All the cells in your body have the same DNA, but they express — turn off or on — different genes depending on their function. Studying how the “wrong” genes are sometimes activated in cells can teach us a lot about what causes cancer to develop and also suggest ways to treat it.
Memorial Sloan Kettering physician-scientist Ross Levine has dedicated his career to treating patients with leukemia and other blood disorders and to studying the genetic changes that cause normal blood cells to become cancerous.
MSK researchers are studying genetic changes that turn normal cells into cancerous ones.
“What we like to do in my lab is to open up the hood and examine the circuitry of the leukemia, in a way that hopefully can tell us what makes this cancer tick,” explains Dr. Levine, an investigator in the Human Oncology and Pathogenesis Program.
His latest study, published recently in the journal Cancer Cell, has revealed important insights about how different mutations act together to distort a blood cell’s identity and make leukemia more aggressive — and it has also yielded clues about how drugs could reprogram these cancerous cells back to normal.
Focus on Cancer Epigenetics
What Dr. Levine has discovered — along with other investigators at MSK and elsewhere — is that many of the genes that are mutated in leukemia encode for proteins that control epigenetic processes. Epigenetics refers to information that can be passed down from parent cell to daughter cell but is not encoded in the DNA sequence, meaning that it’s not hereditary. Epigenetic changes are linked to many types of cancer because when cells don’t express the right gene at the right time, uncontrolled growth often results.
MSK is devoting considerable efforts to the study of epigenetics, one of the fastest-growing fields of cancer research, including through the recent establishment of the Center for Epigenetics Research, headed by physician-scientist Scott Armstrong.Back to top
Answering the Fundamental Questions
Dr. Levine’s work aims to answer central questions about leukemia: “What are the specific genes and proteins that are mutated, and how do those mutations actually cause the leukemia?” he asks. “More importantly, what happens when you reverse the effects of those mutations?”
Earlier research from his team examined samples from more than 500 patients with acute myeloid leukemia (AML) and determined that certain combinations of gene mutations could be used to predict which patients would respond to traditional chemotherapy and which had more aggressive disease that would require a different approach.
Treatment of more aggressive disease may require a new approach.
Based on findings from that study, the team engineered mice with gene mutations that mimicked this more aggressive form of disease. In the current study, the researchers developed a new AML mouse model to figure out how these combinations of mutations function to change the epigenetics of the leukemia cells.
“When these mutations work together, they’re telling the cells not to use the normal genes that are important for the normal behavior of blood cells,” Dr. Levine says. “The cells forget their identity and don’t do the things they’re supposed to do.”
The investigators were then able to put back a silenced gene and study the outcome. “What was remarkable was that the leukemia cells didn’t die — they recovered their normal behavior and became normal cells,” he says. “The cells slowly went away, and the mice no longer had leukemia.”Back to top
Reprogramming Diseased Cells
Dr. Levine’s lab is now focused on finding drugs and other approaches that will enable them to reeducate and reprogram leukemia cells. Several clinical trials at MSK are already using a similar tactic, and early results are promising.
In addition, the researchers are looking at ways these cells can be eliminated once they are reprogrammed to be less harmful and easier to attack.
“This research shows how we can use state-of-the-art epigenetic technologies to uncover the wiring of these cells, and then show that by restoring the normal wiring, we can actually change their behavior,” he concludes.Back to top