Childrens Hospital Los Angeles and the National Institute of Arthritis and Muscolosketetal and Skin Diseases Identify Mutator Protein Causing Drug-Resistance in Leukemia
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The finding could lead to the development of therapies that improve survival in leukemia patients
LOS ANGELES – Researchers at The Saban Research Institute of Childrens Hospital Los Angeles and the National Institute of Arthritis and Muscoloskeletal and Skin Diseases (NIAMS) have discovered high concentration of a mutator protein in cells that develop resistance to drug treatment in leukemia. The finding, which appears in the Sept. 8, 2009, issue of the journal Cancer Cell, provides an explanation as to why leukemia cells often become drug-resistant and may lead to the development of therapies that improve survival in leukemia patients.
A research team led by Markus Müschen, M.D., Ph.D., director of the Leukemia Research Program at The Saban Rsearch Institute, director of the Leukemia and Lymphoma Program at the USC/Norris Comprehensive Cancer Center and associate professor of pediatrics at the Keck School of Medicine of the University of Southern California, found that the protein AID, which normally mutates antibody genes in B cells, triggers resistance to Gleevec® in chronic myeloid leukemia (CML) patients.
Gleevec® represents the standard treatment for CML and was introduced as the first example of target-specific cancer therapy 10 years ago. Nonetheless, CML cells often develop resistance to Gleevec® and when that resistance occurs, these patients have very limited treatment options. While the problem of Gleevec®-resistance is well known and affects many of the nearly 25,000 patients that currently live with CML in the United States, how drug-resistance develops remained a mystery.
The work done by Dr. Müschen and his colleagues now elucidates a central mechanism of drug-resistance in CML. The multi-investigator study received major contributions from researchers at Childrens Hospital Los Angeles and faculty from the Keck School of Medicine: Michael R. Lieber, M.D., Ph.D., John Groffen, Ph.D., Yong-mi Kim, M.D., and Nora Heisterkamp, Ph.D.
“Before this, we did not know why some patients developed resistance to Gleevec®,” Dr. Müschen said. “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 in the United States are newly diagnosed with CML, a slowly progressing cancer that usually occurs during or after middle age and rarely occurs in children. In CML, an unusually high number of hemapoietic 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.
“The involvement of the mutator enzyme AID exemplifies that the Darwinian principle of ‘survival of the fittest’ also explains how drug-resistance arises in leukemia,” Dr. Müschen said. “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® was first approved by the U.S. Food and Drug Administration in 2001 for the treatment of CML. At the time of its approval, it was hailed as “…a magic bullet,” increasing overall survival for CML patients to 95 percent over a five-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, resulting in 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 ts 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.
For years, scientists studied CML for clues as to why and how some patients transition from the slow-moving chronic stage of the disease into the blast crisis stage. The USC-NIAMS study 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 exclusively to antibody-coding genes. However, in blast cells, AID works unchecked to promote overall genetic instability by hyper-mutating tumor suppressor and DNA repair genes. 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,” Dr. Müschen said. Several inhibitors of AID are currently being tested in his laboratory.
Founded in 1901, Childrens Hospital Los Angeles has been treating the most seriously ill and injured children in Los Angeles for more than a century, and it is acknowledged throughout the United States and around the world for its leadership in pediatric and adolescent health. Childrens Hospital is one of America’s premier teaching hospitals, affiliated with the Keck School of Medicine of the University of Southern California since 1932. It is a national leader in pediatric research.
Investigators at The Saban Research Institute of Childrens Hospital Los Angeles are working to create a world in which all children are healthy – a world in which they are no longer threatened by such diseases as cancer, congenital heart defects, diabetes, sickle cell anemia, epilepsy, immune deficiencies and respiratory disorders. They ask basic questions about human biology, find new ways to see inside the body, explore genetic mysteries, develop promising drug treatments and test preventive strategies – scientific inquiries that benefit both children and adults. The Saban Research Institute is among the largest and most productive pediatric research facilities in the United States, with 91 investigators at work on 232 laboratory studies, clinical trials and community-based research and health services. It is one of the few freestanding research centers in the nation to combine scientific laboratory inquiry with patient clinical care – dedicated exclusively to children - and its base of knowledge is widely considered to be among the best in pediatric medicine.
Since 1990, U.S. News & World Report and its panel of board-certified pediatricians have named Childrens Hospital Los Angeles one of the top pediatric facilities in the nation. Childrens Hospital Los Angeles is one of only 10 children’s hospitals in the nation – and the only children’s hospital on the West Coast – ranked in all 10 pediatric specialties in the U.S. News & World Report rankings and named to the magazine’s “Honor Roll” of children’s hospitals.
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