Spotlight on Research 2009

September 2009 (historical)

B-Cell Mutator Enzyme Promotes Resistance to Gleevec in Chronic Myeloid Leukemia

A protein that normally mutates antibody genes in B cells triggers resistance to the drug Gleevec in patients with chronic myeloid leukemia (CML), according to a study conducted by researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), and the University of Southern California (USC). The scientists found that the protein, activation-induced cytidine deaminase (AID), exists in high concentrations in CML cells that develop resistance to the drug, in comparison to CML cells that are effectively treated with the drug. This finding may lead to the development of therapies to improve survival in CML patients who develop drug-resistance. The study appeared in the journal Cancer Cell.

"Before this, we did not know why some patients developed resistance to Gleevec," said Rafael Casellas, Ph.D., an investigator in the Genomics and Immunity group at the NIAMS and lead for the NIAMS team. "Now that we know at least one mechanism we can work to develop therapies to counter the effects of AID in the chronic phase of the disease."

CML is a slowly progressing cancer that usually occurs during or after middle age, and rarely occurs in children. In CML, an unusually high number of hematopoietic stem cells (blood cell progenitors) that were slated to become immune system cells instead develop into cancerous cells that don't die off, resulting in damage to the bone marrow and blood.

Gleevec (imatinib mesylate) was first approved for treatment of CML by the U.S. Food and Drug Administration in 2001 after research showed that it increased overall survival for CML patients to 95 percent over a 5-year period. The drug works by inhibiting the action of a cancer-causing protein called BCR-ABL1 kinase. In most CML patients, the drug's continuous inhibition of this protein is enough to keep the cancer at bay. However, in some patients, the gene that codes for the protein mutates, resulting in variations to the BCR-ABL1 protein. Gleevec is ineffective in blocking these variant proteins. When patients develop resistance to the drug, they quickly transition from the chronic phase of CML to a condition called blast crisis progression, or fatal B lymphoid blast crisis (LBC), which has an average survival time of less than seven months.

For years, scientists have been studying CML for clues as to how and why some patients transition from the slow-moving chronic stage of the disease into the blast crisis stage. In the current study, the researchers from NIAMS and USC discovered that blast cells, in comparison to chronic phase cells, expressed high concentrations of AID, a B-cell specific enzyme that under normal conditions mutates antibody-coding genes that help B cells fight pathogens. In healthy B cells, AID activity is tightly controlled to ensure that mutation is targeted primarily to antibody-coding genes. However, in blast cells, AID works unchecked to promote overall genetic instability by hypermutating tumor suppressor and DNA repair genes. The researchers also found that if they increased the concentrations of AID in chronic phase CML cells, these cells rapidly transitioned into blast cells and became Gleevec resistant.

"The results show that not only is AID involved in the transition to blast crisis, but that it actually has a causative role in the development of BCR-ABL1 mutations that lead to Gleevec resistance and blast crisis progression," said Casellas.

The study was also funded by grants from the NIH's National Cancer Institute.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at 301-495-4484 or 877-22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Reference: Klemm L, Duy C, Iacobucci I, Kuchen S, von Levetzow G, Feldhahn N, Henke N, Li Z, Hoffmann TK, Kim Y, Hofmann W, Jumaa H, Groffen J, Heisterkamp N, Martinelli G, Lieber MR, Casellas R, Müschen M. The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia. Cancer Cell. 2009 Sept 8;16:232-45.