Type 2 calreticulin mutations activate ATF6 to promote BCL-xL–mediated survival in myeloproliferative neoplasms
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.
Authors
- Isabelle Plo (ORCID: https://orcid.org/0000-0002-5915-6910)
- Caner Saygin (ORCID: https://orcid.org/0000-0001-7617-8356)
- Nathan M. Krah (ORCID: https://orcid.org/0009-0003-8297-7359)
- Jacky Gomez-Villa
- Callie Brown (ORCID: https://orcid.org/0009-0009-4356-343X)
- Oscar Borsani (ORCID: https://orcid.org/0000-0001-7805-7806)
- Ilaria Carola Casetti (ORCID: https://orcid.org/0000-0001-5232-9543)
- Daniela Pietra (ORCID: https://orcid.org/0000-0002-6575-8766)
- Mirielle C. Nauman (ORCID: https://orcid.org/0000-0002-1339-4745)
- C.B. Henning (ORCID: https://orcid.org/0000-0002-7324-4802)
- Silvia Catricalà (ORCID: https://orcid.org/0000-0001-8294-1768)
- Michele Ciboddo (ORCID: https://orcid.org/0000-0002-5175-5185)
- Maihi Fujita (ORCID: https://orcid.org/0000-0003-2619-1637)
- Nicole Arellano (ORCID: https://orcid.org/0000-0003-1618-0467)
- Elisa Rumi (ORCID: https://orcid.org/0000-0002-7572-9504)
- Caroline Marty (ORCID: https://orcid.org/0000-0003-4350-2302)
- Ami B. Patel (ORCID: https://orcid.org/0000-0002-5374-3831)
- William L. Heaton
- Saveg Yadav (ORCID: https://orcid.org/0000-0001-8401-7894)
- Amy K Chen
- Shannon Elf (ORCID: https://orcid.org/0000-0002-8845-3818)
- Marco Marchetti (ORCID: https://orcid.org/0000-0003-0776-0486)
- Daniele Vanni (ORCID: https://orcid.org/0000-0003-3812-2399)
- Parker Bowden (ORCID: https://orcid.org/0009-0007-2757-2905)
- Abigail Runnels
- Melissa Gaviria
Institutions
- University of Helsinki (FI)
- Inserm (FR)
- University of Utah (US)
- University of Pavia (IT)
- Université Paris-Saclay (FR)
- Huntsman Cancer Institute (US)
- Institut Gustave Roussy (FR)
- University of Chicago (US)
- May Institute (US)
- Institute of Human Genetics (PL)
- Policlinico San Matteo Fondazione (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Star Center (US)
Publication Details
- Journal
- Blood
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1182/blood.2024026940
- Citations
- 3
- Primary Topic
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 4.88
Funders
- National Science Foundation
- Leukemia and Lymphoma Society
- Incyte
- Swedish Orphan Biovitrum
- National Institutes of Health
- Genentech