Abundant expression of zinc finger protein 521 (ZNF521) in AMLs correlates with specific genetic aberrations and contributes to the leukaemic phenotype in AMLs with MLL rearrangements.

ZNF521 is a transcription co-factor highly abundant in haematopoietic stem and early progenitor cells. A wealth of experimental evidence has implicated ZNF521 in the control of the homeostasis of the immature cell compartment in diverse tissues including blood bone and brain. This role is mediated by the inhibition of transcription factors essential for lineage specification like EBF1, GATA1, C/EBP alpha, ZNF423 and Runx2. Inappropriate expression of regulatory proteins, associated to specific genetic aberrations, can be critical for leukaemogenesis. To understand if ZNF521 is relevant in this process we investigated its expression in a variety of gene profiling datasets of acute leukaemias. ZNF521 is expressed in the majority of AMLs and T-ALLs but not B-ALLs. In AMLs, its abundance correlates with specific genetic aberrations: relatively low levels are detected in AMLs with FLT3 aberrations and APLs, whereas high expression is associated to MLL rearrangements. ZNF521 appears to be a direct target of MLL oncoproteins, since its expression is enhanced in CD34+ cells transduced with MLL-AF9 or MLL-ENL. Finally, significantly higher amounts of ZNF521 mRNA are present in AML stem cells compared to stem cells-depleted populations. To establish if ZNF521 has a role in the MLL phenotype we modulated its expression in AML cells with MLL rearrangements. Silencing of ZNF521 in THP-1 cells, and in CD34+ cells transformed by MLL-AF9, inhibited their growth or clonogenicity in semisolid media, whereas enforced expression of the protein in ZNF521-negative MV4;11 cells strongly enhanced their clonogenicity. These data suggest that ZNF521 contributes to the homeostasis of the immature compartment in AMLs, and its expression may be particularly critical in the AMLs bearing MLL aberrations.