The Importance of an In-depth Study of Immunoglobulin Gene Rearrangements When Ascertaining the Clonal Relationship between Concomitant Chronic Lymphocytic Leukemia and Multiple Myeloma

Abstract

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are hematological disorders that occur at different stages of B-cell development. It has been shown that CLL B-cells can differentiate into plasma cells in vitro and in vivo. CLL is the most frequent adult leukemia in the western world. It is a heterogeneous disease, characterized by clonal proliferation and the accumulation of mature CD5+ B lymphocytes (1). MM is a clonal plasma cell malignancy that accounts for more than 10% of all hematologic cancers (2). Although secondary cancers [particularly solid tumors (3–5)] can occur with CLL and MM, the concomitant occurrence of these two disorders in the same patient is rare [for a review of the few reported cases, see Ref. (6)]. The clonal relationship between these diseases has not always been clarified but is important in terms of understanding the pathogenesis and optimizing treatment. The clonal relationship between CLL and MM can be evaluated by (i) analyzing immunoglobulin (Ig) heavy chain and light chain (Ig kappa light chain and Ig lambda light chain) gene rearrangement, (ii) identifying and comparing somatic mutations, and (iii) studying chromosomic aberrations. Nevertheless, Ig rearrangements must always be interpreted in the light of specific phenomena such as allelic exclusion, B-cell receptor (BCR) revision (VH and DH gene replacement), BCR editing, and somatic mutations—events that were not considered in previous studies. These issues can be addressed by sequencing the rearranged Ig genes from sorted populations and interpreting the generated data. In the present study, we evaluated the putative clonal relationship between the two diseases by combining DNA copy number analysis with an assessment of Ig gene rearrangements [clonality assessment, V(D)J sequencing, and somatic hypermutation analysis] in highly enriched CD19+ CD5+ (CLL) and CD38+ CD138+ (MM) cell populations. Array comparative genomic hybridization data suggested a possible phylogenic progression from CLL to MM. Moreover, V(D)J sequencing indicated that both CLL and MM cells used the same VH and JH genes but different DH genes. However, in-depth analysis and interpretation of Ig gene rearrangements ultimately suggested that the two diseases had distinct clonal origins.

RETRACTED ARTICLE: Up-regulation of microRNA-497 inhibits the proliferation, migration and invasion but increases the apoptosis of multiple myeloma cells through the MAPK/ERK signaling pathway by targeting Raf-1

“…MM is a disease related to a hematological disorder that appears at various stages of β-cells, and it accounts for 1% of all cancers, as well as 10% of hematological malignancies [32,33]. Based on recent studies, miRs have been identified as tumor-suppressor genes and play important roles in tumor pathogenesis [34,35].…”

Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective

“…The authors hypothesized that serum Ig is produced by PCs differentiated from leukemic cells ( 23 ). Concomitant PC malignancies and CLL have been reported in several studies ( 231 , 232 ). Several studies showed that differentiation of CLL cells into ASPCs can occur spontaneously in vivo ( 23 , 24 ).…”

CD5+ B lymphoproliferative disorder with subsequent development of plasma cell leukaemia: Diagnostic and aetiologic reasoning

“…However, a common clonal origin is not a consistent finding, with many cases reporting a biclonal origin (6,8,10,12,34). It is noteworthy that discrepant results can be obtained for the same patient by phenotypic (i.e., with expression of different light chains and immunoglobulin isotypes) and molecular findings, supporting the need for clarifying the most accurate approach for clonality assessment (3,6,33,35). It is noteworthy that discrepant results can be obtained for the same patient by phenotypic (i.e., with expression of different light chains and immunoglobulin isotypes) and molecular findings, supporting the need for clarifying the most accurate approach for clonality assessment (3,6,33,35).…”

“…This lack of concordance could originate from heterogeneity of cases as well as from the use of divergent methods, such as immunophenotypic, cytogenetic and molecular studies. It is noteworthy that discrepant results can be obtained for the same patient by phenotypic (i.e., with expression of different light chains and immunoglobulin isotypes) and molecular findings, supporting the need for clarifying the most accurate approach for clonality assessment (3,6,33,35).…”