The preferentially expressed antigen in melanoma (PRAME) inhibits myeloid differentiation in normal hematopoietic and leukemic progenitor cells

Abstract

The preferentially expressed antigen in melanoma (PRAME) is expressed in several hematologic malignancies, but either is not expressed or is expressed at only low levels in normal hematopoietic cells, making it a target for cancer therapy. PRAME is a tumor-associated antigen and has been described as a corepressor of retinoic acid signaling in solid tumor cells, but its function in hematopoietic cells is unknown. PRAME mRNA expression increased with chronic myeloid leukemia (CML) disease progression and its detection in late chronic-phase CML patients before tyrosine kinase inhibitor therapy was associated with poorer therapeutic responses and ABL tyrosine kinase domain point mutations. In leukemia cell lines, PRAME protein expression inhibited granulocytic differentiation only in cell lines that differentiate along this lineage after all-trans retinoic acid (ATRA) exposure. Forced PRAME expression in normal hematopoietic progenitors, however, inhibited myeloid differentiation both in the presence and absence of ATRA, and this phenotype was reversed when PRAME was silenced in primary CML progenitors. These observations suggest that PRAME inhibits myeloid differentiation in certain myeloid leukemias, and that its function in these cells is lineage and phenotype dependent. Lastly, these observations suggest that PRAME is a target for both prognostic and therapeutic applications. (Blood. 2009;114: 3299-3308) Introduction PRAME, or the preferentially expressed antigen in melanoma, was originally described as an HLA-A24-restricted tumor-associated antigen in melanoma. 1 PRAME is expressed in a number malignancies; however, its expression is low or absent in various normal tissues, including CD34 ϩ hematopoietic progenitors. [2][3][4] Until recently its function remained unknown. Epping et al have characterized PRAME as a ligand-dependent corepressor of retinoic acid receptor ␣ (RAR␣), RAR␤, and RAR␥ signaling. 5 The authors demonstrated that PRAME protein expression in solid tumor cell lines inhibited differentiation in the presence of the RAR␣ ligand all-trans retinoic acid (ATRA). The authors also hypothesized that the polycomb group protein EZH2 may act together with PRAME to mediate the block in differentiation. 5 In hematologic malignancies PRAME is expressed in 22% to 62% of unsorted bone marrow (BM) or peripheral blood (PB) samples from chronic myeloid leukemia (CML) patients and in 25% to 62% of pediatric acute myeloid leukemia (AML) cases. [2][3][4]6 In our analyses of gene expression that increased with CML progression and also discriminated leukemic blasts from normal CD34 ϩ sorted BM, PRAME demonstrated the most statistically significantly increased expression with disease progression. 2 PRAME hypomethylation may contribute to its increased expression in blast crisis (BC) CML and AML. 7,8 Whereas increased PRAME expression is associated with poor outcomes in solid tumors, 9-11 the data in hematologic malignancies appear contradictory. Increased PRAME expression discriminates acute megakaryoblastic leukemi...

Chronic myeloid leukemia: mechanisms of blastic transformation

“…In support of this suggestion, expression studies revealed that BCR-ABL1 dramatically perturbs the CML transcriptome (31), resulting in altered expression of genes, some of which (e.g., PRAME, MZF1, EVI-1, WT1, and JUN-B) might play a role in BP (19,(32)(33)(34). Nonetheless, the posttranscriptional, translational, and posttranslational effects of high BCR-ABL1 levels result in the constitutive activation of factors with reported mitogenic, antiapoptotic, and antidifferentiation activity (e.g., MAPK ERK1/2 , MYC, JAK2, YES-1, LYN, hnRNP-E2, MDM2, STAT5, BMI-1, and BCL-2) and inhibition of major key regulators of cellular processes, such as those regulated by the tumor suppressors p53, CCAAT/enhancer binding protein-α (C/EBPα), and PP2A (19,29,35).…”

Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome

“…A previous transcriptome comparison found the expression of testis-cancer antigen PRAME as the discriminative marker of DS AMKL compared with DS TMD, 44 and the overexpression of this gene is known to be due to demethylation of the regulatory regions and is established as a potential driver event in tumorigenesis 52 and inhibitor of differentiation in myeloid leukemic precursor cells. 53 Interestingly, overexpression of PRAME was found to be part of the progression program for CML, in synergy with deregulation of the WNT/b-catenin pathway. 54 In conclusion, our data demonstrate that DS AMKLs form by accumulation of multiple somatic SCNAs and point mutations in genes known as drivers of leukemogenesis.…”

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…36 PRAME acts as a 'natural' antagonist of the retinoic acid (RA) receptor and disrupts its downstream signaling, thereby preventing normal RA-induced differentiation. 36 Oehler et al 48 have demonstrated the potential involvement of PRAME in the differentiation arrest that accompanies the conversion of chronic phase CML to blast crisis. 48 A similar observation has been recently made for MUC1.…”

“…36 Oehler et al 48 have demonstrated the potential involvement of PRAME in the differentiation arrest that accompanies the conversion of chronic phase CML to blast crisis. 48 A similar observation has been recently made for MUC1. 49 Finally, accumulating evidence also suggests a critical role for the downregulation of WT1 in the process of myeloid differentiation (reviewed in Yang et al 15 and Sugiyama et al 16 ).…”