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Preclinical research suggests a pair of histone-modifying proteins may be promising therapeutic targets for NPM1-mutated acute myeloid leukemia (AML).
Investigators found that these proteins—MLL and DOT1L—play key roles in NPM1-mutated AML.
Pharmacologic inhibition of either protein alone produced anti-leukemic activity in vitro and in vivo, but inhibiting both proteins together had a more profound effect.
Michael Kühn, MD, of the Mainz University Medical Center in Mainz, Germany, and his colleagues reported these findings in Cancer Discovery.
The investigators noted that nearly all NPM1-mutated AMLs are characterized by aberrant HOX expression, and FLT3 is concomitantly mutated in roughly 60% of these cases. However, it hasn’t been clear how mutant NPM1 cells maintain aberrant gene expression.
With this study, Dr Kühn and his colleagues showed that MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1-mutated AML.
The investigators were able to demonstrate that survival of NPM1-mutated AML cells depends on these 2 proteins. And NPM1-mutated AML is “exceptionally dependent” on the menin binding site in MLL1.
The team tested MI-503, a menin–MLL1 inhibitor, and the DOT1L inhibitor EPZ4777 in human and murine models of NPM1-mutated AML.
Each of the drugs reduced the activity of HOX genes in NPM1-mutated AML cells, but combining the drugs resulted in near-complete inactivation of HOX genes.
When given alone, EPZ4777 and MI-503 each reduced the proliferation and colony-forming potential of NPM1-mutated AML cells in vitro. And each of the drugs prolonged survival in mouse models of NPM1-mutated AML.
However, EPZ4777 and MI-503 given in combination significantly delayed the onset of leukemia and significantly prolonged survival when compared to either drug given alone.
The investigators said this suggests that inhibiting both DOT1L and menin–MLL1 affects leukemia-initiating cells, and this approach represents the first molecularly targeted treatment of NPM1-mutated AML that works by reversing a key mechanism of leukemogenesis.
They added that this research paves the way for trials assessing EPZ4777 and MI-503 in patients with NPM1-mutated AML.
