Researchers explore leukemia genetics

The findings of a new Yale study yield the potential to diagnose leukemia more comprehensively, as well as to develop a novel therapeutic treatment.

Prior research showed that the TET2 gene is responsible for suppressing tumor growth, and that mutations in the TET2 gene allow tumors to proliferate. In a study published in the journal Cell Reports on Oct. 10, researchers at the Yale School of Medicine helped to show that an abundance of microRNAs (miRNAs), small pieces of RNA, inhibit the expression of a functional copy of the tumor-suppressing gene TET2. These results suggest that patients with an abundance of these microRNAs may also be more at-risk for leukemia — even if they don’t have a TET2 mutation. The findings have implications for using miRNAs as a diagnostic test for cancer and for personalizing treatment regimens, Yale senior author and professor of genetics Jun Lu said.

“Previously, it was thought that this kind of leukemia can only be classified based on the TET’s mutation status, but the picture is incomplete,” Lu said. “Our findings can really help doctors have a more complete picture of leukemia patients, and due to this information, help patients in terms of their treatment.”

Researchers discovered the TET2 mutation as an indicator for cancer in 2009, and since then, the pathway between microRNAs and TET genes has been demonstrated, but not in the context of leukemia, said study co-author and Yale professor of genetics In-Hyun Park.

Lu and his team tested the suppression of TET2 by mouse and human miRNAS, and identified over thirty miRNAS that inhibit TET2 expression. They found that a forced overexpression of TET2-targeting miRNAs resulted in subsequent malignant blood formations.

The discovery of miRNAs as a marker of leukemia has therapeutic and diagnostic consequences, Lu said. Because TET2 mutations have been associated with leukemia, companies have been developing diagnostic tests for TET2 mutations. However, Lu said that this study indicates that solely looking for mutations in these tests will not be sufficient.

In fact, miRNAs themselves could have significant diagnostic capabilities. Through analyzing levels of miRNAs in patients, doctors could potentially predict TET2 levels and the subsequent susceptibility to leukemia, said study co-author and professor of pediatrics at Harvard University Yi Zhang.

The study’s findings can also influence the treatment of leukemia. Using miRNAs as a determinant in the severity of leukemia cases can help doctors decide whether to spare patients who lack these markers from aggressive bone marrow transplants and high-dose chemotherapy treatment, or to start treatment earlier for patients who lack mutations but have high levels of miRNAs, Lu said.

Zhang added that it may be possible to manipulate and control miRNA to block its effects and reduce the likelihood of leukemia.

“It’s a new field, including the TET2 gene as a diagnostic,” Lu said. “The TET2 mutation has not been completely translated immediately into the clinic, but researchers know that it is extremely important. We’re hoping that with the TET2 mutation and microRNAs, we can push this frontier forward to helping patients.”

Lu said he hopes to expand his findings of this most recent research beyond the one hospital from this study.

Since January 2010, approximately 287,963 men and women in the U.S. have had or currently have leukemia.