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Int J Cancer. 2016 Apr 1;138(7):1657-69. doi: 10.1002/ijc.29920. Epub 2015 Nov 25.

Integrative analysis of copy number and gene expression data suggests novel pathogenetic mechanisms in primary myelofibrosis.

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Life Sciences Department University of Modena and Reggio Emilia, Centre for Regenerative Medicine, via Gottardi N.100, Modena, 41125, Italy.
Center for Genome Research, University of Modena and Reggio Emilia, via Campi N.287, Modena, 41125, Italy.
Department of Experimental and Clinical Medicine, Laboratorio Congiunto MMPC, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence, Italy.
IRCCS Policlinico S.Matteo Foundation, Center for the Study of Myelofibrosis, Pavia, Italy.
Hematology, Az. Osp. Papa Giovanni XXIII, Bergamo, Italy.
Department of Hematology Oncology, IRCCS Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy.


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.


HMGXB4; PAOX; copy number; megakaryocyte; primary myelofibrosis

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