BCR/ABL Oncogene Controls MICA Translation.

MHC class I chain-related molecules (MIC) participate in immune surveillance of cancer through the engagement of NKG2D, an activating receptor on NK and T-cells. However, the release of soluble forms of MIC (sMIC) by the tumor may impair this response by decreasing NKG2D surface expression. The molecular basis for MIC expression in tumors is poorly understood. In chronic myeloid leukemia (CML), a malignancy caused by the BCR/ABL fusion oncoprotein., leukemic hematopoietic CD34+ cells expressed MICA at the cell surface, whereas hematopoietic CD34+ cells from healthy donors did not. At diagnosis, CML patients showed increased serum levels of sMICA and a decreased NKG2D expression on NK and CD8+ T-cells. Upon imatinib mesylate (IM) therapy, a specific BCR/ABL inhibitor, serum sMICA and NKG2D expression returned to normal levels. In BCR/ABL positive K562 cell line, IM decreased both surface MICA/B expression and NKG2D-mediated lysis by NK cells. Silencing BCR/ABL gene expression directly evidenced its role in the control of MICA expression. IM did not affect MICA mRNA levels but decreased MICA protein expression and sMICA release. Sucrose density gradient fractionation of cytoplasmic extracts from K562 treated with IM showed a shift in the distribution of MICA mRNA from the polysomal toward the monosomal fractions, favoring a decreased translation. Among the major pathways activated by BCR/ABL that regulate translation, PI3K and mTOR were shown to also control MICA expression. These data provide evidence for a direct control of MICA expression by BCR/ABL oncogene and indicate that post-transcriptional mechanisms may participate to the regulation of MICA expression.