TY  - JOUR
A1  - Siemund, Anna Lena
A1  - Hanewald, Thomas
A1  - Kowarz, Eric
A1  - Marschalek, Rolf
T1  - MLL-AF4 and a murinized pSer-variant thereof are turning on the nucleolar stress pathway
T2  - Cell & bioscience
N2  - 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: 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: 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.
KW  - MLL-r acute leukemia
KW  - MLL
KW  - AF4
KW  - Fusion proteins
KW  - pSer domain
KW  - SL1
KW  - Ribosome biogenesis
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/69500
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-695002
SN  - 2045-3701
N1  - Open Access funding enabled and organized by Projekt DEAL.
N1  - This work has been conducted and performed within the framework of the DFG grants MA 1876/12-1 and MA 1876/13-1.
N1  - The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
VL  - 12
IS  - art. 47
SP  - 1
EP  - 15
PB  - BioMed Central
CY  - London
ER  -