A somatic mutation in moesin drives progression into acute myeloid leukemia
(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.
(Less)
- author
- organization
-
- Division of Molecular Hematology (DMH)
- Developmental Hematopoiesis (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Breast cancer Proteogenomics (research group)
- Biomarkers and epidemiology
- Proteomic Hematology (research group)
- Division of Molecular Medicine and Gene Therapy
- publishing date
- 2022
- 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
- 2024-09-18 04:40:05
@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}}, }