PRAME Gene Expression in Childhood Acute Lymphoblastic Leukemia: Impact on Prognosis

Abdel-Malak, Camelia; Yahya, Raida S.; Elghannam, Doaa M.; El-Khadragy, A E; Messih, Hanaa M. Abd El

doi:10.7754/clin.lab.2013.121137

Cited by 16 publications

(12 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PRAME expression has been demonstrated in a variety of solid and haematological malignancies 3‐6 . High PRAME tumour expression has been associated with poor prognosis in several solid tumours, increased risk of metastases and shorter disease‐free and overall survival, 7 whereas it has been found to predict a more favourable outcome in acute myeloid and lymphoblastic leukaemia 5,8‐12 . Several studies suggest that PRAME can induce cell proliferation, reduce cytotoxic drug sensitivity and inhibit apoptosis in a variety of cancers 13‐16 .…”

Section: Introductionmentioning

confidence: 99%

Cancer testis antigen PRAME: An anti‐cancer target with immunomodulatory potential

Belič

Thomas

Al-Khadairi

et al. 2021

J Cellular Molecular Medi

View full text Add to dashboard Cite

PReferentially expressed Antigen in Melanoma (PRAME) is a cancer testis antigen with restricted expression in somatic tissues and re‐expression in poor prognostic solid tumours. PRAME has been extensively investigated as a target for immunotherapy, however, its role in modulating the anti‐tumour immune response remains largely unknown. Here, we show that PRAME tumour expression is associated with worse survival in the TCGA breast cancer cohort, particularly in immune‐unfavourable tumours. Using direct and indirect co‐culture models, we found that PRAME overexpressing MDA‐MB‐468 breast cancer cells inhibit T cell activation and cytolytic potential, which could be partly restored by silencing of PRAME. Furthermore, silencing of PRAME reduced expression of several immune checkpoints and their ligands, including PD‐1, LAG3, PD‐L1, CD86, Gal‐9 and VISTA. Interestingly, silencing of PRAME induced cancer cell killing to levels similar to anti‐PD‐L1 atezolizumab treatment. Comprehensive analysis of soluble inflammatory mediators and cancer cell expression of immune‐related genes showed that PRAME tumour expression can suppress the expression and secretion of multiple pro‐inflammatory cytokines, and mediators of T cell activation, differentiation and cytolysis. Together, our data indicate that targeting of PRAME offers a potential, novel dual therapeutic approach to specifically target tumour cells and regulate immune activation in the tumour microenvironment.

show abstract

Section: Introductionmentioning

confidence: 99%

Cancer testis antigen PRAME: An anti‐cancer target with immunomodulatory potential

Belič

Thomas

Al-Khadairi

et al. 2021

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…As a tumor-associated antigen (TAA), PRAME expression level is low in normal tissues and normal bone marrow, but it is highly increased in a variety of solid tumors and hematologic malignancies (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The majority of patients with acute myeloid leukemia (AML) overexpress PRAME (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Methylation pattern of preferentially expressed antigen of melanoma in acute myeloid leukemia and myelodysplastic syndromes

et al. 2017

View full text Add to dashboard Cite

Abstract. Preferentially expressed antigen of melanoma (PRAME), a tumor-associated antigen, is overexpressed in a variety of hematologic malignancies with a great variation in expression. The majority of patients with acute myeloid leukemia (AML) 1-eight-twenty one (ETO) + AML and a certain number of myelodysplastic syndromes (MDS) have an abnormally high increase in PRAME expression level. The landscape of PRAME methylation requires evaluation in order to determine the most relevant sites and the exact association of its methylation with expression level and type of disease. In the present study, bone marrow samples collected from 8 AML1-ETO + AML, 4 MDS, 3 AML1-ETO -AML and 2 normal volunteers underwent bisulfate sequencing to analyze the methylation status of all four 5'-C-phosphate-G-3' (CpG) regions within the entire PRAME gene. The median PRAME transcript level of 15 patients was 204.5% (range, 0.02-710.3%). PRAME transcript levels were inversely associated with the degree of methylation of the -389 to -146 CpG sites (r=-0.69; P=0.002) in the 3' part of the promoter region and the +132 to +363 CpG sites (r=-0.69; P=0.006) in the exon 1b region. However, not every sample strictly followed this correlation: Certain samples with high degrees of methylation demonstrated abnormally high expression levels, and vice versa. The methylation ratios of CpG sites in exon 1a were low for all samples (range, 0.0-13.8%), and those in exon 2 were similar in 16 samples (range, 72.4-93.4%), with the exception of one patient with high expression (425.2%) and significantly low degree of methylation in the PRAME gene (22.2%). MDS patients revealed similar methylation ratios in the 3' section of the promoter region, but tended to have lower methylation ratios in the exon 1b region (P=0.62 and P=0.09, respectively) compared with those observed in AML1-ETO + patients with AML and similar degree of PRAME overexpression. Therefore, the hypomethylation of CpG sites in the 3' part of the promoter region and in exon 1b was typically found with PRAME overexpression in AML and MDS. Methylation of other CpG islands, epigenetic and genetic mechanisms, and type of disease may also be involved.

show abstract

“…However, one such mechanism occurs within the cell, and the binding sites are unknown; thus, inhibitors like monoclonal antibodies cannot be easily managed. No mechanisms associated with its cell-surface localization have been so far reported, thus given its selective expression on several cancer cells, including lymphoma cells [4,5], the use of antibodies against the outer protein regions can be envisaged for CAR-T-based immunotherapies where no specific functions of the protein must be modulated. Recent evidence has indeed shed light on PRAME as a cell-surface cancer biomarker [17] and as a target for TCR mimic antibodies (TCRm) [18,19], opening the possibility for effective CAR-based T cell therapies.…”

Section: Discussionmentioning

confidence: 99%

“…In most of them, its presence is associated with a poor prognosis [3]. High levels of PRAME expression are correlated with favorable outcomes following chemotherapy treatments of hematological malignancies, such as acute myeloid and lymphoblastic leukemia [4,5].…”

Section: Introductionmentioning

confidence: 99%

Development of a New Highly Selective Monoclonal Antibody against Preferentially Expressed Antigen in Melanoma (PRAME) and Identification of the Target Epitope by Bio-Layer Interferometry

Sivaccumar

Leonardi

Iaccarino

et al. 2021

IJMS

View full text Add to dashboard Cite

Background: Monoclonal antibodies (mAbs) against cancer biomarkers are key reagents in diagnosis and therapy. One such relevant biomarker is a preferentially expressed antigen in melanoma (PRAME) that is selectively expressed in many tumors. Knowing mAb’s epitope is of utmost importance for understanding the potential activity and therapeutic prospective of the reagents. Methods: We generated a mAb against PRAME immunizing mice with PRAME fragment 161–415; the affinity of the antibody for the protein was evaluated by ELISA and SPR, and its ability to detect the protein in cells was probed by cytofluorimetry and Western blotting experiments. The antibody epitope was identified immobilizing the mAb on bio-layer interferometry (BLI) sensor chip, capturing protein fragments obtained following trypsin digestion and performing mass spectrometry analyses. Results: A mAb against PRAME with an affinity of 35 pM was obtained and characterized. Its epitope on PRAME was localized on residues 202–212, taking advantage of the low volumes and lack of fluidics underlying the BLI settings. Conclusions: The new anti-PRAME mAb recognizes the folded protein on the surface of cell membranes suggesting that the antibody’s epitope is well exposed. BLI sensor chips can be used to identify antibody epitopes.

show abstract

PRAME Gene Expression in Childhood Acute Lymphoblastic Leukemia: Impact on Prognosis

Cited by 16 publications

References 0 publications

Cancer testis antigen PRAME: An anti‐cancer target with immunomodulatory potential

Cancer testis antigen PRAME: An anti‐cancer target with immunomodulatory potential

Methylation pattern of preferentially expressed antigen of melanoma in acute myeloid leukemia and myelodysplastic syndromes

Development of a New Highly Selective Monoclonal Antibody against Preferentially Expressed Antigen in Melanoma (PRAME) and Identification of the Target Epitope by Bio-Layer Interferometry

Contact Info

Product

Resources

About