Identification of miRNAs Involved in Leukemic Transformation and/or B cell Development

miRNAs regulate numerous physiologic processes and also contribute to diseases such as cancer. Our goal is to identify miRNAs involved in the regulation of B cell development or that contribute to the oncogenic transformation of B cells by the Abelson Murine Leukemia Virus (AMuLV) and to identify the targets and processes they regulate. The chemotherapeutic agent STI-571 (Gleevec) specifically inhibits the oncogenic tyrosine kinase expressed by AMuLV. We observed previously that STI-571 treatment of Abelson pro-B leukemia cells results in their exit from the cell cycle and differentiation to a pre-B cell-like state. We used this system to conduct a microarray-based screen for miRNAs regulated by v-Abl activity.

We observed the upregulation of a group of miRNAs once v-Abl was inactivated and B cell progression was allowed; a smaller subset of miRNAs were downregulated with this treatment.  When individually overexpressed in Abelson pro-B cells, two of these regulated miRNAs result in the induction of germline kappa transcription, a critical aspect of the normal pro-to-pre-B cell transition. We have elucidated pathways through which these miRNAs regulate germline kappa transcription by performing EMSA analysis on known kappa locus transcriptional activators.  We are in the process of examining potential miRNA targets that may result in the observed regulation of germline kappa transcription. Our goal is test whether these pathways are similarly regulated during primary B cell development.