Abstract
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 (1). 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 (2).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 the biological activities in the nuecleolus.Results: Based on our results, we have to conclude that MLL-AF4 is predominantly localizing in the nucleolus, thereby interfering withPol I transcription, and subsequently,also ribosomebiogenesis. The murinized pSer-variant is more localizing in the nucleus, which may explain their different biological behavior. Of note, AF4-MLL is cooperating at the molecular level with MLL-AF4, but not with the pSer-murinized version of it.Conclusion: This study provides new insights and a molecular explanation for the known 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 is not. This has several consequences for our understanding of t(4;11) leukemia which is by far the most frequent leukemia in infants, childhood and adults suffering from MLL-r acute leukemia.