Type 2 calreticulin mutations activate ATF6 to promote BCL-xL–mediated survival in myeloproliferative neoplasms
Abstract
Abstract Most calreticulin (CALR) mutations in myeloproliferative neoplasms are classified as either type 1, a 52–base pair deletion (CALRdel52); or type 2, a 5–base pair insertion (CALRins5). Both are gain-of-function (GOF) mutations that generate an identical mutant C-terminal tail, which mediates the binding to, and activation of, the thrombopoietin receptor myeloproliferative leukemia protein (MPL). We recently reported that despite this shared GOF, CALRdel52 but not CALRins5 mutations cause loss of calcium binding function, leading to activation of, and dependency on, the inositol-requiring enzyme 1/X-box binding protein 1 pathway of the unfolded protein response (UPR). This led us to ask whether CALRins5 mutations activate and depend on a different UPR pathway, and whether this is likewise mediated by a mutation type–specific loss-of-function (LOF). Here, we show that CALRins5 mutations lead to activation of the activating transcription factor 6 (ATF6) pathway of the UPR due to loss of CALR chaperone function. This LOF is caused by interference of the CALRins5 mutant C terminus with key chaperone residue H170. Furthermore, we show that CALRins5 cells are partially dependent on ATF6 for cytokine-independent growth, and identify B-cell lymphoma extra large as a transcriptional target of ATF6 that promotes type 2 CALR-mutant cell survival.
Article Details
Authors (26)
Nicole S. Arellano
The University of Utah
William L. Heaton
1Division of Hematology and Hematological Malignancies, The University of Utah, Salt Lake City, UT
Mirielle C. Nauman
3Ben May Department for Cancer Research, The University of Chicago, Chicago, IL
Abigail E. Runnels
1Division of Hematology and Hematological Malignancies, The University of Utah, Salt Lake City, UT
Jacky Gomez-Villa
3Ben May Department for Cancer Research, The University of Chicago, Chicago, IL
Daniele Vanni
3Ben May Department for Cancer Research, The University of Chicago, Chicago, IL
Melissa Gaviria
3Ben May Department for Cancer Research, The University of Chicago, Chicago, IL
Maihi Fujita
1Division of Hematology and Hematological Malignancies, The University of Utah, Salt Lake City, UT
Nathan M. Krah
Michele Ciboddo
3Ben May Department for Cancer Research, The University of Chicago, Chicago, IL
Saveg Yadav
1Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
Callie T. Brown
1Division of Hematology and Hematological Malignancies, The University of Utah, Salt Lake City, UT
Parker D. Bowden
1Division of Hematology and Hematological Malignancies, The University of Utah, Salt Lake City, UT
Amy K. Chen
3Ben May Department for Cancer Research, The University of Chicago, Chicago, IL
Christopher Henning
3Ben May Department for Cancer Research, The University of Chicago, Chicago, IL
Silvia Catricalà
6Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
Ilaria Carola Casetti
4Department of Molecular Medicine, University of Pavia, Pavia, Italy
Oscar Borsani
4Department of Molecular Medicine, University of Pavia, Pavia, Italy
Elisa Rumi
19Department of Molecular Medicine, University of Pavia, Pavia, Italy
Daniela Pietra
6Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
Isabelle Plo
INSERM Unité Mixte de Recherche 1287, Villejuif, France
Caroline Marty
Marco Marchetti
Department of Human Genetics, Immunology, Inflammation and Infections Disease Initiative-Utah Center for Genetic Discovery Bioinformatics Core, University of Utah
Ami B. Patel
1Division of Hematology and Hematological Malignancies, The University of Utah, Salt Lake City, UT
Caner Saygin
9Department of Medicine, University of Chicago, Chicago, IL
Shannon E. Elf
The University of Utah