title: Integrative analysis of copy number and gene expression data suggests novel pathogenetic mechanisms in primary myelofibrosis.
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.
authors.affiliation: Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Salati
authors.affiliation: Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Zini
authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Nuzzo
authors.affiliation: Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.affiliation: Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pennucci
authors.affiliation: Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
authors.forename: Zelia
authors.initials: Z
authors.lastname: Prudente
authors.affiliation: Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Ruberti
authors.affiliation: Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Rontauroli
authors.affiliation: Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
authors.forename: Ruggiero
authors.initials: R
authors.lastname: Norfo
authors.affiliation: Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bianchi
authors.affiliation: Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Bogani
authors.affiliation: Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Rotunno
authors.affiliation: Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Fanelli
authors.affiliation: Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Mannarelli
authors.affiliation: IRCCS Policlinico S.Matteo Foundation, Center for the Study of Myelofibrosis, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Rosti
authors.affiliation: Hematology, Az. Osp. Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Salmoiraghi
authors.affiliation: Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: IRCCS Policlinico S.Matteo Foundation, Center for the Study of Myelofibrosis, Pavia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
authors.affiliation: Hematology, Az. Osp. Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Tagliafico
authors.affiliation: Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.affiliation: Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Manfredini
mesh_terms: D002869:Chromosome Aberrations; D018274:Electroporation; D018628:Gene Dosage; D024261:HMGB2 Protein / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome; D000097667:Polyamine Oxidase
chemical_list: D024261:HMGB2 Protein; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000097667:Polyamine Oxidase; C527734:HMGXB4 protein, human
keywords: HMGXB4; PAOX; copy number; megakaryocyte; primary myelofibrosis