Proto-oncogene PML controls genes devoted to MHC class I antigen presentation

Abstract

Fragments of foreign antigens associated with class I molecules of the major histocompatibility complex (MHC) are presented at the cell surface to elicit an immune response. This presentation requires the coordinated expression of several genes contained in the MHC, including those encoding the MHC class I heavy chain, the proteins LMP-2 and LMP-7, which are involved in the proteasomal degradation of cytosolic antigens into peptide fragments that are destined for association with MHC class I molecules, and TAP-1 and TAP-2, which transport these fragments across the membrane of the endoplasmic reticulum at the start of their journey to the cell surface. In many virus-transformed cell lines and spontaneous tumours, these genes are simultaneously repressed. However, the key factor(s) that are essential for their expression and repression have not been identified. Here we report that the proto-oncogene product PML induces expression of LMP-2, LMP-7, TAP-1 and TAP-2 in an MHC-class I-negative, recurrent tumour, leading to the re-expression of cell-surface MHC in tumours and to rejection of the tumours. PML also regulates MHC expression in untransformed fibroblasts. We conclude that malfunction of PML may enable a tumour to evade the immune defence of its host.

Adaptive immunity cooperates with liposomalall-trans-retinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia

“…The APL tumors generated in our mouse model uniformly express MHC Class I (and frequently express MHC Class II), and lethal doses of tumor cells are efficiently cleared when adoptively transferred into allogeneically incompatible mice (see above). These observations contradict the prediction that MHC Class I might be down-regulated by PML-RAR␣ (25). Murine APL cells do not seem to be immunologically ''cloaked,'' nor are they resistant to clearance in vivo.…”

HLA class I in acute promyelocytic leukemia (APL): possible correlation with clinical outcome

“…25 In fact, no direct binding to HLA-A*0201, B*5101 and B*4402 molecules was found for any of the nonapeptides possibly generated from the APL bcr1 and bcr3 fusion region. 26,27 Another possible explanation comes from the recent observation by Zheng et al 28 that mutations involving PML downregulate MHC expression with a dominant-negative mechanism acting on transcription of the genes involved in antigen processing. According to these authors, malfunction of PML consequent to its fusion with RAR␣ might be the reason why TAP-1, TAP-2, LMP-2, LMP-7 and cell surface MHC class I are barely detectable on the NB4 APL cell line.…”

Host defense, viruses and apoptosis

“…It is also noteworthy that PML has also been proposed to control MHC expression and confer resistance to viral infection. 117 NB's are frequently targeted by DNA viruses such as herpesviruses and adenovirus, perhaps to disrupt their function. 118 Certainly, overexpression of PML in rat or mouse fibroblasts induces rapid cell death and correlates with NB formation.…”