title: 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 cellsin vitroandin 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 (VHand DHgene 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 VHand JHgenes but different DHgenes. However, in-depth analysis and interpretation of Ig gene rearrangements ultimately suggested that the two diseases had distinct clonal origins.
authors.affiliation: Laboratoire d'Oncobiologie Moléculaire, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France; EA 4666 Lymphocyte Normal - Pathologique et Cancers, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Trudel
authors.affiliation: EA 4666 Lymphocyte Normal - Pathologique et Cancers, Université de Picardie Jules Verne , Amiens , France.
authors.forename: Hussein
authors.initials: H
authors.lastname: Ghamlouch
authors.affiliation: Laboratoire d'Oncobiologie Moléculaire, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France; EA 4666 Lymphocyte Normal - Pathologique et Cancers, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dremaux
authors.affiliation: Service d'Hématologie Clinique, Centre Hospitalier Universitaire Amiens Picardie , Amiens , France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Delette
authors.affiliation: Laboratoire d'Hématologie, Centre Hospitalier Universitaire Amiens Picardie , Amiens , France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Harrivel
authors.affiliation: EA 4666 Lymphocyte Normal - Pathologique et Cancers, Université de Picardie Jules Verne, Amiens, France; Service d'Hématologie Clinique, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Marolleau
authors.affiliation: Laboratoire d'Oncobiologie Moléculaire, Centre Hospitalier Universitaire Amiens Picardie, Amiens, France; EA 4666 Lymphocyte Normal - Pathologique et Cancers, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gubler
keywords: DNA copy number; cell sorting; clonal origin; concomitant hematological malignancies; immunoglobulin gene rearrangement