title: In vivo dynamics of stable chronic lymphocytic leukemia inversely correlate with somatic hypermutation levels and suggest no major leukemic turnover in bone marrow.
abstract: Although accumulating evidence indicates that chronic lymphocytic leukemia (CLL) is a disease with appreciable cell dynamics, it remains uncertain whether this also applies to patients with stable disease. In this study, (2)H(2)O was administered to a clinically homogeneous cohort of nine stable, untreated CLL patients. CLL dynamics in blood and bone marrow were determined and compared with normal B-cell dynamics in blood from five healthy individuals who underwent a similar (2)H(2)O labeling protocol. Average CLL turnover rates (0.08-0.35% of the clone per day) were approximately 2-fold lower than average B-cell turnover rates from healthy individuals (0.34-0.89%), whereas the rate at which labeled CLL cells in blood disappeared (0.00-0.39% of B cells per day) was approximately 10-fold lower compared with labeled B cells from healthy individuals (1.57-4.24% per day). Leukemic cell turnover variables inversely correlated with the level of somatic hypermutation of the CLL clone (IgVH mutations). Although CLL cells in bone marrow had a higher level of label enrichment than CLL cells in blood, no difference between proliferation rates and proapoptotic and antiapoptotic profiles of CLL cells from these compartments was observed. These data suggest that, in stable disease, there is a biological relationship between the degree of somatic hypermutation of the CLL clone and its dynamics in vivo. Furthermore, in contrast to lymph nodes, the bone marrow does not seem to be a major CLL proliferation site.
authors.affiliation: Department of Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: van Gent
authors.forename: Arnon P
authors.initials: AP
authors.lastname: Kater
authors.forename: Sigrid A
authors.initials: SA
authors.lastname: Otto
authors.forename: A
authors.initials: A
authors.lastname: Jaspers
authors.forename: José A M
authors.initials: JA
authors.lastname: Borghans
authors.forename: Nienke
authors.initials: N
authors.lastname: Vrisekoop
authors.forename: Mariëtte A T
authors.initials: MA
authors.lastname: Ackermans
authors.forename: An F C
authors.initials: AF
authors.lastname: Ruiter
authors.forename: Shulamiet
authors.initials: S
authors.lastname: Wittebol
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
authors.forename: Marinus H J
authors.initials: MH
authors.lastname: van Oers
authors.forename: Kiki
authors.initials: K
authors.lastname: Tesselaar
authors.forename: Marie José
authors.initials: MJ
authors.lastname: Kersten
authors.forename: Frank
authors.initials: F
authors.lastname: Miedema
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007223:Infant; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D008297:Male; D009154:Mutation; D012334:RNA, Neoplasm / Q000235:genetics
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D012334:RNA, Neoplasm