BCR/ABL Oncogene Directly Controls MHC Class I Chain-Related Molecule A Expression in Chronic Myelogenous Leukemia

Boissel N, Rea D, Tieng V, Dulphy N, Brun M, Cayuela JM, Rousselot P, Tamouza R, Le Bouteiller P, Mahon FX, Steinle A, Charron D, Dombret H, Toubert A
Source: J Immunol
Publication Date: (2006)
Issue: 176(8): 5108-5116
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Cells used in publication:
Species: human
Tissue Origin: blood
Nucleofector® I/II/2b
MHC class I chain-related molecules (MIC) participate in immune surveillance of cancer through engagement of the NKG2D-activating receptor on NK and T cells. Decreased NKG2D expression and function upon chronic exposure to NKG2D ligands and/or soluble forms of MIC (sMIC) may participate in immune escape. In chronic myeloid leukemia, a malignancy caused by the BCR/ABL fusion oncoprotein, we showed cell surface expression of MICA on leukemic, but not healthy, donor hemopoietic CD34(+) cells. At diagnosis, chronic myeloid leukemia patients had abnormally high serum levels of sMICA and weak NKG2D expression on NK and CD8(+) T cells, which were restored by imatinib mesylate (IM) therapy. In the BCR/ABL(+) cell line K562, 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 production and release. Sucrose density gradient fractionation of K562 cytoplasmic extracts treated with IM showed a shift in the distribution of MICA mRNA from the polysomal toward the monosomal fractions, consistent with decreased translation. Among the major pathways activated by BCR/ABL that regulate translation, PI3K and mammalian target of rapamycin were shown to control MICA expression. These data provide evidence for direct control of MICA expression by an oncogene in human malignancy and indicate that posttranscriptional mechanisms may participate in the regulation of MICA expression.