In vivo Dynamics of Stable Chronic Lymphocytic Leukemia Inversely Correlate with Somatic Hypermutation Levels and Suggest No Major Leukemic Turnover in Bone Marrow

Rogier van Gent, Arnon P. Kater, Sigrid A. Otto, A. Jaspers, José A. M. Borghans, Nienke Vrisekoop, Mariëtte A. T. Ackermans, An F. C. Ruiter, Shulamiet Wittebol, Eric Eldering, Marinus H. J. van Oers, Kiki Tesselaar, Marie José Kersten, Frank Miedema

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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 (H2O)-H-2 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 (H2O)-H-2 labeling protocol. Average CLL turnover rates (0.08-0.35% of the clone per day) were similar to 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 similar to 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. [Cancer Res 2008;68(24):10137-44]
Original languageEnglish
Pages (from-to)10137-10144
JournalCancer Research
Volume68
Issue number24
DOIs
Publication statusPublished - 2008

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