GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia.

ABSTRACT

Imatinib is the first molecularly targeted compound for chronic myeloid leukemia (CML) capable to inhibit BCR-ABL kinase activity. However, recent clinical evidence indicates that a substantial proportion of CML patients exhibit BCR-ABL-dependent or independent resistance to imatinib. Despite the importance of imatinib resistance in CML, the underlying molecular mechanisms of this resistance are largely unknown. Here, we identified GCA (grancalcin) as a critical regulator of imatinib resistance in chronic phase CML via activation of autophagy. Mechanistically, we demonstrated that GCA activates TRAF6 ubiquitin ligase activity to induce Lys63 ubiquitination of ULK1, a crucial regulator of autophagy, resulting in its stabilization and activation. We also highlighted the role of GCA-TRAF6-ULK1 autophagy regulatory axis in imatinib resistance. Our findings represent the basis for novel therapeutic strategies against CML.Abbreviation ACTB/ß-actin actin beta; ADM adrenomedullin; AMBRA1 autophagy and beclin 1 regulator 1; AMPK AMP-activated protein kinase; ANXA5 annexin A5; CP cytogenetic response; CML chronic myeloid leukemia; CUL3 cullin 3; GAPDH glyceraldehyde-3-phosphate dehydrogenase; GCA grancalcin; Dx at diagnosis; E-64-d (2S,3S)-trans-Epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester; IMres Imatinib resistance; KLHL20 Kelch-like protein 20; LRMP lymphoid-restricted membrane protein; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MMR major molecular response; NH4Cl ammonium chloride; PBMCs peripheral blood mononuclear cells; PTPRC protein tyrosine phosphatase, receptor type, C; SQSTM1/p62 sequestosome 1; SYK spleen associated tyrosine kinase; TAP1 transporter 1, ATP binding cassette subfamily B member; TKIs ABL-specific tyrosine kinase inhibitors; TLR9 toll- like receptor 9; TRAF6 TNF receptor associated factor 6; ULK1 unc-51 like autophagy activating kinase 1.