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Global methylation patterns in Primary Plasma Cell leukemia

ABSTRACT: Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM), which is associated with a very poor prognosis. Specific molecular patterns distinguish pPCL in comparison to MM and in relation to main genomic alterations. In the present study, a whole-genome methylation profiling analysis by high-density array revealed a global gene hypomethylation profile in pPCL. Lower methylation levels were particularly observed in the promoter and 5’ untranslated regions (5’UTR), whereas higher levels were evidenced in gene body or 3’ untranslated regions (3’UTR). CpG islands (CGI) resulted largely hypomethylated, whereas higher methylation levels were observed in CGI distal regions. Peculiar differential methylation patterns were identified in association to major chromosomal aberrations and DIS3 mutational status and involved genes playing roles in cell migration, bone metabolism, transcription regulation or DNA damage response. Finally, decreasing methylation levels were evidenced for few genes in association to MM disease progression, from healthy condition to MM and pPCL. Our data may provide new insights into the molecular characterization of pPCL patients, thus being potentially useful in the prognostic stratification or identification of novel molecular targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104770 | GEO | 2018/10/10

REPOSITORIES: GEO

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Project description:Plasma cell leukemia (PCL) is a rare form of plasma cell dyscrasia that presents either as a progression of previously diagnosed multiple myeloma (MM), namely secondary PCL (sPCL), or as the initial manifestation of disease, namely primary PCL (pPCL). Although presenting signs and symptoms include those seen in MM, pPCL is characterized by several aspects that clearly define more aggressive course. To provide insights into the biology of pPCL, we have investigated the transcriptional profiles of a cohort of 21 newly-diagnosed, homogeneously treated pPCL patients included in a multicenter prospective clinical trial. All but one pPCL had one of the main IGH translocations, whose associated transcriptional signatures resembled those observed in MM. A 503-gene signature was identified that distinguished pPCL from MM, from which emerged 28 genes whose trend in expression levels was found associated with the progressive stages of plasma cell dyscrasia in a large dataset of cases from multiple institutions, including samples from normal donors throughout PCL. The transcriptional pattern of the pPCL series was then evaluated in association with outcome. Three genes were identified having expression levels correlated with response to the first-line treatment with lenalidomide/dexamethasone, whereas a 27-gene signature was identified associated with overall survival independently of molecular alterations, hematological parameters and renal function. Overall, our data contribute to a fine dissection of pPCL and may provide novel insights into the molecular definition of a subgroup of high-risk pPCL. This series of microarray experiments contains the gene expression profiles of purified plasma cells (PCs) obtained from 21 pPCL and 55 MM at diagnosis. PCs were purified from bone marrow samples using CD138 immunomagnetic microbeads according to the manufacturer's instructions (MidiMACS system, Miltenyi Biotec); the purity of the positively selected PCs was assessed by morphology and flow cytometry and was > 90% in all cases. 5.5 micrograms of single-stranded DNA target obtained from 100 ng of purified total RNA was fragmented and then labeled using the WT Terminal Labeling Kit according to the standard Affymetrix protocol (GeneChipÂ¨ Whole Transcript (WT) Sense Target Labeling Assay Manual). The fragmented labeled single-stranded DNA target was hybridized for 16 hours and 30 minutes at 45Â¡C on GeneChipÂ¨ Gene 1.0 ST array according to the standard Affymetrix protocol. Washing and scanning were performed using GeneChip System of Affymetrix (GeneChip Hybridization Oven 640, GeneChip Fluidics Station 450 and GeneChip Scanner 7G). Log2-transformed expression values were extracted from CEL files and normalized using NetAffx Transcript Cluster Annotations, Release 31 and robust multi-array average (RMA) procedure in Expression Console software (Affymetrix Inc.). Non-annotated transcript clusters were discarded. The expression values of transcript cluster ID specific for loci representing naturally occurring read-through transcriptions or mapped to more than one chromosomal location were summarized as median value for each sample. gene expression analysis of 21 primary Plasma Cell Leukemia and 55 multiple myeloma tumors

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Global methylation patterns in Primary Plasma Cell leukemia

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