of General Medical Sciences
By analyzing the whole genomes of 3-year-old twin sisters—one healthy and one with multi-lineage leukemia (MLL)—researchers have identified a possible therapeutic target for leukemias.
Their research pointed to a molecular pathway involving the gene SETD2, which can mutate in blood cells as DNA is being transcribed and replicated.
The team confirmed the importance of this pathway via follow-up experiments using samples from leukemia patients and mouse models of the disease.
“We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events,” said Gang Huang, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“This provided a strong basis for comparison and analysis. 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.”
Dr Huang and his colleagues recounted this discovery in Nature Genetics.
The team showed that the onset of aggressive and acute leukemia is fueled by a spiraling cascade of multiple genetic mutations and chromosomal translocations.
In comparing data from the twins, the researchers identified a chromosomal translocation in the MLL-NRIP3 fusion gene.
When they activated MLL-NRIP3 in mouse models, the animals developed MLL, but it took a long period of time. This suggests that additional epigenetic and molecular events must be involved to induce full-blown leukemia.
The researchers went on to show that activation of MLL-NRIP3 cooperated with the molecular cascade (including mutations in SETD2) to cause leukemia.
The initial clue came when the team was looking for additional genomic alterations in the leukemic cells of the sick twin. They discovered that activation of MLL-NRIP3 started the molecular cascade that led to bi-allelic mutations in SETD2, a tumor suppressor that regulates the histone modification protein H3K36me3.
During transcriptional elongation, SETD2 and H3K36me3 normally mark the zone for accurate gene transcription along the DNA. In the case of the sick twin, the mutations and molecular cascade disrupted the H3K36me3 mark, leading to abnormal transcription and MLL.
To confirm the importance of these findings, the researchers analyzed blood samples from 241 patients—134 with acute myeloid leukemia and 107 with acute lymphoblastic leukemia. This revealed 19 somatic SETD2 mutations in 15 patients (6.2%).
SETD2 mutations were more common in patients with MLL rearrangements than those without—22.6% (6/27) and 4.6% (8/173), respectively. And patients with SETD2 mutations had decreased levels of global H3K36me3.
In follow-up tests on cell cultures of pre-leukemic cells and mouse models, the researchers saw the same progression of genetic mutations and related molecular events fuel the growth of leukemic cells.
The team also noticed that SETD2 mutation activated 2 genes—mTOR and JAK-STAT—that are known to contribute to leukemia and other cancers. So the researchers decided to test 2 mTOR inhibitors—Torin1 and rapamycin—on pre-leukemic cells generated by SETD2 mutations.
That treatment prompted a marked decrease in cell growth, indicating that SETD2 mutations activate numerous molecular pathways to generate leukemia.
Dr Huang said the tests also suggest there are multiple opportunities to find new molecular targets for developing more effective drugs—in particular, those that would target the MLL fusion-SETD2-H3K36me3 pathway to treat acute and aggressive leukemias.
The researchers are following up their current study by identifying additional pathways activated by mutations of SETD2. They also are looking for possible new molecular targets and therapeutic strategies to block disruptions in the SETD2-H3K36me3 pathway.
