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Targeting autophagy in chronic myeloid leukemia through inhibition of the core autophagy protein ATG4B Porter, Vanessa Lynn


Treatment of chronic myeloid leukemia (CML) targets the BCR-ABL1 fusion oncoprotein that characterizes its pathogenesis using tyrosine kinase inhibitors (TKIs); however, drug resistance and relapse can occur when BCR-ABL1-independant survival pathways such as autophagy are activated. Our lab found that the key autophagy enzyme ATG4B is upregulated in CML stem/progenitor cells from patients that clinically do not respond to TKIs vs. patients that do. Knockdown of ATG4B was found to suppress autophagy and sensitize CML cells to TKIs. This study investigates if combined suppression of BCR-ABL1 and ATG4B by novel ABL1 and ATG4B inhibitors in autophagy-inducing conditions may present a novel therapeutic approach to overcome TKI-resistance in CML. I found that inhibition of ATG4B by DB2 significantly inhibits growth and induces apoptosis in CML cell lines alone and in combination with TKIs when autophagy is induced during serum deprivation. There also is a decrease in colony forming cells after DB2+TKI treatment compared to TKIs alone in non-responding CML cells (p<0.05) but is well tolerated in normal bone marrow. Inhibition of ATG4B by DB inhibitors alters autophagy as seen by an accumulation of autophagosomes detected by western blots and florescent tracking. When DB2 is combined with TKI treatment in an aggressive mouse leukemia model, there are no significant differences in the leukemia burden between TKI treatment alone and the combination. However, another model shows that when ATG4B knockdown is combined with 70% caloric restriction, LC3B accumulates in the leukemic cells, and the mice have decreased engraftment and prolonged survival compared to the fed scrambled control mice, suggesting activation of autophagy is important to potentiate loss of ATG4B. This study presents ATG4B inhibition as a specific means to target autophagy and circumvent drug resistance in CML.

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