbuxani S, Schneider RK, Oakes SA, Elf SE. Type 1 but not type 2 calreticulin mutations activate the IRE1a/XBP1 pathway of the unfolded protein response to drive myeloproliferative neoplasms. Blood Cancer Discov. 2022 Apr 11.

Flyer: (Click to enlarge)