The DH/PH domain of BCR-ABL mediates INKT cell immunosubversion in chronic myeloid leukemia by downregulating cell-surface CD1D expression in myeloid dendritic cells (TUM10P.1038)

Abstract

Abstract Chronic myeloid leukemia (CML) is associated with a rearrangement between the Abelson (ABL) and the BCR genes, generating a chimeric fusion gene. The constitutive tyrosine-kinase (TK) activity linked to ABL is sufficient to induce malignant transformation while BCR contains a DH/PH domain ensuring activation of the Rho/ROCK pathway that is implicated in the control of mobility of leukemia cells. iNKT cells constitute a distinct population of T cells that recognize glycolipids as α-GC presented by CD1d, and are believed to play a key role in cancer immunosurveillance. CML in chronic phase (CP) is associated with functional deficiencies of iNKT cells. Here, we hypothesized that the anergic status of iNKT cells during CML-CP results from BCR-ABL-dependent dysfunctions in APC. Accordingly, CML mDC downregulated their cell surface expression of CD1d, as compared to mDC from healthy individuals. Since Rho/ROCK pathway is a negative regulator of CD1d expression, we surmised that its enhancement by the DH/PH domain of BCR-ABL is responsible for the impaired cell-surface CD1d expression in CML mDC. In favor of this hypothesis, we showed that treatment of PBMC by Rho/ROCK inhibitors restores in vitro cell-surface expression levels of CD1d on CML-CP mDC as well as expansion of CM-CP iNKT cells in response to α-GC. Altogether, these results indicate that the DH/PH domain of BCR-ABL mediates iNKT-cell immunosubversion in CML patients by downregulating cell-surface CD1d expression in mDC.