MLL-AF4 and a murinized pSer-variant thereof are turning on the nucleolar stress pathway.
AF4
Fusion proteins
MLL
MLL-r acute leukemia
Ribosome biogenesis
SL1
pSer domain
Journal
Cell & bioscience
ISSN: 2045-3701
Titre abrégé: Cell Biosci
Pays: England
ID NLM: 101561195
Informations de publication
Date de publication:
25 Apr 2022
25 Apr 2022
Historique:
received:
25
07
2021
accepted:
29
03
2022
entrez:
26
4
2022
pubmed:
27
4
2022
medline:
27
4
2022
Statut:
epublish
Résumé
Recent pathomolecular studies on the MLL-AF4 fusion protein revealed that the murinized version of MLL-AF4, the MLL-Af4 fusion protein, was able to induce leukemia when expressed in murine or human hematopoietic stem/progenitor cells (Lin et al. in Cancer Cell 30:737-749, 2016). In parallel, a group from Japan demonstrated that the pSer domain of the AF4 protein, as well as the pSer domain of the MLL-AF4 fusion is able to bind the Pol I transcription factor complex SL1 (Okuda et al. in Nat Commun 6:8869, 2015). Here, we investigated the human MLL-AF4 and a pSer-murinized version thereof for their functional properties in mammalian cells. Gene expression profiling studies were complemented by intracellular localization studies and functional experiments concerning their biological activities in the nucleolus. Based on our results, we have to conclude that MLL-AF4 is predominantly localizing inside the nucleolus, thereby interfering with Pol I transcription and ribosome biogenesis. The murinized pSer-variant is localizing more to the nucleus, which may suggest a different biological behavior. Of note, AF4-MLL seems to cooperate at the molecular level with MLL-AF4 to steer target gene transcription, but not with the pSer-murinized version of it. This study provides new insights and a molecular explanation for the described differences between hMLL-hAF4 (not leukemogenic) and hMLL-mAf4 (leukemogenic). While the human pSer domain is able to efficiently recruit the SL1 transcription factor complex, the murine counterpart seems to be not. This has several consequences for our understanding of t(4;11) leukemia which is the most frequent leukemia in infants, childhood and adults suffering from MLL-r acute leukemia.
Sections du résumé
BACKGROUND
BACKGROUND
Recent pathomolecular studies on the MLL-AF4 fusion protein revealed that the murinized version of MLL-AF4, the MLL-Af4 fusion protein, was able to induce leukemia when expressed in murine or human hematopoietic stem/progenitor cells (Lin et al. in Cancer Cell 30:737-749, 2016). In parallel, a group from Japan demonstrated that the pSer domain of the AF4 protein, as well as the pSer domain of the MLL-AF4 fusion is able to bind the Pol I transcription factor complex SL1 (Okuda et al. in Nat Commun 6:8869, 2015). Here, we investigated the human MLL-AF4 and a pSer-murinized version thereof for their functional properties in mammalian cells. Gene expression profiling studies were complemented by intracellular localization studies and functional experiments concerning their biological activities in the nucleolus.
RESULTS
RESULTS
Based on our results, we have to conclude that MLL-AF4 is predominantly localizing inside the nucleolus, thereby interfering with Pol I transcription and ribosome biogenesis. The murinized pSer-variant is localizing more to the nucleus, which may suggest a different biological behavior. Of note, AF4-MLL seems to cooperate at the molecular level with MLL-AF4 to steer target gene transcription, but not with the pSer-murinized version of it.
CONCLUSION
CONCLUSIONS
This study provides new insights and a molecular explanation for the described differences between hMLL-hAF4 (not leukemogenic) and hMLL-mAf4 (leukemogenic). While the human pSer domain is able to efficiently recruit the SL1 transcription factor complex, the murine counterpart seems to be not. This has several consequences for our understanding of t(4;11) leukemia which is the most frequent leukemia in infants, childhood and adults suffering from MLL-r acute leukemia.
Identifiants
pubmed: 35468859
doi: 10.1186/s13578-022-00781-y
pii: 10.1186/s13578-022-00781-y
pmc: PMC9036721
doi:
Types de publication
Journal Article
Langues
eng
Pagination
47Subventions
Organisme : deutsche forschungsgemeinschaft
ID : MA 1876/12-1
Organisme : deutsche forschungsgemeinschaft
ID : MA 1876/13-1
Informations de copyright
© 2022. The Author(s).
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