Leukemia Inversely Correlate with Somatic Hypermutation Levels and Suggest No Major Leukemic Turnover in Bone Marrow

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Cancer Research 68, 10137-10144, December 15, 2008. doi:

10.1158/0008-5472.CAN-08-2325

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 Gent1, Arnon P. Kater3, Sigrid A. Otto1, A. Jaspers3, José A.M.

Borghans1,2, Nienke Vrisekoop1, Mariëtte A.T. Ackermans4, An F.C. Ruiter4,

Shulamiet Wittebol6, Eldering5, Marinus H.J. van Oers3, Kiki Tesselaar1,

Marie José Kersten3 and Miedema1

1 Department of Immunology, University Medical Center Utrecht; 2 Theoretical

Biology, Utrecht University, Utrecht, the Netherlands; Departments of 3

Hematology, 4 Endocrinology and Metabolism, and 5 Experimental Immunology,

Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;

and 6 Department of Internal Medicine, Meander Medical Center, Amersfoort, the

Netherlands

Requests for reprints: Miedema, Department of Immunology, University

Medical Center Utrecht, Lundlaan 6, P. O. Box 85090, 3508 AB Utrecht, the

Netherlands. Phone: 31-88-7557675; Fax: 31-88-7554305; E-mail:

f.miedema@... .

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, 2H2O 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 2H2O labeling protocol. Average CLL turnover rates (0.08-0.35% of the

clone per day) were 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 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]