Researchers at the Keck School of Medicine of the University of Southern California (USC) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have discovered high concentrations of a specific mutator protein in cells that develop resistance to drug treatment in chronic myeloid leukemia (CML). The finding helps explain why CML cells become drug-resistant and may lead to the development of therapies that improve survival in CML patients.

Researchers led by Markus Müschen, M.D., director of the Leukemia and Lymphoma program at the USC Norris Comprehensive Cancer Center found that the protein, activation-induced cytidine deaminase (AID), which normally mutates antibody genes in B cells, triggers resistance to Gleevec®, the standard treatment for CML patients. CML cells often develop resistance to Gleevec®, limiting treatment options for many patients living with CML.

The multi-investigator study, which features major contributions from USC faculty colleagues Michael Lieber, M.D. Ph.D., John Groffen, Ph.D., Yong-mi Kim, M.D. and Nora Heisterkamp, Ph.D., is published in the current issue of Cancer Cell.

"Before this, we did not know why some patients developed resistance to Gleevec®," said Müschen. "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."

Every year, 4,500 patients are diagnosed with CML in the United States; nearly 25,000 have the disease today. 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 damage the bone marrow and blood.

"The involvement of the mutator enzyme AID exemplifies that the Darwinian principle of 'survival of fittest' also explains how drug-resistance arises in leukemia," said Müschen. "Not all mutations introduced by AID are favorable for the leukemia cells, but those that confer drug-resistance provide an enormous survival advantage for the leukemia cells."

Gleevec® increases overall survival for CML patients to 95 percent over a five-year period. The drug inhibits 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. 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, with an average survival range of less than seven months.

"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 Rafael Casellas, Ph.D., co-author of the study and leader of the Genomics and Immunity group at NIAMS.

The USC-NIAMS study discovered that blast cells, in comparison to chronic phase cells, expressed high concentrations of AID. The researchers also found that increasing the concentrations of AID in chronic phase CML cells caused the cells to rapidly transition into blast crisis and become resistant to Gleevec®.

The ongoing project is supported by two research grants from the National Institutes of Health. "Future work will focus on prevention of AID activity early on in CML patients," said Müschen. Several inhibitors of AID are currently being tested in his laboratory.

Citation:
"The B cell mutator AID promotes B lymphoid blast crisis and drug-resistance in chronic myeloid leukemia."
Klemm L, Duy C, Iacobucci I, Kuchen S, Feldhahn N, Henke N, Li Z, Kim YM, Hofmann WK, Jumaa H, Groffen J, Heisterkamp N, Martinelli G, Lieber MR, Casellas R & Müschen M.
Cancer Cell 16: (September 8, 2009)

Source
University of Southern California

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