Researchers discover genetic differences between lethal and treatable forms of leukemia - Epigenetic diagnosis and therapies, a new strategy for treating cancer.
A tumor's genetic profile is often useful when diagnosing and deciding on treatment for certain cancers, but inexplicably, genetically similar leukemias in different patients do not always respond well to the same therapy. Weill Cornell Medical College researchers believe they may have discovered what distinguishes these patients by evaluating the "epigenetic" differences between patients with acute myeloid leukemia (AML).
In recent years it has been appreciated that there are additional chemical codes in addition to DNA sequence that control the behavior of normal and malignant cells. These additional codes are called "epi"genetic since they are contained outside of the DNA sequence.
The investigators have concluded that much of the inter-patient difference in leukemia cell behavior is dependent on a patient's specific epigenetic alterations. These results are expected to lead to tailored cancer therapies for patients who fall within the different epi-genetically defined cancer subtypes.
The promising findings are published today in the journal Cancer Cell .
To make their conclusions, Dr. Ari Melnick, the study's senior author and associate professor of medicine from the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College, and colleagues studied a specific epigenetic marker called DNA methylation, which plays a critical role in controlling gene expression.
They examined the DNA methylation patterning of 14,000 genes in 344 patients diagnosed with AML. By grouping these patients according to their DNA methylation profile, Dr. Melnick and his team were able to separate patients into 16 different groups. Five of these groups defined completely new AML subtypes that shared no other known feature, besides the newly discovered methylation similarities.
"The epigenetic difference between the AML subtypes may play a critical role in determining the responsiveness of the disease to therapy," says Dr. Melnick.
Traditionally, AML patients are treated with first-line chemotherapy drugs. If they fail, patients are classified as having a more severe and difficult-to-treat disease, and are then given a more aggressive therapy, like a bone marrow transplant. Being able to tell which patients are most likely to fail standard treatments could lead to the administration of more precise therapies at the outset of treatment.
They also concluded that a set of 15-gene DNA methylation biomarker was highly predictive of overall patient survival. "The findings have the potential to tell physicians whether or not a patient has a relatively easy or difficult disease to treat, and tailor a patient's therapy accordingly," explains Dr. Melnick. "This saves time trying therapies that will eventually prove to have no effect."
In addition, the investigators discovered a set of 45 genes that are almost universally methylated in AML patients. Methylation of these genes was far more common than any genetic mutation associated with AML, and could provide new ways to more effectively therapeutically target AML in the future.
"Investigators from the Sackler Center at Weill Cornell are leaders in the field of decoding epigenetic information from human tumors and ascertaining their clinical impact," says Dr. Andrew I. Schafer, chairman of the Department of Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical College. "Such findings will lead to the development of new therapies that give hope to cancer patients who are now without effective treatment."
Collaborators on this study include Maria E. Figueroa, Yushan Li, Xutao Deng, Paul J. Christos, Lucy Skrabanek, Fabien Campagne and Madhu Mazumda, all from Weill Cornell; Elizabeth Schifano and James Booth, from Cornell University, Ithaca, New York; Sanne Lugthart, Claudia Erpelinck-Verschueren, Peter J.M. Valk, Wim van Putten, Bob Lawenberg and Ruud Delwel from Erasmus University Medical Center, Rotterdam, The Netherlands; and John M. Greally from Albert Einstein College of Medicine, New York.
This study was supported by a Translational Research grant from the Leukemia and Lymphoma Society to Drs. Melnick and Delwel.
The Raymond and Beverly Sackler Center for Biomedical and Physical Sciences of Weill Cornell Medical College brings together a multidisciplinary team of scientists for the purpose of catalyzing major advances in medicine. By harnessing the combined power of experimental approaches rooted in the physical and biological sciences, Sackler Center investigators can best accelerate the pace of discovery and translate these findings for the benefit of patients with various medical conditions including but not limited to cancer.
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances - including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Affiliated with NewYork-Presbyterian Hospital and Methodist Hospital in Houston, Weill Cornell is one of only two medical colleges in the country with dual hospital affiliations. For more information, visit www.med.cornell.edu
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