Oncogenic All1 fusion proteins target Drosha-mediated microRNA processing.
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.
Nakamura
Tatsuya
T
*Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210.
Canaani
Eli
E
Croce
Carlo M
CM
D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000209:etiology / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D043244:Ribonuclease III / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
C403194:ALL1-AF4 fusion protein, human; C497422:KMT2A protein, human; C474558:MLL-AF9 fusion protein, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C517918:DROSHA protein, human; D043244:Ribonuclease III