The CALR mutations enhance the expression of the immunosuppressive proteins GARP and LAP on peripheral blood lymphocytes through increased binding of activated platelets

Morten Orebo Holmström, Josephine Hallundbæk Ruders, Caroline Hasselbalch Riley, Morten Kranker Larsen, Jacob Handlos Grauslund, Lasse Kjær, Vibe Skov, Christina Ellervik, Belinda B. Guo, Matthew Linden, Hans Carl Hasselbalch, Mads Hald Andersen

Research output: Contribution to journalArticlepeer-review

Abstract

Recently, an antibody which inhibits the glycoprotein A repetitions predominant (GARP)-mediated release of active transforming growth factor beta (TGFβ) from the TGFβ propeptide latency-associated peptide (LAP) showed preclinical activity in a murine model of the chronic myeloproliferative neoplasms (MPN). Consequently, we investigated the expression of the immunosuppressive molecules LAP and GARP on peripheral blood lymphocytes from 56 MPN patients and 11 healthy donors (HD). We found that lymphocytes from patients with MPN express higher levels of LAP and GARP with no strong differences found between the different MPN diagnoses. The impact of clinical parameters on the expression of LAP and GARP by lymphocytes showed that patients with calreticulin (CALR)mut MPN have increased expression compared with HD and patients with the Januskinase2 (JAK2) mutation. The fraction of lymphocytes bound to activated platelets (aPLT) strongly correlate to LAP and GARP expression suggesting that it is not the lymphocytes themselves but aPLT, which confer the increased expression of GARP and LAP on MPN patient lymphocytes. Notably, no differences in neither platelet counts nor anti-thrombotic therapy was identified between patients with JAK2- and CALRmut patients. Analysis of platelet gene expression failed to identify differences in expression of relevant genes between JAK2- and CALRmut patients.

Original languageEnglish
Pages (from-to)1417-1429
Number of pages13
JournalBritish Journal of Haematology
Volume205
Issue number4
Early online date20 Aug 2024
DOIs
Publication statusPublished - Oct 2024

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