Leukemia: study of twin sisters leads to novel molecular discovery
According to the National Cancer Institute, 2013 saw approximately 48,610 new cases of leukemia diagnosed in the US. Now, from analyzing the genomes of twin 3-year-old-sisters - one with and one without aggressive leukemia - researchers have discovered a new molecular target that could be used to treat deadly and recurring forms of the disease.
This is according to a study recently published in the journal Nature Genetics.
The international research team, including Gang Huang of the Cincinnati Children's Hospital Medical Center, says they discovered a molecular pathway involving SETD2 - a gene that is able to mutate in blood cells while DNA is deciphered and duplicated.
To reach their discovery, the researchers investigated the genomes of two monozygotic twin sisters, meaning they came from a single egg.
"We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events. This provided a strong basis for comparison and analysis," says Huang.
According to the researchers, aggressive forms of leukemia such as MLL are quick to develop and rapidly progress in patients. This means fast treatment is needed through chemotherapy, radiation or bone marrow transplantation.
Approximately 70% of patients with AML respond to initial chemotherapy, but depending on the subtype of this leukemia, 5-year survival rates can range between 15-70%. These figures prompt the need for better targeted treatment for the disease.
Communication between MLL-NRIP3 and SETD2 caused multi-lineage leukemia
When comparing the blood cells of each twin sister, the researchers discovered that a chromosomal translocation is created in the MLL-NRIP3 fusion leukemia gene.
Chromosomal translocations are a series of multiple gene locations that contribute to the development of aggressive and acute leukemia.
Using laboratory mouse models, the investigators activated the MLL-NRIP3 gene. They found that the mice developed MLL but the onset of the disease was slow, prompting them to believe that other mechanisms played a role in the development of leukemia.
Further investigation that analyzed additional genomic alterations on the blood cells of the twin sister with leukemia led to the discovery that the MLL-NRIP3 gene triggered a "molecular cascade." This caused mutations in the SETD2 gene.
The SETD2 gene is a tumor suppressor and enzyme that regulates H3K36me3 - a modification protein.
The communication between the MLL-NRIP3 gene and the molecular pathway that involved the SETD2 gene was found to cause MLL.
Explaining the discovery, Huang says:
"We identified a gene mutation involving SETD2 that contributes to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells."
The researchers add that SETD2 and H3K36me3 usually flag the area that has accurate gene transcription along the DNA. This is called transcriptional elongation.
The investigators found that in the twin sister who had leukemia, the gene mutations and molecular cascade interfered with the H3K36me3 mark. This caused abnormal transcription and the development of MLL.
Potential for new molecular targets and treatment for leukemia
The researchers then analyzed the blood samples of 241 people who had various forms of acute leukemia. Of these patients, 6.2% had SETD2 mutations. These patients also had a form of leukemia linked to major chromosomal translocations and interference of the H3K36me3 mark.
More tests involving cell cultures of pre-leukemic cells and mouse models revealed the same gene mutations and molecular process that prompt the growth of leukemic cells.
Furthermore, the investigators discovered that the SETD2 mutation triggered two genes - MTOR and JAK-STAT - that are known to play a part in the development of cancer and leukemia.
On testing two targeted molecular inhibitors of MTOR on pre-leukemic cells that are created by mutations in the SETD2 gene, the researchers found there was reduced cell growth. This suggests that SETD2 mutations trigger a variety of pathways in order to cause leukemia.
From this, the investigators note that it is possible to uncover new molecular targets and that this will open the doors for better drugs to treat aggressive forms of leukemia.
Commenting on the findings, the researchers say:
"The existence of SETD2 mutations in a range of hematopoietic malignancies as well as non-hematopoietic malignancies suggests that the SETD2-H3K36me3 pathway may be a common tumor-suppressive mechanism for cancer, thereby offering a new opportunity for the development of cancer diagnostics and therapeutics."
Future studies will involve attempting to identify new molecular targets that are triggered by SETD2 mutations, as well as searching for new molecular targets and treatments that stop interference in the MLL fusion-SETD2-H3K36me3 pathway.
Medical News Today recently reported on a study detailing a leukemia pill that may be able to "melt away" cancer cells.
Written by Honor Whiteman
Copyright: Medical News Today
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