Potential New Treatment Targets in Acute Myeloid Leukemia
Gene overexpressed in AML may offer new target for halting the spread of cancer.
Researchers recently gained a better understanding of gene MN1’s role in the cause of aggressive acute myeloid leukemia (AML).
"There's a gene called meningioma-1 or MN1,” said investigator Kathrin Bernt, MD. “When it's overexpressed in AML, the prognosis is poor. And when you take this gene and put it in mouse bone marrow, it causes aggressive leukemia. However, it hasn't been clear quite what this gene does."
In order to find a target that can kill cancer, researchers examined cancer development between MN1 alteration and aggressive AML.
"Unfortunately, it is currently impossible to use a medicine to directly target a gene,” Bernt said. “We can't simply switch off MN1. Instead, we must look for essential steps between the existence of gene alteration and the advent of cancer in which to intervene. We can't target MN1, but we can target the program that has to be there for MN1 to do its job."
Researchers induced the overexpression of MN1 in mouse models to study which genes changed in response. The results of the MN1 overexpression was the activation of HoxA9 and Meis1 genes that were previously known to predispose cells to develop AML.
These genes are dependent on chromatin regulators, which help control the DNA structure as it is packed or unpacked with storage to be “read.”
Two chromatin regulators were found, Mll1 and Dot1l, which are necessary to form the environment MN1 needs to develop leukemia. Although MN1 cannot be targeted, Mll1 and Dot1l can.
"In mice, we put MN1 in first, leading to AML,” Bernt said. “Then we knocked out these chromatic regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed."
Since the results in mouse models were promising, researchers decided to test this approach on samples of human AML with MN1 overexpression and HoxA9 and Meis1 — key targets of Mll1 and Dot1l. The results of a study published in the Journal of Clinical Investigation showed that human AML samples were killed.
Currently, an existing phase 1 clinical trial is testing an anti-cancer agent called EPZ-5676, which inhibits Dot1l. The study includes pediatric patients suffering from aggressive forms of leukemia (NCT02141828) marked by a different gene rearrangements, especially deviations in the MLL1 gene.
"The existing trial targets patients with rearrangements in the gene MLL1,” Bernt said. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition, namely patients with MN1 overexpression."
Before researchers can collaborate in the clinical trial using EPZ-5676 against AML marked by MN1 overexpression, they have to overcome several challenges.
"Overexpression exists along a spectrum,” Bernt said. “At what degree of MN1 overexpression does it become clinically significant?”
More work will need to be conducted on AML samples in order to determine when the cutoff of MN1 overexpression is so that the disease is susceptible to the Dot1l inhibition. With further studies, researchers believe it could lead to the development of a targeted treatment for AML patients.