Identification of a melanoma antigen, PRAME, as a BCR/ABL‐inducible gene

Abstract

In order to elucidate molecular events in BCR/ABLinduced transformation, we adopted a polymerase chain reaction (PCR)-based technique of differential display and compared mRNA expression in human factor-dependent cells, TF-1, with that in factor-independent cells, ID-1, which were established from TF-1 cells by transfection of BCR/ABL. Cloning and sequencing of a gene which was upregulated in ID-1 cells revealed that the gene was identical to a melanoma antigen, PRAME. Our present study demonstrated that PRAME was markedly expressed in primary leukemic cells with chronic myeloid leukemia (CML) in blastic crisis and Philadelphia (Ph) + -acute lymphoblastic leukemia (ALL), in which BCR/ABL played an important role as a pathogenic gene. Moreover, comparison of PRAME expression among CD34 + cells with CML in blastic, accelerated, and chronic phases revealed a higher expression in CML in advanced phases. Thus PRAME was considered to be a good candidate for a marker of Ph + -leukemic blast cells as well as a new target antigen of leukemic blast cells that cytotoxic T cells can recognize.z 2000 Federation of European Biochemical Societies.

BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients

“…These data suggest that TRAIL downregulation has a central role in tumor initiation and/or progression, and that TRAIL reexpression is a promising therapeutic avenue for killing transformed cell lines without affecting normal cells. PRAME is frequently expressed in many different cancers (Epping and Bernards, 2006), including BCR-ABL-positive leukemia (Watari et al, 2000;Radich et al, 2006;Yong et al, 2008). We confirmed that PRAME is a target for BCR-ABL tyrosine-kinase signaling pathways and showed that PRAME expression correlates well with BCR-ABL in CML patients, in particular, as a marker of disease progression.…”

A Causal Role for the Human Tumor Antigen Preferentially Expressed Antigen of Melanoma in Cancer

“…Patients with the BCR/ABL t(9;22) (Ph+) and AML1/ETO t(8;21) translocations show particularly high PRAME mRNA levels (8,15,16). It cannot be excluded, however, that the correlation of PRAME expression with good prognosis is secondary to its correlation with these translocations (17).…”

“…It cannot be excluded, however, that the correlation of PRAME expression with good prognosis is secondary to its correlation with these translocations (17). Indeed, it has been shown that PRAME is a BCR/ABL-inducible gene (15).…”

“…24), suggesting that epigenetic control mechanisms underlie the silencing of PRAME in most adult tissues. PRAME was up-regulated in BCR/ABL-transduced cells, suggesting a role for BCR/ABL in the activation of PRAME (15). Many more of these oncogene or pathway-induced mechanisms of PRAME up-regulation may exist and it will be important to identify the mechanisms that cause PRAME to become selectively activated during oncogenesis.…”

BCR/ABL-mediated downregulation of genes implicated in cell adhesion and motility leads to impaired migration toward CCR7 ligands CCL19 and CCL21 in primary BCR/ABL-positive cells

“…Deregulated gene expression has been studied in BCR/ABL-transformed cell lines, [18][19][20][21] and we have recently reported on the increased expression of a number of genes in primary CD34 þ cells as a result of p210 BCR/ABL . 22,23 We here hypothesized that presence of p210 BCR/ABL may also downregulate expression of known and yet to be identified genes that may contribute to BCR/ABL-mediated malignant transformation in CML.…”