Autocrine secretion of soluble factors drives growth and survival via b-RAF kinase signaling in acute myeloid leukemia
Marszal, Lindsay Nicole
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One third of all childhood cancer diagnoses are leukemias, making it is the most common cancer found in children. While overall survival for acute lymphoid leukemia (ALL) has improved greatly over the past 20 years, the survival rate for acute myeloid leukemia (AML) is still lagging behind. There are many biological classes of AML, several of which are largely resistant to intensive chemotherapy, necessitating the investigation of alternative treatment approaches. In particular, aberrant activation of the ERK signaling pathway has been associated with resistance to chemotherapy and decreased survival. The RAF kinases are central components of the ERK signaling pathway that are rarely mutated but often activated in AML. To understand the therapeutic potential of RAF kinase inhibition in AML, we investigated the susceptibility of AML cell lines to the novel pan-RAF kinase inhibitor AZ628. This work identified classes of RAF kinase inhibition sensitive and resistant cell lines, with the resistance associated with secretion of soluble factors that enhance AML cell growth and survival. This therapeutically relevant finding led to the development of a new approach for the analysis of secreted proteomes elaborated by AML cells, with the identification of candidate autocrine survival factors. This knowledge promises to lead to the identification of improved targets of therapy in order to improve the treatment of patients with AML.
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