The gene NM23-M2 Is frequently mutated in leukemia

In more than 15 retrovirally induced primary mouse leukemias, we identified proviral integrations in or near the promoter region of the nm23-M2 gene. Nm23-M2 belongs to a family of highly conserved genes, encoding nucleoside diphosphate kinases. Furthermore, nm23-M2 is a transcription factor for the c-Myc proto-oncogene. Nm23-H2, the human homologue of nm23-M2, as well as the isoform nm23-H1, have been identified as indicators for poor prognosis in human hematopoietic malignancies. Whether this high nm23 expression is the result of mutations has never been documented. Here, we show that nm23-M2 is frequently mutated in mouse leukemias. We also demonstrate that in normal hematopoietic progenitors, expression of nm23-M2 is tightly controlled by hematopoietic growth factors (HGFs) at a post-transcriptional level. Association of nm23-M2 mRNA with polysomes, required for translation, was strictly dependent on HGFs. Preliminary studies suggest that nm23-M2 mutations in leukemias result in HGF-independent association of the mRNA with polysomes. Nucleotide sequencing demonstrated the presence of fusion transcripts of the retroviral long terminal repeat (LTR) and nm23-M2. Thus, the virus integration causes alterations 5ʹ of the nm23-M2 mRNA, highly suggesting that the post-transcriptional regulation of the gene is affected. Our studies domonstrate a novel mechanism of aberrant proto-oncogene expression, i.e. altered translational regulation, instead of up regulation of proto-oncogene mRNA levels.