Study Identifies Functional Cooperative Mutations of SETD2 in the Development of Acute Leukemia
Using data from the whole-genome sequencing of a pair of 3-year-old female monozygotic twins, one healthy and one with the multilineage form of acute myeloid leukemia (AML), a team of scientists from China and the United States have identified a novel molecular target that could offer a new opportunity in the treatment of both hematologic and solid tumor cancers. The study is published in Nature Genetics.
In comparing the blood cells of the twin sisters, the researchers found an intrachromosomal translocation that gave rise to the MLL-NRIP3 fusion gene in the sister with AML. When they activated the MLL-NRIP3 gene in mouse models, the mice developed the same type of leukemia, but it took 46.5 days, suggesting that there had to be additional cooperative epigenetic and molecular events in the development of induced leukemia.
The scientists then demonstrated that activation of the MLL-NRIP3 fusion gene in the twin with leukemia cooperated with the molecular cascade, including mutations in SETD2, causing the multilineage form of AML. They discovered that activation of the MLL-NRIP3 fusion leukemia started the molecular cascade that led to biallelic mutations in SETD2—a tumor suppressor and enzyme that regulates a specific histone modification protein called H3K36me3.
Role as Tumor Suppressor
Next, the researchers analyzed blood samples from 241 cohorts with different forms of acute leukemia. SETD2 mutations were found in 6.2% of the patients and were associated with multiple major chromosomal aberrations and disruption of the H3K36me3 mark.
“Our mutational analysis, together with in vivo and in vitro functional assays, demonstrates that loss of function of SETD2 is a critical event in facilitating both disease initiation and progression through decreased H3K36me3 in leukemias characterized by MLL fusion, MLL-PTD, or AML1-ETO. Thus, a SETD2 mutation–mediated decrease of H3K36me3 may be an independent and distinct epigenetic mechanism to potentiate leukemic transformation and progression in cooperation with another genetic or epigenetic abnormality,” wrote the researchers.
Chromosomal translocations occur in more than 50% of leukemias and lymphomas and are increasingly being observed in solid tumors. The existence of SETD2 mutations in a range of both blood and solid tumor cancers suggests that the SETD2-H3K36me3 pathway may be a common tumor-suppressive mechanism for cancer, offering a new opportunity for the development of cancer diagnostics and therapeutics, concluded the researchers.
Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center, Tao Cheng, MD, of Chinese Academy of Medical Sciences and Peking Union Medical College, and Qian-fei Wang, PhD, of Beijing Institute of Genomics, Chinese Academy of Sciences, are the corresponding authors of the Nature Genetics article.
Funding for the study was supported by the China Ministry of Science and Technology, the Chinese Academy of Sciences, the National Natural Science Foundation of China, and the Tianjin Municipal Science and Technology Commission. The study authors reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
