Mutant calreticulin-driven myeloproliferative neoplasms favour the emergence of TIGIT-positive NK cells
Abstract Myeloproliferative neoplasms (MPNs) are chronic diseases characterized by an excessive production of myeloid blood cells. Janus kinase ( JAK2 ) V617F is the most common mutation in MPNs but a substantial proportion of patients harbour calreticulin ( CALR ) mutations—an attractive target for emerging immunotherapies. Natural killer (NK) cells have a central role in the elimination of malignant cells, but NK cells of MPN patients have reduced activity. Thus, reactivating their function might improve the disease outcome. Here, we demonstrate that NK cells from a CALR -mutant mouse model exhibit normal maturation but enhanced degranulation. Consistently, NK cells from CALR -mutant patients exhibit preserved degranulation ability, exceeding that observed in JAK2 -mutant patients. Notably, NK cells from CALR -, but not JAK2 -mutant patients express high levels of the immune checkpoint TIGIT possibly due to increased abundance of immunomodulatory proteins in the plasma. Moreover, CD34⁺ cells from MPN patients express elevated levels of the TIGIT ligand CD112. TIGIT blockade results in reduced platelet numbers in a transplant mouse model. These findings suggest that NK cells in CALR -mutant MPNs are activated but functionally constrained when encountering TIGIT ligand–expressing target cells, providing a strong rationale for exploring TIGIT blockade to restore NK-cell immunity in this disease subset.
Authors
- Klaus Podar (ORCID: https://orcid.org/0000-0002-7414-3632)
- Brian Ringhofer
- Carl C. Crodel (ORCID: https://orcid.org/0009-0000-2160-1452)
- Gregor Hoermann (ORCID: https://orcid.org/0000-0002-7374-4380)
- Johannes Foßelteder (ORCID: https://orcid.org/0000-0002-0241-6822)
- Sophie Edtmayer (ORCID: https://orcid.org/0000-0002-8896-436X)
- Andreas Reinisch (ORCID: https://orcid.org/0000-0001-9333-7689)
- Karoline Kollmann (ORCID: https://orcid.org/0000-0002-7937-4245)
- Armin Zebisch (ORCID: https://orcid.org/0000-0002-4861-7021)
- Sascha Klee (ORCID: https://orcid.org/0000-0002-0321-1255)
- Elisabeth Gamper (ORCID: https://orcid.org/0009-0007-8439-4148)
- Uwe Graichen (ORCID: https://orcid.org/0000-0003-2144-4682)
- Agnieszka Witalisz‐Siepracka (ORCID: https://orcid.org/0000-0003-0237-0745)
- Petra Pavić
- Anthony Richard Green (ORCID: https://orcid.org/0000-0002-9795-0218)
- Thorsten Klampfl (ORCID: https://orcid.org/0000-0002-6666-9773)
- Sabine Geiselhart (ORCID: https://orcid.org/0000-0002-4749-3485)
- Dagmar Stoiber (ORCID: https://orcid.org/0000-0002-8824-0767)
- Theresa Harm
- Bernhard Zdársky (ORCID: https://orcid.org/0000-0001-8033-3435)
- Florian Heinrich Heidel (ORCID: https://orcid.org/0000-0003-2438-1955)
- Joachim Wolff
- Juan Li
Institutions
- University of Veterinary Medicine Vienna (AT)
- Medical University of Graz (AT)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Medizinische Hochschule Hannover (DE)
- Munich Leukemia Laboratory (Germany) (DE)
- Universitätsklinikum Krems (AT)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Jena University Hospital (DE)
- Karl Landsteiner University of Health Sciences (AT)
- Wellcome Trust (GB)
Publication Details
- Journal
- Leukemia
- Published
- 2026-11-03
- DOI
- https://doi.org/10.1038/s41375-026-03175-y
- Primary Topic
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00