B cell chronic lymphocytic leukemia (CLL) is an incurable disease in which cells in the bone marrow grow and survive to the point where they become abnormal and malignant (leukemic). The progression of the disease is slow and there has been a lack of information regarding the rate of production of CLL cells, and the time-course of their death.

For years, doctors and scientists believed that CLL was a static disease of long-lived lymphocytes -- that the leukemia cells were both immortal and born at a slow rate, causing the slow rise in cell count over time. But researchers had been unable to find any problems with the programmed cell death machinery in CLL cells. This was a hint that perhaps the leukemia cells were not immortal, a hypothesis tested by Nicholas Chiorazzi and colleagues in a paper appearing online on February 10 in advance of publication in the March 1 print edition of the Journal of Clinical Investigation. This new study shows that leukemia cells are born at a fast rate and do indeed die. The slow rise in the cell count over time can be attributed to the difference between the birth and death rates of the cells, according to the study.

The researchers at the Institute for Medical Research at North Shore-LIJ analyzed the kinetics of CLL cells in vivo by employing a non-radioactive labeling technique - using "heavy water" to track cell production. Heavy water is made using a form of hydrogen that has twice its normal mass, making the water molecule "heavier" than normal. The special hydrogen serves as a tag that enables researchers to track the utilization of water in the body. The hydrogen incorporates into glucose and the tagged glucose eventually makes its way into the cell's DNA.

Researchers gave 19 individuals with CLL a small dose of heavy water every day for 84 days, and the tagged water was incorporated into the DNA of the leukemia cells. This provided the researchers a way to track the cell division, or "birth" of new leukemia cells. Chiorazzi and his team calculated birth and death rates of the leukemic cells and found that, contrary to expectations, production and destruction of CLL cells is highly variable, and does not exhibit a steady birth and death rate as previously thought.

The data also reveal that a correlation exists between the rate at which CLL cells are born and the clinical activity or progression of the disease in a patient. The disease activity may vary over time and this may be the result of fluctuations in birth and/or death rates of the CLL cells.

This challenges the dogma that CLL is a purely accumulative disorder where leukemic cells accumulate because they cannot die. Clearly CLL is a disease in which there is a dynamic interplay between rates of cell division and cell death. The data could enable physicians to predict disease progression.

TITLE: In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells

AUTHOR CONTACT: Chiorazzi, Nicholas
Institute for Medical Research at North Shore-LIJ Manhasset, NY, USA
Phone: (516) 562-1232; Fax: (516) 562-1683; E-mail: nchizzinshs.edu

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Contact: Stacie Bloom - staciebloomthe-jci
Journal of Clinical Investigation, March 1, 2005