Date of Award
Doctor of Philosophy (PhD)
Molecular and Cellular Biochemistry Program
The goal of this study is to determine the role of Toll-like receptor (TLR) signaling in acute myeloid leukemia (AML). AML is a hematopoietic malignancy that predominately affects the elderly. The median age of AML diagnosis is 67 years old. The standard of care of AML is treatment with cytotoxic chemotherapy, which elderly patients are often unable to tolerate. To identify novel pathways as potential targets for treatment, a microarray on AML primary patient samples was performed to determine the expression of key inflammatory genes. This microarray, and other published datasets, showed that TLR are overexpressed in myelomonocytic (M4) and monocytic (M5) AML subtypes. TLRs are components of the innate immune system that sense and respond to inflammatory stimuli from infections or tissue injury. TLR signaling is mediated by one of two adaptor proteins, myeloid differentiation factor 88 (MYD88) or Toll/IL1 receptor (TIR) containing adaptor molecule 1 (TICAM-1). Inhibition of kinases downstream from these receptors inhibits MLL-AF9 leukemia cell growth. To investigate TLR signaling in the setting of AML, two models were employed. First, inducible genetic deletion of the Myd88 gene in MLL-AF9 leukemia cells was applied. Myd88 was determined to be required for leukemia cell stemness, colony forming potential, proliferation, resistance to chemotherapy, and leukemogenesis in vivo. Next TICAM-1 expression was suppressed by shRNA in human and murine models and found to have similar effects, protecting leukemia cell stemness, proliferation, colony forming potential, and leukemogenesis in vivo. Knockdown of downstream kinases, IL-1 receptor-associated kinase 1 for Myd88, and Tank-binding kinase for Ticam-1, failed to recapitulate these phenotypes. While the exact mechanism of Myd88 pro-leukemic function remains undetermined, TICAM-1 was shown to protect protein levels of receptor-interacting protein kinase 1 (RIPK1) and RIPK3, and TICAM-1 knockdown in human ML-2 or murine MLL-AF9 cells resulted in corresponding loss of RIPK1 and RIPK3. Together, these data indicate that TLR-associated adaptor proteins participate in pro-leukemia signaling pathways independently from TLR-associated kinases. These findings have implications for the treatment of AML and suggest that targeted disruption or inhibitions of MYD88 or TICAM-1-dependent signaling pathways might have clinical benefit.
Cannova, Joseph Michael, "Divergent Pro-Leukemic Effects of MYD88 and TICAM-1/TRIF Mediated Toll-Like Receptor Signaling" (2018). Dissertations. 2780.
Copyright © 2018 Joseph Michael Cannova