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1. Heterozygous and homozygous JAK2(V617F) states modeled by induced pluripotent stem cells from myeloproliferative neoplasm patients.

Author

Joseph Saliba, Sofiane Hamidi, Gaëlle Lenglet, Thierry Langlois, Jingkui Yin, Xénia Cabagnols, Lise Secardin, Céline Legrand, Anne Galy, Paule Opolon, Baya Benyahia, Eric Solary, Olivier A Bernard, Longyun Chen, Najet Debili, Hana Raslova, Françoise Norol, William Vainchenker, Isabelle Plo, and Antonio Di Stefano

Subjects
Medicine, Science
Abstract

JAK2(V617F) is the predominant mutation in myeloproliferative neoplasms (MPN). Modeling MPN in a human context might be helpful for the screening of molecules targeting JAK2 and its intracellular signaling. We describe here the derivation of induced pluripotent stem (iPS) cell lines from 2 polycythemia vera patients carrying a heterozygous and a homozygous mutated JAK2(V617F), respectively. In the patient with homozygous JAK2(V617F), additional ASXL1 mutation and chromosome 20 allowed partial delineation of the clonal architecture and assignation of the cellular origin of the derived iPS cell lines. The marked difference in the response to erythropoietin (EPO) between homozygous and heterozygous cell lines correlated with the constitutive activation level of signaling pathways. Strikingly, heterozygous iPS cells showed thrombopoietin (TPO)-independent formation of megakaryocytic colonies, but not EPO-independent erythroid colony formation. JAK2, PI3K and HSP90 inhibitors were able to block spontaneous and EPO-induced growth of erythroid colonies from GPA(+)CD41(+) cells derived from iPS cells. Altogether, this study brings the proof of concept that iPS can be used for studying MPN pathogenesis, clonal architecture, and drug efficacy.

Published
2013
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2. Different impact of calreticulin mutations on human hematopoiesis in myeloproliferative neoplasms

Author

Stefan N. Constantinescu, Xénia Cabagnols, Florence Lorre, Philippe Rameau, Caroline Marty, Florence Pasquier, Valérie Ugo, Jerome Rey, Matthieu Mosca, Isabelle Plo, Amandine Tisserand, William Vainchenker, Mira El-Khoury, Fabrizia Favale, Lydia Roy, Christophe Marzac, Hana Raslova, Najet Debili, Gaëlle Vertenoeil, Olivier Bluteau, Eric Solary, Nicole Casadevall, Graciela Rabadan Moraes, Jean-Christophe Ianotto, UCL - SSS/DDUV/SIGN - Cell signalling, and UCL - (SLuc) Service d'hématologie

Subjects
Male, 0301 basic medicine, Cancer Research, 03 medical and health sciences, 0302 clinical medicine, Megakaryocyte, Genetics, medicine, Humans, Progenitor cell, Myelofibrosis, Molecular Biology, Dominance (genetics), Myeloproliferative Disorders, biology, Essential thrombocythemia, medicine.disease, Phenotype, Hematopoiesis, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, biology.protein, Cancer research, Female, Calreticulin
Abstract

Mutations of calreticulin (CALRm) define a subtype of myeloproliferative neoplasms (MPN). We studied the biological and genetic features of CALR-mutated essential thrombocythemia and myelofibrosis patients. In most cases, CALRm were found in granulocytes, monocytes, B and NK cells, but also in T cells. However, the type 1 CALRm spreads more easily than the type 2 CALRm in lymphoid cells. The CALRm were also associated with an early clonal dominance at the level of hematopoietic stem and progenitor cells (HSPC) with no significant increase during granulo/monocytic differentiation in most cases. Moreover, we found that half of type 2 CALRm patients harbors some homozygous progenitors. Those patients were associated with a higher clonal dominance during granulo/monocytic differentiation than patients with only heterozygous type 2 CALRm progenitors. When associated mutations were present, CALRm were the first genetic event suggesting that they are both the initiating and phenotypic event. In blood, type 1 CALRm led to a greater increased number of all types of progenitors compared with the type 2 CALRm. However, both types of CALRm induced an increase in megakaryocytic progenitors associated with a ruxolitinib-sensitive independent growth and with a mild constitutive signaling in megakaryocytes. At the transcriptional level, type 1 CALRm seems to deregulate more pathways than the type 2 CALRm in megakaryocytes. Altogether, our results show that CALRm modify both the HSPC and megakaryocyte biology with a stronger effect for type 1 than for type 2 CALRm.

Published
2020

3. Myeloproliferative Neoplasms: JAK2 Signaling Pathway as a Central Target for Therapy

Author

Isabelle Plo, Lise Secardin, William Vainchenker, Florence Pasquier, and Xénia Cabagnols

Subjects
Cancer Research, Antineoplastic Agents, Gene mutation, Biology, Germline, Polycythemia vera, hemic and lymphatic diseases, medicine, Animals, Humans, Molecular Targeted Therapy, Epigenetics, Myelofibrosis, Protein Kinase Inhibitors, Genetics, Myeloproliferative Disorders, Essential thrombocythemia, Hematology, Janus Kinase 2, medicine.disease, Phenotype, Enzyme Activation, Oncology, Mutation, biology.protein, Calreticulin, Signal Transduction
Abstract

The discovery of the JAK2V617F mutation followed by the discovery of other genetic abnormalities allowed important progress in the understanding of the pathogenesis and management of myeloproliferative neoplasms (MPN)s. Classical Breakpoint cluster region-Abelson (BCR-ABL)-negative neoplasms include 3 main disorders: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Genomic studies have shown that these disorders are more heterogeneous than previously thought with 3 main entities corresponding to different gene mutations: the JAK2 disorder, essentially due to JAK2V617F mutation, which includes nearly all PVs and a majority of ETs and PMFs with a continuum between these diseases and the myeloproliferative leukemia (MPL) and calreticulin (CALR) disorders, which include a fraction of ET and PMF. All of these mutations lead to a JAK2 constitutive activation. Murine models either with JAK2V617F or MPLW515L, but also with JAK2 or MPL germ line mutations found in hereditary thrombocytosis, have demonstrated that they are drivers of myeloproliferation. However, the myeloproliferative driver mutation is still unknown in approximately 15% of ET and PMF, but appears to also target the JAK/Signal Transducer and Activator of Transcription (STAT) pathway. However, other mutations in genes involved in epigenetics or splicing also can be present and can predate or follow mutations in signaling. They are involved either in clonal dominance or in phenotypic changes, more particularly in PMF. They can be associated with leukemic progression and might have an important prognostic value such as additional sex comb-like 1 mutations. Despite this heterogeneity, it is tempting to target JAK2 and its signaling for therapy. However in PMF, Adenosine Tri-Phosphate (ATP)-competitive JAK2 inhibitors have shown their interest, but also their important limitations. Thus, other approaches are required, which are discussed in this review.

Published
2014
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4. A CALR Mutation Preceding BCR-ABL1 in an Atypical Myeloproliferative Neoplasm

Author

William Vainchenker, Jean-Michel Cayuela, and Xénia Cabagnols

Subjects
Pathology, medicine.medical_specialty, Thrombocytosis, business.industry, Event (relativity), Myeloid leukemia, Chromosomal translocation, General Medicine, medicine.disease, Bcr abl1, hemic and lymphatic diseases, Cancer research, Medicine, CALR Mutation, Genetic Change, business, Myeloproliferative neoplasm
Abstract

A case is described in which a patient with chronic myeloid leukemia associated with thrombocytosis was shown to have a CALR mutation as an initial genetic change and BCR–ABL1 translocation as a secondary event leading to a clinically unusual myeloproliferative neoplasm.

Published
2015
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5. Differential association of calreticulin type 1 and type 2 mutations with myelofibrosis and essential thrombocytemia: relevance for disease evolution

Author

Xénia Cabagnols, J Mondet, Isabelle Plo, Pascale Saussoy, Florence Pasquier, Jean-Christophe Ianotto, Laurent Knoops, Nicole Casadevall, Olivier Mansier, Vincent Ribrag, C Marzac, Eric Solary, Marie-Christiane Vekemans, M J Mozziconacci, Eric Lippert, Anne Murati, Stefan N. Constantinescu, Jean-François Viallard, François Girodon, Jean-Philippe Defour, Olivier Bluteau, J H Alexandre, Valérie Ugo, P Mossuz, William Vainchenker, Laboratoire d'Hématologie Biologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département d'hématologie, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), TheREx, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Laboratoire d'hématologie cellulaire et moléculaire (DBPC), CHU Grenoble-CHU Grenoble, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bordeaux (UB), Service de Médecine Interne et Maladies Infectieuses [Pessac], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [Lille], Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de recherche translationnelle, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence du Globule Rouge, Villejuif, France, Institut Gustave Roussy (IGR), UCL - SSS/DDUV - Institut de Duve, UCL - (SLuc) Service de biologie hématologique, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire d'hématologie cellulaire et moléculaire (DBPC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Laboratoire d'hématologie cellulaire et moléculaire ( DBPC ), Université Grenoble Alpes - UFR Pharmacie ( UGA UFRP ), Université Grenoble Alpes ( UGA ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Chimie Organique et Bioorganique : Reactivité et Analyse ( COBRA ), Centre National de la Recherche Scientifique ( CNRS ) -Institut de Chimie Organique Fine ( IRCOF ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Gustave Roussy ( IGR ) -Université Paris-Sud - Paris 11 ( UP11 ), Institut Gustave Roussy ( IGR ), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hopital Necker-Enfants Malades, Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Male, Adult, Cancer Research, Adolescent, Essential/*genetics, [SDV]Life Sciences [q-bio], Essential Thrombocytemia, Biology, medicine.disease_cause, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Protein Isoforms, Humans, Thrombocythemia, Myelofibrosis, Child, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Aged, Genetics, Aged, 80 and over, 0303 health sciences, Mutation, [ SDV ] Life Sciences [q-bio], Protein Isoforms/*genetics, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, medicine.disease, Calreticulin/*genetics, Disease evolution, Oncology, Aged 80 and over, Primary Myelofibrosis, 030220 oncology & carcinogenesis, biology.protein, Female, Calreticulin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Thrombocythemia, Essential, Primary Myelofibrosis/*genetics
Abstract

Differential association of calreticulin type 1 and type 2 mutations with myelofibrosis and essential thrombocytemia: relevance for disease evolution

Published
2014
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6. Heterozygous and homozygous JAK2(V617F) states modeled by induced pluripotent stem cells from myeloproliferative neoplasm patients

Author

Hana Raslova, Najet Debili, Eric Solary, Céline Legrand, William Vainchenker, Françoise Norol, Xénia Cabagnols, Sofiane Hamidi, Longyun Chen, Joseph Saliba, Antonio Di Stefano, Gaëlle Lenglet, Isabelle Plo, Paule Opolon, Thierry Langlois, Lise Secardin, Anne Galy, Olivier Bernard, Baya Benyahia, Jingkui Yin, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, The Hong Kong Polytechnic University [Hong Kong] (POLYU), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Immunologie moléculaire et biothérapies innovantes (IMBI), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Hématopoïèse normale et pathologique, Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
Science, Cellular differentiation, Cells, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, Loss of heterozygosity, Erythropoietin/pharmacology, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, Myeloproliferative Disorders, Janus Kinase 2/genetics/*metabolism, hemic and lymphatic diseases, Thrombopoietin/pharmacology, medicine, Humans, Induced pluripotent stem cell, Signal Transduction/drug effects/genetics, Erythropoietin, Cells, Cultured, Thrombopoietin, Myeloproliferative neoplasm, 030304 developmental biology, Repressor Proteins/genetics/metabolism, 0303 health sciences, Induced Pluripotent Stem Cells/*cytology/*metabolism, Multidisciplinary, Janus kinase 2, Cultured, biology, Myeloproliferative Disorders/genetics/*metabolism, food and beverages, Janus Kinase 2, medicine.disease, Molecular biology, Repressor Proteins, Phosphatidylinositol 3-Kinases/genetics/metabolism, 030220 oncology & carcinogenesis, biology.protein, Medicine, Signal Transduction, Research Article
Abstract

International audience; JAK2(V617F) is the predominant mutation in myeloproliferative neoplasms (MPN). Modeling MPN in a human context might be helpful for the screening of molecules targeting JAK2 and its intracellular signaling. We describe here the derivation of induced pluripotent stem (iPS) cell lines from 2 polycythemia vera patients carrying a heterozygous and a homozygous mutated JAK2(V617F), respectively. In the patient with homozygous JAK2(V617F), additional ASXL1 mutation and chromosome 20 allowed partial delineation of the clonal architecture and assignation of the cellular origin of the derived iPS cell lines. The marked difference in the response to erythropoietin (EPO) between homozygous and heterozygous cell lines correlated with the constitutive activation level of signaling pathways. Strikingly, heterozygous iPS cells showed thrombopoietin (TPO)-independent formation of megakaryocytic colonies, but not EPO-independent erythroid colony formation. JAK2, PI3K and HSP90 inhibitors were able to block spontaneous and EPO-induced growth of erythroid colonies from GPA(+)CD41(+) cells derived from iPS cells. Altogether, this study brings the proof of concept that iPS can be used for studying MPN pathogenesis, clonal architecture, and drug efficacy.

Published
2013
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7. Differential Association of Calreticulin Type 1 and Type 2 Mutations with Myelofibrosis and Essential Thrombocytemia: Relevance for Disease Evolution

Author

Ollivier Legrand, Anne Murati, Stefan N. Constantinescu, Pascale Saussoy, Marie-Christianne Vekemans, Jean Christophe Ianotto, Valérie Ugo, Isabelle Plo, William Vainchenker, Olivier Bluteau, M J Mozziconacci, Vincent Ribrag, Jean François Viallard, Christophe Marzac, Olivier Mansier, François Girodon, Nicole Casadevall, Eric Lippert, Florence Pasquier, Eric Solary, Alexandre Ji-Hye, Laurent Knoops, Xénia Cabagnols, Jean-Philippe Defour, Pascal Mossuz, and Julie Mondet

Subjects
medicine.medical_specialty, Immunology, Population, medicine.disease_cause, Biochemistry, Asymptomatic, Gastroenterology, Internal medicine, medicine, Platelet, Allele, Myelofibrosis, education, Mutation, education.field_of_study, biology, Thrombocytosis, business.industry, Cell Biology, Hematology, medicine.disease, biology.protein, medicine.symptom, business, Calreticulin
Abstract

Recent advances in myeloproliferative neoplasms (MPN) have highlighted the prevalence of mutations in the calreticulin gene (CALR), bringing a major new actor in these disorders. CALR mutations were reported in 25% of ET and in 35% of MF patients, which were non-mutated for JAK2 and MPL. CALR mutations lead to a frame-shift generating a common 36 amino acids C-terminal end and loss of the KDEL motif. Two variants account for 85% of the CALR mutations in ET and PMF: type 1, a 52-bp deletion and type2, a 5-bp insertion. 572 MPN patients negative for JAK2 and MPL mutations were collected from several French and Belgian hospitals. In our series, 396 patients were diagnosed as ET, 108 as MF and 68 as mixed MDS/MPN. We identified mutations of CALR in 368 patients (63.3%). The remaining 204 patients were designated as triple negative. In MF there was an over representation of type 1 mutation (70%) and an under representation of type 2 mutation (13%) as compared to patients with ET. This bias was associated with a higher allelic burden of CALR mutation in MF. MF patients represent a quite homogeneous group, mostly composed of men diagnosed at a median age of 62.5 with a low hemoglobin concentration (10.1 g/dl) and a low platelet count (median at 237 x 109/l). In ET patients the clinical presentation was more heterogeneous. They were mostly women (more than 61%) at a median age of diagnosis of 57 with a median platelet count of 724 x 109/l. In CALR mutated patients there were no sex prevalence and a more important thrombocytosis (785 x 109/l). The type of CALR mutation impacted also age and platelet count. We report the caracterisation of triple negative patients. In ETs they were mostly women (76.9%), particularly for ET patients under 50 years old that were almost exclusively women (27/28). In MF, triple negative patients presented a low hemoglobin concentration (8.85 g/dl) and a low leukocyte count (1.995 x 109/l). A striking characteristic is their platelet count, which was significantly lower than their group mates either in ET or in MF. This lower platelet count may suggest that in the general population, putative asymptomatic triple negative ET male patients could be retrieved, which would only be diagnosed at more advanced age with a symptomatic MF. Taken together, our results underline the differences between the two most frequent types of CALR mutation and show that CALR mutated patients should not be considered as a single entity. Disclosures No relevant conflicts of interest to declare.

Published
2014
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8. Endogenous megakaryocytic colonies underline association between megakaryocytes and calreticulin mutations in essential thrombocythemia

Author

Julie Mondet, Ji-Hye Park, Audrey Menard, Christophe Marzac, Serge Carillo, Emmanuel Pourcelot, Francois Girodon, Xenia Cabagnols, Laurence Lodé, Nuria Socoro, Martine Chauvet, Claude-Eric Bulabois, Pascale Cony-Makhoul, Selim Corm, Jean-Yves Cahn, and Pascal Mossuz

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2015
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