Scientists disprove two tenets of common leukemia

Scientists at the Institute for Medical Research at North Shore-LIJ have made a discovery that refutes two longstanding beliefs about the most common leukemia in the western hemisphere. Due to the relatively slow disease progression of chronic lymphocytic leukemia (CLL), doctors thought it was caused by a gradual accumulation of leukemia cells that could not die. The new findings, published online today in the Journal of Clinical Investigation, prove the exact opposite. The study will appear in the journal’s March 2005 print issue.

For decades, doctors and scientists believed that CLL was a static disease of long-lived white blood cells (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 leukemia cells’ process of cell suicide, called apoptosis, a normal part of the cell life cycle for which all cells are programmed. This was a hint that perhaps the leukemia cells were not immortal. Using a clever study design that required subjects only to drink water and give blood samples, the research team, led by Nicholas Chiorazzi, MD, director and CEO of the Institute for Medical Research, found that the 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 scientists also found that there appeared to be a connection between poorer patient outcomes and the faster birth rates of the leukemia cells, regardless of the rate of cell death. “This particular finding may prove helpful in identifying patients who are at risk for worsening disease in advance of showing any clinical signs of deterioration,” said Dr. Chiorazzi. He cautioned, however, that additional research is needed to establish its potential in guiding prognostic and treatment decisions. The study was small, examining 19 CLL patients.

A larger trial is already underway to gain greater insights into the correlation and its potential clinical applications. The multicenter study is being led by Kanti Rai, MD, associate investigator with the Institute for Medical Research, chief of the Division of Hematology-Oncology at Long Island Jewish (LIJ) Medical Center and a world-renowned expert on CLL. More than 25 years ago, Dr. Rai developed a staging system for CLL that is still used today. Tahrun Wasil, MD, another well-known attending hematologist-oncologist at LIJ, is co-leading the trial with Dr. Rai. The study is being conducted in conjunction with the CLL Research Consortium (CRC), a multi-institutional project funded by the National Institutes of Health. The CRC includes LIJ Medical Center, University of California at San Diego, M.D. Anderson Cancer Center, Ohio State University, Johns Hopkins University, Dana Farber Cancer Institute, Mayo Clinic, and several sites that perform laboratory work alone, including the Burnham Institute and Sydney Kimmel Cancer Center.

To test his theory that leukemia cells were not immortal, Dr. Chiorazzi used “heavy water” to track cell production. Heavy water is simply water that weighs more at the molecular level than normal. Among its many uses in the body, water gets incorporated into everyone’s DNA. When a cell divides into two, the new cell gets an exact copy of the DNA from the original cell, so the incorporated heavy water serves as a tag that allows scientists to track the birth of new cells.

The researchers gave individuals with CLL a small dose of heavy water — about two ounces — every day over the course of 12 weeks, enough time for the cells to incorporate a sufficient amount into their DNA. From blood samples, they calculated the birth and death rates of leukemia cells. They found that CLL is very much a dynamic process composed of mortal cells that proliferate and die, often with a high turnover, and not a static disease in which leukemia cells slowly build up because they cannot die, as previously thought.