Asian Scientist (Feb. 20, 2014) – Researchers who analyzed the genomes of a pair of 3-year-old twins, one healthy and one with aggressive leukemia, have identified a novel drug target for treating recurring and deadly malignancies.
In their study, published in Nature Genetics, the researchers took advantage of the unique opportunity to compare the whole genomes of the monozygotic twin sisters (which means they came from a single egg). The sick sister had a particularly acute and aggressive form of the acute myeloid leukemia (AML) known as MLL, or multi-lineage leukemia.
In comparing the blood cells of both twin sisters, these researchers identified a chromosomal translocation that generated what is known as the MLL-NRIP3 fusion leukemia gene.
When they activated the MLL-NRIP3 gene in laboratory mouse models, the animals developed the same type of leukemia, but it took a long period of time for them to do so. This suggested that there had to be additional cooperative events that induce full-blown leukemia.
By looking for additional genomic alterations in the leukemic blood cells of the sick twin sister, they went on to demonstrate that two mutations in the gene SETD2 cooperated with the activation of the MLL-NRIP leukemia gene to cause MLL.
The researchers then analyzed blood samples from 241 people who had different forms acute leukemia and found SETD2 mutations in samples from 6.2 percent of those patients. Patients with SETD2 mutations also had a leukemia associated with major chromosomal translocations.
In follow up tests on cell cultures of pre-leukemic cells and mouse models, researchers saw the same progression of gene mutations and related molecular events fuel the growth of leukemic cells.
Researchers also noticed that mutation of SETD2 activated two genes (MTOR and JAK-STAT) that are known to contribute to cancer and leukemia. The scientists then showed that two existing targeted molecular inhibitors of MTOR markedly decreased the growth of pre-leukemic cells generated by SETD2 gene mutations.
Researchers are following up their current study by looking for additional pathways activated by mutations of SETD2. They also are looking possible new molecular targets and therapeutic strategies that can target this pathway.
The article can be found at: Zhu X et al. (2014) Identification Of Functional Cooperative Mutations Of SETD2 In Human Acute Leukemia.
——
Source: Cincinnati Children’s Hospital Medical Center; Photo: Josh Hawley/Flickr/CC.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.
