A rare opportunity to study the whole genomes of identical twin sisters has revealed a promising new target for developing better treatments against a deadly malignancy.
The study involved twin 3-year-old girls, one of whom was healthy while the other developed mixed-lineage leukemia (MLL), a particularly aggressive form of acute myeloid leukemia (AML). By comparing the girls’ blood cells, scientists in China and the United States identified a cascade of cancer-fueling gene mutations and DNA misalignments that traced back to mutations in the gene SETD2 from both parents.
The research team reported their findings online Feb. 9 in Nature Genetics.
“These mutations contribute to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells,” says Gang Huang, PhD, a cancer researcher at Cincinnati Children’s and a co-corresponding author of the study.
In the sick twin sister, the disease process began with activation of the MLL-NRIP3 fusion leukemia gene. This, in turn, started a molecular cascade leading to mutations in the gene SETD2 from both parents. This gene normally suppresses tumor growth by regulating a protein called H3K36me3. During normal cell replication, the protein helps guide accurate gene transcription along the DNA. But the SETD2 mutations disrupt this process and fuel the development of MLL.
The SETD2 mutations also activated two other signaling pathways (mTOR and JAK-STAT) that are known to contribute to cancer and leukemia.
After confirming this progression of events in tests using cell cultures of pre-leukemic cells and mouse models, researchers analyzed blood samples from 241 people with various forms of leukemia. SETD2 mutations were found in 6.2 percent of the samples, and patients with SETD2 mutations had leukemia associated with major chromosomal translocations and disruption of the H3K36me3 mark.
The scientists went on to test two mTOR-inhibiting medications on the pre-leukemic cells generated by the SETD2 gene mutations. The treatments resulted in a marked decrease in cell growth.
Huang says these tests demonstrate that there are multiple opportunities to improve MLL treatment. The researchers plan to continue their work by looking for drugs that can target the MLL fusion-SETD2-H3K36me3 pathway. They also continue to look for additional pathways activated by SETD2 mutations.
The twin sisters’ genomes were compared at the laboratory of co-corresponding author Qian-fei Wang, PhD, Beijing Institute of Genomics. Several other institutions in China and a research center in Chicago also collaborated on the study.