BCR-ABL enhances the prolyl isomerase activity of Pin 1 by interacting with DAPK1 in ph+ ALL

Abstract

Philadelphia chromosome (Ph)/BCR-ABL-positive (ph⁺ ) ALL is the most common genetic abnormality associated with ALL and has been shown to confer the worst prognosis to both children and adults. Increasing evidence has revealed that the dysregulation of prolyl isomerase Pin 1 contributes to multicancer development and progression, including ALL, although the underlying molecular mechanisms remain unclear. Here, we report that the expression of Pin 1 was enhanced in ph⁺ ALL patient samples and was associated positively with the expression of BCR-ABL. Genetically or pharmacologically inhibiting Pin 1 expression or activity produces potent therapeutic efficacy against ph⁺ ALL. We further demonstrated that BCR-ABL enhances the prolyl isomerase activity of Pin 1 by decreasing the phosphorylated level of Pin 1 at Ser 71 and interacting with DAPK1. The inhibition of BCR-ABL activity by imatinib in human ph⁺ ALL cells reduces the prolyl isomerase activity of Pin 1, further suggesting a key role of the newly identified BCR-ABL-Pin 1 axis in ph⁺ ALL progression. Thus, the combined suppression of Pin 1 and BCR-ABL proteins may be exploited as an additional target therapy for ph⁺ ALL.

Keywords: ALL; BCR-ABL; DAPK1; Pin 1; protein-protein interaction.