Integrated differential transcriptome maps of Acute Megakaryoblastic Leukemia (AMKL) in children with or without Down Syndrome (DS).

Maria Chiara Pelleri,Lorenza Vitale,Pierluigi Strippoli,Allison Piovesan,Anna Concetta Berardi,Maria Caracausi

doi:10.1186/s12920-014-0063-z

Abstract

BackgroundThe incidence of Acute Megakaryoblastic Leukemia (AMKL) is 500-fold higher in children with Down Syndrome (DS) compared with non-DS children, but the relevance of trisomy 21 as a specific background of AMKL in DS is still an open issue. Several Authors have determined gene expression profiles by microarray analysis in DS and/or non-DS AMKL. Due to the rarity of AMKL, these studies were typically limited to a small group of samples.MethodsWe generated integrated quantitative transcriptome maps by systematic meta-analysis from any available gene expression profile dataset related to AMKL in pediatric age. This task has been accomplished using a tool recently described by us for the generation and the analysis of quantitative transcriptome maps, TRAM (Transcriptome Mapper), which allows effective integration of data obtained from different experimenters, experimental platforms and data sources. This allowed us to explore gene expression changes involved in transition from normal megakaryocytes (MK, n=19) to DS (n=43) or non-DS (n=45) AMKL blasts, including the analysis of Transient Myeloproliferative Disorder (TMD, n=20), a pre-leukemia condition.ResultsWe propose a biological model of the transcriptome depicting progressive changes from MK to TMD and then to DS AMKL. The data indicate the repression of genes involved in MK differentiation, in particular the cluster on chromosome 4 including PF4 (platelet factor 4) and PPBP (pro-platelet basic protein); the gene for the mitogen-activated protein kinase MAP3K10 and the thrombopoietin receptor gene MPL. Moreover, comparing both DS and non-DS AMKL with MK, we identified three potential clinical markers of progression to AMKL: TMEM241 (transmembrane protein 241) was the most over-expressed single gene, while APOC2 (apolipoprotein C-II) and ZNF587B (zinc finger protein 587B) appear to be the most discriminant markers of progression, specifically to DS AMKL. Finally, the chromosome 21 (chr21) genes resulted to be the most over-expressed in DS and non-DS AMKL, as well as in TMD, pointing out a key role of chr21 genes in differentiating AMKL from MK.ConclusionsOur study presents an integrated original model of the DS AMLK transcriptome, providing the identification of genes relevant for its pathophysiology which can potentially be new clinical markers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-014-0063-z) contains supplementary material, which is available to authorized users.

Highlights

The incidence of Acute Megakaryoblastic Leukemia (AMKL) is 500-fold higher in children with Down Syndrome (DS) compared with non-DS children, but the relevance of trisomy 21 as a specific background of AMKL in DS is still an open issue
Database search The Gene Expression Omnibus (GEO) [30] search allowed the retrievement of three additional works describing data possibly useful for meta-analysis [19,24,38]
The lack of inclusion of these works in the literature search was due to failure of using the ''AMKL'' acronym and assigning the MeSH Term "Leukemia, Megakaryoblastic, Acute" during the PubMed indexing process

Summary

Introduction

The incidence of Acute Megakaryoblastic Leukemia (AMKL) is 500-fold higher in children with Down Syndrome (DS) compared with non-DS children, but the relevance of trisomy 21 as a specific background of AMKL in DS is still an open issue. In nearly half of the cases, these childhood leukemias are classified as megakaryoblastic leukemia (AMKL), a relatively rare subtype of AML known as AML M7, according to French–American–British (FAB) classification, whose incidence increases by 500-fold in children with DS by the age of 4 years as compared to the chromosomally normal population (reviewed in [13]). This observation strongly suggests that trisomy 21 directly contributes to the neoplastic transformation of hematopoietic cells, in particular in the megakaryocyte lineage cells. GATA1 mutations in DS cells give rise to a short, truncated form of GATA1 (GATA1s) transcription factor that, in this form, is not able to establish normal interactions with other gene regulators [17]

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