The National Cancer Center and Kyoto University have elucidated the mechanism that causes canceration of acute leukemia with MLL gene mutation, which is highly malignant and common in infants, at the molecular level, and high anti-antibiotic therapy with two molecular-targeted drugs. It was experimentally proved that a tumor effect can be expected.The results will be published in the American scientific journal "The Journal of Clinical Investigation".
Acute leukemia develops when a genetic abnormality occurs at an early stage during leukocyte growth, and cancerous cells proliferate indefinitely. Mutations in the MLL gene are found in 5-10% of all acute leukemia cases, especially in infants with acute lymphocytic leukemia.The survival rate is extremely low at about 40%.There was no effective treatment because the mechanism at the molecular level has not been elucidated.
This time, the research team used chromatin immunoprecipitation to identify the genomic region in which the MLL mutant protein and its binding proteins (AF4, DOT1L) are localized.Furthermore, using mice, it was found that the MLL mutant protein causes abnormal gene activation via the binding protein.It was found that AF4 and DOT1L, which have different functions, work complementarily to strongly activate gene expression and cause canceration.
Based on this result, we investigated the combined use of MLL complex formation inhibitor and DOT4L enzyme activity inhibitor, which inhibit the activities of AF1 and DOT1L, respectively.The combination of the two agents, even at low concentrations, which is not very effective as a single agent, efficiently inhibited the growth of MLL leukemia cells and induced differentiation.In addition, transplantation of leukemia cells exposed to the two drugs for 2 days into the body of mice caused almost no leukemia.From this, it was confirmed that inhibition of AF3 and DOT2L activities at the same time has a high antitumor effect.
In the future, combination therapy of these two molecular-targeted drugs will be established as an effective treatment method, and it is expected that it will be useful for treatment.
Paper information: [The Journal of Clinical Investigation] Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia
