AMP-activated protein kinase activation primes cytoplasmic translocation and autophagic degradation of the BCR-ABL protein in CML cells

Chronic myeloid leukemia is driven by the BCR‐ABL oncoprotein, a constitutively active protein tyrosine kinase. Although tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of CML patients, the emergence of TKI resistance is an important clinical problem, which deserves additional treatment options based on unique biological properties to CML cells. In this study, we show that metabolic homeostasis is critical for survival of CML cells, especially when the disease is in advanced stages. The BCR‐ABL protein activates AMP‐activated protein kinase (AMPK) for ATP production and the mTOR pathway to suppress autophagy. BCR‐ABL is detected in the nuclei of advanced‐stage CML cells, in which ATP is sufficiently supplied by enhanced glucose metabolism. AMP‐activated protein kinase is further activated under energy‐deprived conditions and triggers autophagy through ULK1 phosphorylation and mTOR inhibition. In addition, AMPK phosphorylates 14‐3‐3 and Beclin 1 to facilitate cytoplasmic translocation of nuclear BCR‐ABL in a BCR‐ABL/14‐3‐3τ/Beclin1/XPO1 complex. Cytoplasmic BCR‐ABL protein undergoes autophagic degradation when intracellular ATP is exhausted by disruption of the energy balance or forced autophagy flux with AMP mimetics, mTOR inhibitors, or arsenic trioxide, leading to apoptotic cell death. This pathway represents a novel therapeutic vulnerability that could be useful for treating TKI‐resistant CML.
BCR‐ABL is translocated to the nucleus under energy‐inflated conditions and returns to the cytoplasm, coinciding with priming of autophagy. Cytoplasmic BCR‐ABL succumbs to autophagic degradation when intracellular ATP is exhausted, providing a novel therapeutic vulnerability.