Role of reciprocal fusions in MLL-r acute leukemia: studying t(4;11) fusion proteins

Two fusion genes, MLL-AF4 and AF4-MLL, have been cloned, stably transfected and tested by induced expression for their molecular functions (48h). DGE results were obtained by the massive amplification of cDNA ends (MACE) technology. The results of this study allow to draw quite important conclusions. Reciprocal fusion proteins deriving from the t(4;11) translocation allow to (1) ubiquitously activate chromatin which results in an increased expression of distinct sets of pseudogenes and lncRNAs, and (2) allow a functional synergism with MLL-AF4. We could also demonstrate that AF4-MLL works in a transient fashion as activated chromatin is maintained also after elimination the AF4-MLL fusion gene (hit & run mechanism). Thus, we have to conclude that an early presence of AF4-MLL is presumably sufficient to allow the development of a pre-leukemia state, while later the AF4-MLL fusion protein might be dispensable. This reflects the diagnostic situation in t(4;11) patients where about 50 % of patients express both fusion genes, while the other 50 % express only the MLL-AF4 allele, a situation associated with an even poorer outcome.

Publication History

Article published online:
13 May 2020