Date of Award
Level of Access
Doctor of Philosophy (PhD)
Second Committee Member
Third Committee Member
Calvin P.H. Vary
Acute myeloid leukemia (AML) manifests a marked heterogeneity in both response to therapy and patient survival, observations that likely reflect its varied pathogenesis. Recent discoveries of new molecular lesions with prognostic significance in AML is enhancing our understanding of leukemia biology and our ability to identify new therapeutic targets. Dysregulation of miRNAs that can act as tumor suppressors or oncogenes can result in tumorigenesis. Our investigations analyze the molecular signatures and signaling cascades of two dysregulated miRNAs; miR-590, an oncogenic microRNA and miR-199b, a tumor suppressor microRNA.
We have identified miR-590 as a candidate oncogenic miRNA that is regulated via the STAT5 pathway, targets FasL, and through an unknown mechanism induces BCL2 expression thus promoting cell survival. Our studies implicate a significant intermediary role for miR-590-5p in AML. This study suggests miR-590-5p to be beneficial as a new target in novel treatment and therapeutic strategies aiming to disrupt aberrant FLT3/STAT5/miR-590-5p signaling in AML, and most importantly, improve patient prognosis.
Our studies have demonstrated that miR-199b was significantly downregulated in AML and targets podocalyxin and discoidin domain receptor 1 to regulate migration. In fact, low miR-199b in AML patients leads to worst overall survival and has prognostic significance with M5 subtype. Our results demonstrate that in vitro loss of miR-199b can lead to myeloproliferation and HSC proliferation while in vitro HDAC inhibitors (AR-42 or Panobinostat) can recover miR-199b expression and promote apoptosis in leukemic cells. Interestingly, in vivo miR-199b silencing in HSCs resulted in weight gain, increased abdominal and marrow adiposity, decreased cortical bone thickness, enlarged hearts, increased serum leptin levels and fatty livers compared to the control mice instead of resulting in a striking myeloproliferative phenotype. Though it appears miR-199b does play some sort of role as a tumor suppressor in AML, it also functions as a novel antiobesity gene and also may have a role in cardiovascular disease.
Obtaining a better molecular understanding of this highly heterogeneous disease will provide opportunities to develop more targeted therapies. By having more targeted therapies, we can hopefully raise the overall survival rates of AML patients and also limit the adverse effects of the disease and treatments to improve quality of life.
Favreau, Amanda Jean, "Cytokine and Epigenetic Regulation of MicroRNA in Acute Myeloid Leukemia" (2015). Electronic Theses and Dissertations. 2313.