Pml and TAp73 Interacting at Nuclear Body and Activated p38MAPK Mediate Imatinib-Induced p53-Independent Apoptosis of Chronic Myeloid Leukemia Cells

Abstract

Imatinib induces apoptosis in chronic myeloid leukemic (CML) cells even with mutant p53. Ras provokes promyelocytic leukemia protein (pml), which promotes apoptosis and senescence in untransformed cells. In CML cells, ras is usually activated; however, the function of pml seems inadequate to induce apoptosis without imatinib. In both BCR-ABL+ p53mutant K562 and Meg-01 CML cells but not in BCR-ABL− HL60 cells, we found imatinib upregulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73, formation of PML-nuclear body (NB), co-localization of TAp73/PML-NB, and expression of bax. Co-immpunoprecipitation of TAp73 and pml was also consistent with the TAp73/PML-NB co-localization. The induced co-localization also occurred to primary CML cells from three out of six patients, including the two with p53mutant. In K562 cells, both inhibiting p38MAPK with SB203580 and silencing pml or TAp73 with short interfering RNAs (siRNAs) abolished the imatinib-induced apoptosis whereas interferon alpha-2a induced additively with imatinib the apoptosis. Notably, interferon alpha-2a increased additively while SB203580 hindered the imatinib-induced phosphorylation of TAp73 and the TAp73/PML-NB co-localization. Together, imatinib induced in some CML cells, especially with mutant p53, a p53-independent proapoptotic mechanism via a p38MAPK/chk2-pml/TAp73 signaling.