Oncogenic All1 fusion proteins target Drosha-mediated microRNA processing

Abstract

MicroRNAs (miRNAs) are noncoding small RNA of approximately 22 bases, which suppress expression of target genes through translational block or degradation of a target's transcript. Recent studies uncovered specific miRNA expression profiles in human malignancies. Nevertheless, the mechanisms underlying cancer-specific miRNA expression are largely unknown. miRNA biogenesis consists of a series of steps beginning with generation of a primary transcript, termed pri-miRNA, and continuing into excision of a stem-loop hairpin structure within pri-miRNA by the nuclear RNaseIII enzyme Drosha, transportation to the cytoplasm, and further processing by a second RNaseIII enzyme Dicer, into a 22-base mature duplex RNA. In principle, alteration in any step during this maturation process could affect miRNA production. The ALL-1 (also termed MLL) gene was originally isolated by virtue of its involvement in recurrent chromosome translocations associated with acute leukemias, particularly in infant and therapy-related leukemias. These translocations result in the fusion of ALL-1 with partner genes and the consequent production of chimeric leukemogenic proteins. Here, we identify specific miRNAs up-regulated in leukemias triggered by All1 fusions. Further, we demonstrate coimmunoprecipitation of the All1/Af4 and All1/Af9 fusions with Drosha, disrupted by treatment with DNase I. Finally, we present evidence from ChIP experiments for All1 fusion protein-mediated recruitment of Drosha to target genes encoding miRNAs. Such recruitment may underlie the enhanced expression of the relevant miRNAs.