Exploring microRNA degradation in T-cell acute lymphoblastic leukemia

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PROJECT SUMMARY Gene expression, the flow of genetic information from DNA to messenger RNA (mRNA) to protein, involves delicate regulation by a group of small RNAs named microRNAs. MicroRNAs can inhibit gene expression by binding to mRNAs and prevent them from being translated into proteins. MicroRNA levels in cancer cells are usually different from the microRNA levels in healthy cells, leading to differential expression of certain cancer-related genes. Controlling microRNA levels therefore offers a promising target for cancer treatment. Recently, we found that when T-cell acute lymphoblastic leukemia (T-ALL) cells are treated with dexamethasone, a glucocorticoid steroid commonly used in leukemia chemotherapy, two highly related and pro-cancer microRNAs (miR-221/222) are degraded by their target mRNA (BIM). This is surprising because microRNAs usually control the levels of their targets, but not the other way around. This is also exciting because it represents an emerging gene regulation mode carried out by the mRNAs and opens up strategies for cancer intervention. In this proposal, we first aim to understand how BIM mRNA triggers miR-221/222 degradation. Our second aim is to explore how miR-221/222 degradation enhances killing of T-ALL cells during chemotherapy. In the final aim, we will develop an innovative biochemical and computational protocol to globally identify sequences in different target mRNAs that can induce miRNA degradation in T-ALL patient samples. Collectively, our efforts will examine a new mechanism of gene regulation in T-ALL, in which mRNAs counteract microRNAs. Because resistance to glucocorticoid is a serious limitation for T-ALL chemotherapy, elucidating the underlying mechanism of resistance may provide the basis for improving current therapeutic interventions. Given that we have discovered a potentially widespread occurrence of the mRNA-induced microRNA degradation pathway in cancer, identifying the mRNAs that can degrade miRNAs and the proteins involved in this process would help develop new therapies to combat T-ALL.