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1.19.2016

Sylvester Researchers Identify Genetic Abnormalities Driving Development of Acute Myeloid Leukemia

Researchers at Sylvester Comprehensive Cancer Center, in close collaboration with Memorial Sloan Kettering Cancer Center (MSKCC), published a study in The Journal of Experimental Medicine on January 11, mapping the interaction of various genetic abnormalities in the development of acute myeloid leukemia (AML).

The project, conducted by first author Megan A. Hatlen, Ph.D., postdoctoral research fellow at MSKCC, was initiated by Stephen D. Nimer, M.D., Director of Sylvester (and formerly of MSKCC), but later joined and co-led by Ross Levine, M.D., Laurence Joseph Dineen Chair in Leukemia Research at MSKCC. Using disease models with AML1-ETO, a gene mutation commonly found in AML, the team of researchers identified two additional mutations, in the genes TET2 and PTPN11, that co-contribute to the development of the disease.

“Four to 12 percent of patients with AML have a translocation between chromosomes 8 and 21,” said Nimer. “However, when we studied the effects of AML1-ETO — one such translocation — in animal models, we only saw disease development after additional treatment with mutagenic agents. This led us to the conclusion that other cooperating events need to occur for AML to develop.”

AML is a cancer of the blood and bone marrow that affects the myeloid line of blood cells. It is a rapidly progressing disease that is characterized by the growth of abnormal white blood cells that accumulate in the bone marrow, interfering with the production of normal blood cells. AML is the most common leukemia in adults in the U.S., but is still rather rare, affecting about 19,000 people per year.

While studying cooperating events in disease models and patients with the AML1-ETO mutation, the team of researchers identified mutations in the enzyme TET2. They showed that loss of TET2 is capable of cooperating with AML1-ETO to initiate AML in vivo. In addition, they identified mutations in the phosphatase PTPN11 and found that co-expression of an activated PTPN11 with AML1-ETO similarly initiates AML.

“This study shows the power of combining mouse and human leukemia studies to identify and credential new combinations of mutations which can cause leukemia,” said Levine.

As part of the study, Nimer and his colleagues also investigated the mutational landscape of AML in mouse models and compared it to AML patients.

“We did not observe a significant difference in the number of variants detected or genes targeted in the mouse models compared with AML patient samples,” said Nimer. In fact, the mouse models of AML1-ETO-driven leukemia seemed to be characterized by mutations in genes also mutated in AML patients. Hatlen, who received her Ph.D. from Weill Cornell Medical College for this work, notes that “systematic comparisons of mutational patterns in malignancies across species may represent a powerful means of identifying driving disease alleles.”

The identification of TET2 loss as a cooperating event in AML1-ETO-positive AML implicates mutations in other genes such as IDH1/2 and WT1 in leukemia initiation. Mutations in these genes have been shown to attenuate TET2 function, resulting in increased DNA methylation. Whether AML1-ETO-positive leukemias harboring mutations in these genes have a unique methylation profile and respond well to demethylating agents is of great interest. Similarly, given that PTPN11 activity is critical to cellular signaling via the MAPK pathway, it will be important to determine whether therapeutics capable of inhibiting this pathway are beneficial to AML1-ETO-positive leukemias with a PTPN11 mutation.

The research was funded by National Institutes of Health R01 grant CA166835 to Nimer, grant CA172636-01 to Levine, and by Memorial Sloan Kettering Cancer Center Support Grant/Core Grant P30 CA008748.

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