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| Status |
Public on May 21, 2018 |
| Title |
Integrative analysis of copy number and gene expression data suggests novel pathogenic mechanisms in Primary Myelofibrosis |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by genome tiling array
Genome variation profiling by SNP array
SNP genotyping by SNP array
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| Summary |
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). Beginning in early 2005, a number of novel mutations involving JAK2, CALR, MPL, TET2, ASXL1, DNMT3a, CBL, IDH1 and IDH2 have been described in MPNs, depicting a really complex genomic landscape for MPNs. To shed light on the genomic lesions that can contribute to disease phenotype and/or development, we integrated gene expression and copy number signals and identified several genomic abnormalities leading to a concordant alteration in gene expression levels. In particular, copy number gain in the polyamine oxidase (PAOX) gene locus is accompanied by a coordinated transcriptional up-regulation in PMF patients. Inhibition of PAOX resulted in rapid cell death in PMF progenitor cells, but not in 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 suggesting that genomic and transcriptional imbalances of HMGXB4 could contribute to the aberrant expansion of the megakaryocytic lineage that characterize PMF patients.
In this study, the authors take advantage of the integrative analysis of gene expression and copy number data to identify the concordant gain/up-regulation of the polyamine oxidase PAOX and the loss/down-regulation of the chromatin modifier HMGXB4. This work sheds light on the influence of genomic abnormalities on gene expression regulation in PMF CD34+ cells and on their contribution to specific features of PMF, such as a hyperplastic megakaryopoiesis.
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| Overall design |
Gene expression profile [GEP; GSE41812, GSE53482] and Copy Number Analysis (CN) were performed on 31 PMF patients and 31 healthy donors (n=16 PB CD34+, n=15 BM CD34+) (1 replicate for each sample).
Please note that [1] the copy number status for the PMF samples have been determined using the HapMap database as a reference, so for this analysis, the nomal donor samples are not required. [2] the accession number for gene expression data for each sample is indicated in the description field.
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| Contributor(s) |
Salati S, Bicciato S, Zini R, Guglielmelli P, Pennucci V, Fanelli T, Bogani C, Rontauroli S, Norfo R, Ruberti S, Prudente Z, Bianchi E, Barosi G, Cazzola M, Rambaldi A, Tagliafico E, Vannucchi AM, Manfredini R |
| Citation(s) |
26547506 |
| Submission date |
May 22, 2015 |
| Last update date |
Jul 13, 2018 |
| Contact name |
Rossella Manfredini |
| E-mail(s) |
manfredini.rossella@unimore.it
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| Phone |
+390592058065
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| Organization name |
Centre for Regenerative Medicine
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| Department |
Life Sciences
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| Street address |
Via Gottardi 100
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| City |
Modena |
| ZIP/Postal code |
41100 |
| Country |
Italy |
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| Platforms (1) |
| GPL16131 |
[CytoScanHD_Array] Affymetrix CytoScan HD Array |
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| Samples (31)
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| GSM1694123 |
PB CD34+ cells from PMF patient 4771 [CN] |
| GSM1694124 |
PB CD34+ cells from PMF patient 4831 [CN] |
| GSM1694125 |
PB CD34+ cells from PMF patient 5005 [CN] |
| GSM1694126 |
PB CD34+ cells from PMF patient 5008 [CN] |
| GSM1694127 |
PB CD34+ cells from PMF patient 5017 [CN] |
| GSM1694128 |
PB CD34+ cells from PMF patient 5024 [CN] |
| GSM1694129 |
PB CD34+ cells from PMF patient 5196 [CN] |
| GSM1694130 |
PB CD34+ cells from PMF patient 5396 [CN] |
| GSM1694131 |
PB CD34+ cells from PMF patient 5566 [CN] |
| GSM1694132 |
PB CD34+ cells from PMF patient 5578 [CN] |
| GSM1694133 |
PB CD34+ cells from PMF patient 5715 [CN] |
| GSM1694134 |
PB CD34+ cells from PMF patient 5719 [CN] |
| GSM1694135 |
PB CD34+ cells from PMF patient 5724 [CN] |
| GSM1694136 |
PB CD34+ cells from PMF patient 5733 [CN] |
| GSM1694137 |
PB CD34+ cells from PMF patient 5757 [CN] |
| GSM1694138 |
PB CD34+ cells from PMF patient 5760 [CN] |
| GSM1694139 |
PB CD34+ cells from PMF patient 5767 [CN] |
| GSM1694140 |
PB CD34+ cells from PMF patient 5776 [CN] |
| GSM1694141 |
PB CD34+ cells from PMF patient 5782 [CN] |
| GSM1694142 |
PB CD34+ cells from PMF patient 5786 [CN] |
| GSM1694143 |
PB CD34+ cells from PMF patient 5793 [CN] |
| GSM1694144 |
PB CD34+ cells from PMF patient 5807 [CN] |
| GSM1694145 |
PB CD34+ cells from PMF patient 5835 [CN] |
| GSM1694146 |
PB CD34+ cells from PMF patient 5848 [CN] |
| GSM1694147 |
PB CD34+ cells from PMF patient PV_13 [CN] |
| GSM1694148 |
PB CD34+ cells from PMF patient PV_27 [CN] |
| GSM1694149 |
PB CD34+ cells from PMF patient PV_29 [CN] |
| GSM1694150 |
PB CD34+ cells from PMF patient PV_40 [CN] |
| GSM1694151 |
PB CD34+ cells from PMF patient PV_41 [CN] |
| GSM1694152 |
PB CD34+ cells from PMF patient PV_46 [CN] |
| GSM1694153 |
PB CD34+ cells from PMF patient PV_47 [CN] |
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| Relations |
| BioProject |
PRJNA284681 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE69161_RAW.tar |
3.4 Gb |
(http)(custom) |
TAR (of CEL, CYCHP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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