Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms.

Autor: Carretta C; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Parenti S; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Bertesi M; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Rontauroli S; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Badii F; Department of Cancer Biology, Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, PA, USA., Tavernari L; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Genovese E; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Malerba M; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Papa E; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Sperduti S; Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.; Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy., Enzo E; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Mirabile M; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Pedrazzi F; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Neroni A; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Tombari C; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Mora B; Ospedale Maggiore Policlinico, Milan, Italy., Maffioli M; S.C. Ematologia, Ospedale di Circolo e Fondazione Macchi-ASST Sette Laghi, Varese, Italy., Mondini M; S.C. Ematologia, Ospedale di Circolo e Fondazione Macchi-ASST Sette Laghi, Varese, Italy., Brociner M; S.C. Ematologia, Ospedale di Circolo e Fondazione Macchi-ASST Sette Laghi, Varese, Italy., Maccaferri M; Hematology Unit, Modena University Hospital, Modena, Italy., Tenedini E; Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy., Martinelli S; Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy., Bartalucci N; CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy.; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy., Bianchi E; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy., Casarini L; Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.; Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy., Potenza L; Hematology Unit, Modena University Hospital, Modena, Italy.; Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy., Luppi M; Hematology Unit, Modena University Hospital, Modena, Italy.; Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy., Tagliafico E; Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy.; Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy., Guglielmelli P; CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy.; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy., Simoni M; Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.; Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy., Passamonti F; Ospedale Maggiore Policlinico, Milan, Italy.; University of Milan, Milan, Italy., Norfo R; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy., Vannucchi AM; CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy.; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy., Manfredini R; Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy. rossella.manfredini@unimore.it.; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. rossella.manfredini@unimore.it.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2024 Aug 23. Date of Electronic Publication: 2024 Aug 23.
DOI: 10.1038/s41375-024-02373-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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