Date of Award
Bachelor of Science (B.S.) in Biology and University Honors
Acute myeloid leukemia -- Treatment, interleukin-1 -- Agonists, Protein kinases -- Inhibitors, Phosphorylation
A major challenge in treating acute myeloid leukemia (AML) is the molecular heterogeneity of the disease. Previously we showed that interleukin-1 (IL-1), promotes the growth of AML cells in ~ 70% of tested primary AML samples. Increased secretion of IL-1 results in increased levels of IL-1 receptor-associated kinase (IRAK1), an essential mediator of innate immunity and inflammatory responses. In this study, we showed overexpression of IRAK1 and its activity in AML across various genetic subtypes, and showed that genetic knockdown of IRAK1 gene by using inducible short hairpin RNA (shRNA) in AML cell lines and primary samples as well as xenograft model showed decrease in viability of leukemic cells. To determine the efficiency of the kinase inhibitor pacritinib, computational modeling along with engineered mutations showed specificity of pacritinib in binding to IRAK1. In compare to quizartinib (a FLT3 inhibitor) and ruxolitinib (a JAK1/2 inhibitor), pacritinib showed a broad sensitivity across AML cell lines as well as primary samples in decreasing the cell viability by reducing IRAK1 phosphorylation. Pacritinib treatment significantly reduced AML progenitors in xenograft model as well. Our data showed important role of IRAK1 in AML survival and how inhibition of its activity might provide beneficial therapeutically outcomes among heterogeneous AML subtypes.
Mohammadhosseini, Mona, "Inhibition of Interleukin-1 Receptor-Associated Kinase-1 is a Therapeutic Strategy for Acute Myeloid Leukemia Subtypes" (2018). University Honors Theses. Paper 561.