JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.
Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms / Carretta, Chiara; Parenti, Sandra; Bertesi, Matteo; Rontauroli, Sebastiano; Badii, Filippo; Tavernari, Lara; Genovese, Elena; Malerba, Marica; Papa, Elisa; Sperduti, Samantha; Enzo, Elena; Mirabile, Margherita; Pedrazzi, Francesca; Neroni, Anita; Tombari, Camilla; Mora, Barbara; Maffioli, Margherita; Mondini, Marco; Brociner, Marco; Maccaferri, Monica; Tenedini, Elena; Martinelli, Silvia; Bartalucci, Niccolò; Bianchi, Elisa; Casarini, Livio; Potenza, Leonardo; Luppi, Mario; Tagliafico, Enrico; Guglielmelli, Paola; Simoni, Manuela; Passamonti, Francesco; Norfo, Ruggiero; Vannucchi, Alessandro Maria; Manfredini, Rossella; Null, Null. - In: LEUKEMIA. - ISSN 0887-6924. - 38:10(2024), pp. 2171-2182. [10.1038/s41375-024-02373-w]
Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms
Carretta, Chiara;Parenti, Sandra;Bertesi, Matteo;Rontauroli, Sebastiano;Tavernari, Lara;Genovese, Elena;Malerba, Marica;Papa, Elisa;Sperduti, Samantha;Enzo, Elena;Mirabile, Margherita;Pedrazzi, Francesca;Neroni, Anita;Tombari, Camilla;Mondini, Marco;Maccaferri, Monica;Tenedini, Elena;Martinelli, Silvia;Bianchi, Elisa;Casarini, Livio;Potenza, Leonardo;Luppi, Mario;Tagliafico, Enrico;Simoni, Manuela;Norfo, Ruggiero;Vannucchi, Alessandro Maria;Manfredini, Rossella
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2024
Abstract
JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.File | Dimensione | Formato | |
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