Integrative analysis of copy number and gene expression data suggests novel pathogenetic mechanisms in primary myelofibrosis
Simona Salati
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorRoberta Zini
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorSimona Nuzzo
Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125 Italy
Search for more papers by this authorPaola Guglielmelli
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorValentina Pennucci
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorZelia Prudente
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorSamantha Ruberti
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorSebastiano Rontauroli
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorRuggiero Norfo
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorElisa Bianchi
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorCostanza Bogani
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorGiada Rotunno
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorTiziana Fanelli
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorCarmela Mannarelli
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorVittorio Rosti
IRCCS Policlinico S.Matteo Foundation, Center for the Study of Myelofibrosis, Pavia, Italy
Search for more papers by this authorSilvia Salmoiraghi
Hematology, Az. Osp. Papa Giovanni XXIII, Bergamo, Italy
Search for more papers by this authorDaniela Pietra
Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy
Search for more papers by this authorSergio Ferrari
Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125 Italy
Search for more papers by this authorGiovanni Barosi
IRCCS Policlinico S.Matteo Foundation, Center for the Study of Myelofibrosis, Pavia, Italy
Search for more papers by this authorAlessandro Rambaldi
Hematology, Az. Osp. Papa Giovanni XXIII, Bergamo, Italy
Search for more papers by this authorMario Cazzola
Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy
Search for more papers by this authorSilvio Bicciato
Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125 Italy
Search for more papers by this authorEnrico Tagliafico
Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125 Italy
Search for more papers by this authorAlessandro M. Vannucchi
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorCorresponding Author
Rossella Manfredini
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Correspondence to: Rossella Manfredini, PhD, Centre for Regenerative Medicine “Stefano Ferrari”, University of Modena and Reggio Emilia, via Gottardi n.100, 41125 Modena, Italy, Tel: +39-059-205-8065, Fax: +39-059-205-8115, E-mail: [email protected]Search for more papers by this authoron behalf of the AGIMM (AIRC Gruppo Italiano Malattie Mieloproliferative) investigators
Search for more papers by this authorSimona Salati
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorRoberta Zini
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorSimona Nuzzo
Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125 Italy
Search for more papers by this authorPaola Guglielmelli
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorValentina Pennucci
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorZelia Prudente
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorSamantha Ruberti
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorSebastiano Rontauroli
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorRuggiero Norfo
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorElisa Bianchi
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Search for more papers by this authorCostanza Bogani
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorGiada Rotunno
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorTiziana Fanelli
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorCarmela Mannarelli
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorVittorio Rosti
IRCCS Policlinico S.Matteo Foundation, Center for the Study of Myelofibrosis, Pavia, Italy
Search for more papers by this authorSilvia Salmoiraghi
Hematology, Az. Osp. Papa Giovanni XXIII, Bergamo, Italy
Search for more papers by this authorDaniela Pietra
Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy
Search for more papers by this authorSergio Ferrari
Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125 Italy
Search for more papers by this authorGiovanni Barosi
IRCCS Policlinico S.Matteo Foundation, Center for the Study of Myelofibrosis, Pavia, Italy
Search for more papers by this authorAlessandro Rambaldi
Hematology, Az. Osp. Papa Giovanni XXIII, Bergamo, Italy
Search for more papers by this authorMario Cazzola
Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy
Search for more papers by this authorSilvio Bicciato
Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125 Italy
Search for more papers by this authorEnrico Tagliafico
Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125 Italy
Search for more papers by this authorAlessandro M. Vannucchi
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
Search for more papers by this authorCorresponding Author
Rossella Manfredini
Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125 Italy
Correspondence to: Rossella Manfredini, PhD, Centre for Regenerative Medicine “Stefano Ferrari”, University of Modena and Reggio Emilia, via Gottardi n.100, 41125 Modena, Italy, Tel: +39-059-205-8065, Fax: +39-059-205-8115, E-mail: [email protected]Search for more papers by this authoron behalf of the AGIMM (AIRC Gruppo Italiano Malattie Mieloproliferative) investigators
Search for more papers by this authorThe authors declare no competing financial interests.
Abstract
Primary myelofibrosis (PMF) is a Myeloproliferative Neoplasm (MPN) characterized by megakaryocyte hyperplasia, progressive bone marrow fibrosis, extramedullary hematopoiesis and transformation to Acute Myeloid Leukemia (AML). A number of phenotypic driver (JAK2, CALR, MPL) and additional subclonal mutations have been described in PMF, pointing to a complex genomic landscape. To discover novel genomic lesions that can contribute to disease phenotype and/or development, gene expression and copy number signals were integrated and several genomic abnormalities leading to a concordant alteration in gene expression levels were identified. In particular, copy number gain in the polyamine oxidase (PAOX) gene locus was accompanied by a coordinated transcriptional up-regulation in PMF patients. PAOX inhibition resulted in rapid cell death of PMF progenitor cells, while sparing normal cells, suggesting that PAOX inhibition could represent a therapeutic strategy to selectively target PMF cells without affecting normal hematopoietic cells' survival. Moreover, copy number loss in the chromatin modifier HMGXB4 gene correlates with a concomitant transcriptional down-regulation in PMF patients. Interestingly, silencing of HMGXB4 induces megakaryocyte differentiation, while inhibiting erythroid development, in human hematopoietic stem/progenitor cells. These results highlight a previously un-reported, yet potentially interesting role of HMGXB4 in the hematopoietic system and suggest that genomic and transcriptional imbalances of HMGXB4 could contribute to the aberrant expansion of the megakaryocytic lineage that characterizes PMF patients.
Abstract
What's new?
Primary myelofibrosis (PMF) is a proliferative hematopoietic stem cell disorder associated in some cases with mutations in the JAK-STAT signal transduction pathway. Here the authors performed a detailed genetic analysis of blood and bone marrow samples and identified the gain of function of the polyamine oxidase PAOX and the loss of function of the chromatin modifier HMGXB4 as novel genomic abnormalities in PMF. This brings new insight into the mechanism of PMF development as in vitro manipulations of the two factors affected resistance to apoptosis and hyperplastic megakaryopoiesis, both features of PMF.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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