A somatic mutation in moesin drives progression into acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg 295 Cys) in the ERM protein moesin that markedly accelerated leukemogenesis. Human cancer-associated moesin mutations at the conserved arginine-295 residue similarly enhanced MLL-ENL–driven leukemogenesis. Mechanistically, the mutation interrupted the stability of moesin and conferred a neomorphic activity to the protein, which converged on enhanced extracellular signal–regulated kinase activity. Thereby, our studies demonstrate a critical role of ERM proteins in AML, with implications also for human cancer.

DNMT3A mutation promotes leukemia development through NAM-NAD metabolic reprogramming

“…The occurrence and development of AML is a complex and multi-step process involving a series of genetic abnormalities [ 31 – 34 ]. One of the main categories is gene mutations related to epigenetic regulation, including DNMT3A, IDH1, IDH2, TET2, MLL, ASXL1, EZH2, UTX and others.…”