Traffic and signalling of calreticulin in myeloproliferative neoplasms (CALTRA)
The project, born as a collaboration between de Duve Institute of the Université Catholique de Louvain (UCL), Belgium and the Ultrastructural Pathology Lab at Victor Babeș Institute in Bucharest, Romania, will attempt to elucidate mechanisms of calreticulin (CRT) trafficking and signalling using leading edge equipment and techniques. Founded in 1974 by Nobel Laureate Christian de Duve, the de Duve Institute is a private, non-profit, basic research institution aiming excellence in the fields of biomedical research. The Institute is a multidisciplinary biomedical research institution that hosts several basic research laboratories of the Faculty of Medicine of UCL and the Brussels Branch of the Ludwig Institute for Cancer Research (LICR). The de Duve Institute has extensive experience in fundamental research in the field of Haematology and the lab led by Prof. Ștefan Constantinescu contributed decisively in the past decade to the characterization of JAK and CRT mutations in myeloproliferative neoplasms (MPNs).
CRT is an endoplasmic reticulum (ER) chaperone protein,which associates with the majority of glycoproteins that pass through the ER, actively participating in their folding, sorting or removal. CRT plays an essential role in regulating ER Ca2+ levels. Mutations of the gene encoding CRT, leading to a modified C-terminus sequence and implicit loss of ER retention, were recently discovered in patients with BCR/ABL negative MPNs, specifically myelofibrosis and essential thrombocythemia. Introducing these mutations into mouse bone marrow cells and transplanting them into lethally irradiated mice, rapidly induces an MPN phenotype, characterized by thrombocytosis and subsequent progression to fibrosis. Disease is driven through the activation of the JAK2/STAT signaling pathway in the presence of the thrombopoietin receptor (MPL), although the exact mechanisms by which mutant CRT activate MPL are unclear. Despite numerous research efforts, the physiological and/or pathological mechanisms by which CRT is released from the ER, transported to the cell surface and secreted into the extra-cellular space, remain largely unknown. Clarifying these mechanisms and understanding how intracellular and extracellular levels of CRT can be controlled, may advance therapies in various fields of biomedicine, from tissue regeneration to hematology.
Conference presentations and publications:
MUTANT CALRETICULINS ASSOCIATED WITH MYELOPROLIFERATIVE NEOPLASM RETAIN IN-VITRO CHAPERONE ACTIVITY
Anita Roy, Didier Colau, Christian Pecquet, Emilie Leroy, Ilyas Chachoua, Emanuel Fertig, Stefan N. Constantinescu
23rd Congress of the European Hematology Association, 14-17 June 2018, Stockholm, Sweden.
SUBCELLULAR LOCALIZATION OF CALRETICULIN MUTANTS IN MYELOPROLIFERATIVE NEOPLASMS
Tudor Emanuel Fertig, Daciana Marta, Silvia-Diana Prelipcean, Anita Roy, Ștefan N. Constantinescu, Mihaela Gherghiceanu
Annual Scientific Meeting - 11th National Pathology Symposium, 22-24 November 2018, Victor Babeș Institute, Bucharest, Romania
SECRETED MUTANT CALRETICULINS AS ROGUE CYTOKINES TRIGGER THROMBOPOIETIN RECEPTOR ACTIVATION SPECIFICALLY IN CALR MUTATED CELLS: PERSPECTIVES FOR MPN THERAPY
Christian Pecquet, Thomas Balligand, Ilyas Chachoua, Anita Roy, Gaelle Vertenoeil, Didier Colau, Emanuel Fertig, Caroline Marty, Harini Nivarthi, Jean-Philippe Defour, Erica Xu, Eva Hug, Heinz Gisslinger, Bettina Gisslinger, Martin Schalling, Ilaria Carola Casetti, Elisa Rumi, Daniela Pietra, Chiara Cavalloni, Luca Arcaini, Mario Cazzola, Norio Komatsu, Yoshihiko Kihara, Yoshitaka Sunami, Yoko Edahiro, Marito Araki, Isabelle Plo, William Vainchenker, Robert Kralovics and Stefan N Constantinescu
American Society of Hematology Annual Meeting, 1-4 December 2018, San Diego, CA.