[Sep. 22] 128th IRCMS Seminar

August 21 2025

We would like to inform you that the 128th IRCMS seminar has been scheduled as below.
* This IRCMS seminar is open to everyone.

Date      : September 22, 2025 (Monday)

Time      : 16:00-17:00

ZOOM　: Meeting ID: 944 9811 9688
            　Passcode: Sem22Sep

Speaker : Shannon Elf, Ph.D. (University of Utah, Huntsman Cancer Institute)

Title        : Calcium-driven metabolic reprogramming in type 1 calreticulin-mutated myeloproliferative neoplasms

Abstract:

Myeloproliferative neoplasms (MPNs) are a group of clonal hematopoietic stem disorders characterized by excess production of mature myeloid cells. These disorders include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Mutations in calreticulin (CALR) represent the second most common mutation in MPNs. CALR is an endoplasmic reticulum (ER) protein that functions to bind calcium (Ca2+) and chaperone nascent polypeptides. CALR mutations result in a +1 base pair frame shift, leading a novel mutant C-terminus. This mutant C-terminus confers gain of function (GOF) binding to and activation of the thrombopoietin receptor (MPL), leading to constitutive JAK/STAT activation. Over 80% of CALR mutations are characterized as type 1 (52bp deletion; CALRdel52) or type 2 (5bp insertion, CALRins5). While both CALRdel52 and CALRins5 share a mutant C-terminus and GOF of MPL binding/activation, they have different clinical presentations. For reasons not yet understood, CALRdel52 patients are more likely to transform to myelofibrosis from essential thrombocythemia than CALRins5 patients. This prompted us to ask if these mutations lead to distinct molecular and/or cellular phenotypes. We previously found that CALRdel52 mutant proteins have a loss of Ca2+ binding function, which leads to depletion of ER Ca2+ through IP3 receptor (IP3R)-mediated efflux.  Here, we show that this Ca2+ localizes to the mitochondria via the IP3R/voltage dependent anion channel 1 (VDAC1)/mitochondrial Ca2+ uniporter (MCU) axis, leading to increased mitochondrial Ca2+ levels in CALRdel52 mutant CD34+ cells. Further, we found that this Ca2+ dysregulation drives a distinct metabolic phenotype in CALRdel52 cells that can be targeted for therapeutic gain. Together, these data represent the first elucidation of the metabolic phenotype of CALRdel52 cells and broadly reveal how Ca2+ homeostasis governs cellular metabolism.

2-3 major papers:

1.Arellano NS, Heaton WL, Nauman MC, Runnels AE, Gomez-Villa J, Vanni D, Gaviria M, Fujita M, Krah NM, Ciboddo M, Yadav S, Brown CT, Bowden PD, Chen AK, Henning C, Catricalà S, Casetti IC, Borsani O, Rumi E, Pietra D, Plo I, Marty C, Marchetti M, Saygin C, Patel AB, Elf SE. Type 2 calreticulin mutations activate ATF6 to promote BCL-xL-mediated survival in myeloproliferative neoplasms. Blood. 2025 May 22:blood.2024026940. doi: 10.1182/blood.2024026940. Epub ahead of print. PMID: 40403318.

2. 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 I but Not Type II Calreticulin Mutations Activate the IRE1α/XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms. Blood Cancer Discov. 2022 Jul 6;3(4):298-315. doi: 10.1158/2643-3230.BCD-21-0144. PMID: 35405004; PMCID: PMC9338758.

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.

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