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A somatic mutation in moesin drives progression into acute myeloid leukemia

Yuan, Ouyang LU ; Ugale, Amol LU ; de Marchi, Tommaso LU ; Anthonydhason, Vimala ; Konturek-Ciesla, Anna LU ; Wan, Haixia LU ; Eldeeb, Mohamed LU ; Drabe, Caroline LU ; Jassinskaja, Maria LU and Hansson, Jenny LU orcid , et al. (2022) In Science Advances 8(16).
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 (Arg295Cys) in the ERM protein moesin that markedly... (More)

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 (Arg295Cys) 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
8
issue
16
article number
eabm9987
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85128682695
  • pmid:35442741
ISSN
2375-2548
DOI
10.1126/sciadv.abm9987
language
English
LU publication?
yes
id
a2b5eee1-314a-4f67-9cd8-d3bdfea55262
date added to LUP
2022-07-05 13:14:42
date last changed
2024-04-16 13:56:25
@article{a2b5eee1-314a-4f67-9cd8-d3bdfea55262,
  abstract     = {{<p>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<sup>295</sup>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.</p>}},
  author       = {{Yuan, Ouyang and Ugale, Amol and de Marchi, Tommaso and Anthonydhason, Vimala and Konturek-Ciesla, Anna and Wan, Haixia and Eldeeb, Mohamed and Drabe, Caroline and Jassinskaja, Maria and Hansson, Jenny and Hidalgo, Isabel and Velasco-Hernandez, Talia and Cammenga, Jörg and Magee, Jeffrey A. and Niméus, Emma and Bryder, David}},
  issn         = {{2375-2548}},
  language     = {{eng}},
  number       = {{16}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{A somatic mutation in moesin drives progression into acute myeloid leukemia}},
  url          = {{http://dx.doi.org/10.1126/sciadv.abm9987}},
  doi          = {{10.1126/sciadv.abm9987}},
  volume       = {{8}},
  year         = {{2022}},
}