Polycythemia vera (PV) and essential thrombocythemia (ET) are Philadelphia-negative myeloproliferative neoplasms (MPNs) characterized by erythrocytosis and thrombocytosis, respectively. Approximately 95% of PV and 50-70% of ET patients harbor the V617F mutation in the exon 14 of JAK2 gene, while about 20-30% of ET patients carry CALRins5 or CALRdel52 mutations. These ET CALR-mutated subjects show higher platelet count and lower thrombotic risk compared to JAK2-mutated patients. Here, we showed that CALR-mutated and JAK2V617F-positive CD34+ cells display different gene and miRNA expression profiles. Indeed, we highlighted several pathways differentially activated between JAK2V617F- and CALR-mutated progenitors, i.e., mTOR, MAPK/PI3K, and MYC pathways. Furthermore, we unveiled that the expression of several genes involved in DNA repair, chromatin remodeling, splicing, and chromatid cohesion are decreased in CALR-mutated cells. According to the low risk of thrombosis in CALR-mutated patients, we also found the downregulation of several genes involved in thrombin signaling and platelet activation. As a whole, these data support the model that CALR-mutated ET could be considered as a distinct disease entity from JAK2V617F-positive MPNs and may provide the molecular basis supporting the different clinical features of these patients.

CALR mutational status identifies different disease subtypes of essential thrombocythemia showing distinct expression profiles / Zini, Roberta; Guglielmelli, Paola; Pietra, Daniela; Rumi, Elisa; Rossi, Chiara; Rontauroli, Sebastiano; Genovese, Elena; Fanelli, Tiziana; Calabresi, Laura; Bianchi, Elisa; Salati, Simona; Cazzola, Mario; Tagliafico, Enrico; Vannucchi, Alessandro M.; Manfredini, Rossella. - In: BLOOD CANCER JOURNAL. - ISSN 2044-5385. - 7:12(2017), pp. 638-651. [10.1038/s41408-017-0010-2]

CALR mutational status identifies different disease subtypes of essential thrombocythemia showing distinct expression profiles

Zini, Roberta;Rossi, Chiara;Rontauroli, Sebastiano;GENOVESE, ELENA;Bianchi, Elisa;Salati, Simona;Tagliafico, Enrico;Manfredini, Rossella
2017

Abstract

Polycythemia vera (PV) and essential thrombocythemia (ET) are Philadelphia-negative myeloproliferative neoplasms (MPNs) characterized by erythrocytosis and thrombocytosis, respectively. Approximately 95% of PV and 50-70% of ET patients harbor the V617F mutation in the exon 14 of JAK2 gene, while about 20-30% of ET patients carry CALRins5 or CALRdel52 mutations. These ET CALR-mutated subjects show higher platelet count and lower thrombotic risk compared to JAK2-mutated patients. Here, we showed that CALR-mutated and JAK2V617F-positive CD34+ cells display different gene and miRNA expression profiles. Indeed, we highlighted several pathways differentially activated between JAK2V617F- and CALR-mutated progenitors, i.e., mTOR, MAPK/PI3K, and MYC pathways. Furthermore, we unveiled that the expression of several genes involved in DNA repair, chromatin remodeling, splicing, and chromatid cohesion are decreased in CALR-mutated cells. According to the low risk of thrombosis in CALR-mutated patients, we also found the downregulation of several genes involved in thrombin signaling and platelet activation. As a whole, these data support the model that CALR-mutated ET could be considered as a distinct disease entity from JAK2V617F-positive MPNs and may provide the molecular basis supporting the different clinical features of these patients.
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CALR mutational status identifies different disease subtypes of essential thrombocythemia showing distinct expression profiles / Zini, Roberta; Guglielmelli, Paola; Pietra, Daniela; Rumi, Elisa; Rossi, Chiara; Rontauroli, Sebastiano; Genovese, Elena; Fanelli, Tiziana; Calabresi, Laura; Bianchi, Elisa; Salati, Simona; Cazzola, Mario; Tagliafico, Enrico; Vannucchi, Alessandro M.; Manfredini, Rossella. - In: BLOOD CANCER JOURNAL. - ISSN 2044-5385. - 7:12(2017), pp. 638-651. [10.1038/s41408-017-0010-2]
Zini, Roberta; Guglielmelli, Paola; Pietra, Daniela; Rumi, Elisa; Rossi, Chiara; Rontauroli, Sebastiano; Genovese, Elena; Fanelli, Tiziana; Calabresi, Laura; Bianchi, Elisa; Salati, Simona; Cazzola, Mario; Tagliafico, Enrico; Vannucchi, Alessandro M.; Manfredini, Rossella
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1153890
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