Activation of Myc family oncogenes, either directly via chromosomal translocations or amplification, or indirectly via mutations in tumor suppressors or mitogenic signaling pathways, is a hallmark of rapidly dividing human leukemia and lymphoma, as well as a cast of other malignancies. Our studies and those of others in the Myc field have shown that the pervasive selection for activating Myc in cancer reflects its normal function as a master transcriptional regulator of genes necessary for cell growth, metabolism and division, as well as responses that appear more germane to the supraphysiological levels of Myc found in tumors, specifically apoptosis, metastasis, and tumor angiogenesis. Our Preliminary Studies have now revealed that Myc controls yet another fundamental cellular process - the turnover of unstable mRNAs harboring AU-rich elements (AREs) in their 3'untranslated regions - and, importantly, they have established that this response is rate-limiting for the development of Myc-induced lymphoma and that it is essential for maintenance of the malignant state. Mechanistically, our data establish that mRNA turnover is controlled by Myc's ability to regulate the transcription of a select cast of genes encoding ARE-binding proteins (AUBPs) that bind to and destabilize or stabilize labile mRNAs harboring AREs. Further, our data indicate that the Myc-to-AUBP response is also manifest during B cell development. Finally, our analyses indicate that this Myc-to-AUBP response is a hallmark of human B cell lymphoma with MYC involvement.
In Specific Aim 1 we will test the hypothesis that c-Myc normally controls the transcription of select AUBPs during B cell development and that these AUBPs and their ARE-containing mRNA targets are necessary for B cell development and proliferation.
In Specific Aim 2 we will define the mechanism by which Myc-regulated AUBPs and their mRNA targets control tumor progression and the maintenance of the malignant state. We will also test the intriguing hypothesis that Myc-regulated AUBPs themselves can function as tumor suppressors or as oncogenes. We submit the proposed studies will identify new targets that play key roles in lymphopoiesis and that can be exploited for the development of new anti-lymphoma drugs that are likely to have activity against other human tumors having MYC involvement.
Our new studies have shown that the c-Myc oncoprotein, which is activated by chromosomal translocations in human lymphoma and leukemia and that is also necessary for normal B cell development, regulates the transcription of a select cast of a AU-binding proteins (AUBPs) that control the turnover of unstable mRNAs that harbor AU-rich elements in their 3'untranslated regions. We have shown this regulatory circuit is a hallmark of human lymphoma with MYC oncogene involvement, that it is operational during B lymphocyte development, that it plays important roles in the progression of Myc-driven B lymphoma, and that it is essential for maintenance of the malignant state. Using validated mouse models, we will define the mechanism(s) by which Myc controls these AUBPs, their roles and specific mRNA targets in B lymphopoiesis, and their roles and select mRNA targets in the development and maintenance of Myc-driven lymphoma.