One of the common genetic abnormalities in acute myeloid leukemia (AML) is the translocation between chromosome 8q22 and chromosome 21q22 [t(8;21)(q22;q22)], which gives rise to the AML1-ETO (AE) fusion gene. AE is a transcription factor that, when expressed, blocks normal myeloid differentiation and is critical to t(8;21) leukemogenesis, leading to the proliferation of immature leukemic blast cells. However, t(8;21) alone is insufficient for leukemia development, which requires additional ?hits.? Interestingly, t(8;21) patient single-cell qPCR data from ourselves and others shows that the AE transcript level is much greater in both t(8;21)+ leukemic/hematopoietic stem cells at diagnosis vs remission, and in t(8;21)+ leukemic blasts vs t(8;21)+ differentiated monocytes/granulocytes. These data suggest that increasing AE transcript levels is important to both blocking differentiation and maintaining t(8;21) leukemia. Additional preliminary data implicates that post-transcriptional stability, associated with specific cis-elements within the AE 3? untranslated region (UTR), is a major contributor to increased AE expression. However, it is unknown which additional trans-factors interact with the AE 3?UTR cis-elements and enhance AE expression in leukemic cells. Identifying the molecular mechanisms of post-transcriptional regulation during leukemogenesis may provide valuable insights into the rational therapeutic drug design for treating related malignancies. This proposal seeks to determine the post-transcriptional mechanisms controlling the enhanced expression of AE and their contribution to the initiation and maintenance of t(8;21) leukemia. The stability of mRNA transcripts is primarily regulated through sequence specific interactions of the 3?UTR with microRNAs (miRNAs) and RNA binding proteins (RBPs), which are both often dysregulated in cancer. Therefore, the proposed studies aim to test the hypothesis that dysfunction of certain AE 3?UTR-interacting miRNAs and RBPs contributes to the enhanced AE expression in t(8;21) leukemic cells.
The specific aims are to identify miRNAs and RBPs that target the AE 3?UTR and determine their contribution to AE expression and t(8;21) leukemia.
The t(8;21) translocation is common, occurring in approximately 10 percent of acute myeloid leukemia patients, and carries a relapse rate of over 50 percent with median survival of five years. This fellowship seeks to determine the factors which regulate the AML1-ETO fusion transcript, a key factor in t(8;21) leukemia. The knowledge gained from this work can be used to better develop novel and effective treatments.
