Genomics of Plasma Cell Leukemia

Abstract

Plasma cell leukemia (PCL) is a rare and highly aggressive plasma cell dyscrasia characterized by the presence of clonal circulating plasma cells in peripheral blood. PCL accounts for approximately 2-4% of all multiple myeloma (MM) cases. PCL can be classified in primary PCL (pPCL) when it appears de novo and in secondary PCL (sPCL) when it arises from a pre-existing relapsed/refractory MM. Despite the improvement in treatment modalities, the prognosis remains very poor. There is growing evidence that pPCL is a different clinicopathological entity as compared to MM, although the mechanisms underlying its pathogenesis are not fully elucidated. The development of new high-throughput technologies, such as microarrays and new generation sequencing (NGS), has contributed to a better understanding of the peculiar biological and clinical features of this disease. Relevant information is now available on cytogenetic alterations, genetic variants, transcriptome, methylation patterns, and non-coding RNA profiles. Additionally, attempts have been made to integrate genomic alterations with gene expression data. However, given the low frequency of PCL, most of the genetic information comes from retrospective studies with a small number of patients, sometimes leading to inconsistent results.

Keywords: PCL; genetics; multiple myeloma; mutations; plasma cell leukemia; primary and secondary PCL; transcriptome.

Figure 1

Genomic abnormalities of primary plasma cell leukemia (pPCL). The updated consensus of the IMWG defines pPCL by the presence of 5% or more circulating plasma cells in peripheral blood. Cytogenetic studies by FISH show predominance of monosomy and deletions of chromosome 13, t(11;14), del(17p), gain/amp(1q) and del(1p). Mutation studies by conventional DNA sequencing, WES, and targeted NGS detect a high frequency of mutations in TP53 and K/NRAS genes. The amino acids most frequently mutated in TP53 are I195, R273, P278, R248, and E285. Activating mutations of K/NRAS most frequently found in pPCL patients affect codons 12, 13, and 61 (G12, G13, and Q61). Immunophenotyping of plasma cells reveals expression of CD38 and CD138 in both pPCL and MM, although higher expression of CD20, CD23, CD28, CD44, and CD45 and lower expression of CD9, CD56, CD71, CD117, and HLA-DR may be found in pPCL compared to MM. Gene expression profiling in pPCL has shown downregulation of genes associated with bone marrow microenvironment and bone diseases in MM, such as DKK1, KIT, and NCAM1 genes. A global hypomethylation profile has been found in pPCL samples. Non-coding RNAs (miRNAs and lncRNAs) are dysregulated in pPCL, and some of them are associated with survival of patients (as shown in the figure).