Original article
Clinical implications of PRAME gene expression in childhood acute myeloid leukemia

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Abstract

The expression of the PRAME gene (preferentially expressed antigen of melanoma) was measured by quantitative reverse transcriptase polymerase chain reaction in 50 children with newly diagnosed acute myeloid leukemia (AML), three samples of CD34+ stem cells, six bone marrow samples, and 10 peripheral blood samples of healthy donors, as well as three AML cell-lines (KG-1, U937, and HL-60). Eight patients were also analyzed in relapse. Contrary to previous reports, we could show that the PRAME gene is expressed by CD34+ stem cells. This might constitute a problem in using PRAME for tumor immunotherapy. Overexpression of PRAME was found in 62% (n=31) of our patients. The rates of overall and disease-free survival in this group were higher than in patients with no or low expression (P<0.05). PRAME expression was negatively correlated to the white blood cell count at diagnosis (P<0.05) and significantly higher in patients with t(8;21). The levels of expression at diagnosis corresponded with those at relapse (P<0.001) and increased levels could be found prior to the relapse in one patient who was regularly monitored. Our results suggest that the expression of PRAME is an indicator of favorable prognosis and could be a useful tool for monitoring minimal residual disease in childhood AML.

Introduction

Contrary to many other malignancies in childhood, acute myeloid leukemia (AML) still carries a very poor prognosis, with a disease-free survival of about 50% after five years in the most successful studies. However, the diagnosis encompasses a very heterogeneous group of leukemias with distinct response to chemotherapy. Investigating the expression of tumor-related genes in AML is aimed at finding parameters that help to distinguish between good and poor prognoses as well as finding candidates for tumor immunotherapy or parameters to monitor minimal residual disease (MRD).

The PRAME gene (preferentially expressed antigen of melanoma) was found to be expressed at high levels in a large fraction of different tumors and adult leukemias. Its normal function is still unknown. Since PRAME is only expressed at low levels in a few normal tissues (testis, adrenals, ovaries, and endometrium) and encodes an antigen recognized by autologous cytolytic T lymphocytes, it might be a good candidate for tumor immunotherapy 1, 2, 3, 4. Van Baren et al. [2] reported PRAME was expressed at high levels in AML carrying the favorable chromosomal t(8;21), but they also found high levels in some patients with adverse karyotypic anomalies such as partial deletion or monosomy of chromosomes 5 or 7. The pattern of PRAME expression in childhood AML, the association between PRAME expression at the time of diagnosis and at the time of relapse, as well as its prognostic relevance in controlled multicenter studies, were not yet examined.

Section snippets

Patients and therapy

All 50 patients were under 20 years of age and diagnosed with previously untreated AML. The main patient characteristics are summarized in Table 1. The diagnosis of AML and its subtypes was determined according to the French–American–British (FAB) classification. The patients were treated according to four consecutive multicenter studies in Germany: AML-I/82 (13 patients), AML-II/87 (18 patients), AML-BFM-93 (11 patients), and AML-BFM-98 (8 patients). All studies included induction therapies

Expression of PRAME in blood, bone marrow, CD34+ stem cells of healthy donors, and AML cell lines

Expresson of PRAME was analyzed in 10 blood samples and six bone marrow samples of healthy donors. After 35 cycles, small signals could be detected in almost all samples, but the PCR product was high enough for quantitative analysis in only three blood and two bone marrow samples. The highest relative PRAME expression in bone marrow was 2.5×10−5. Relative PRAME expression of CD34+ stem cells was about 10 times higher than this. All three samples showed very similar levels: 3.0×10−4, 2.9×10−4

Discussion

In this study we could show that significant levels of the gene PRAME are expressed in about 60% of AML in children. This is a higher percentage than what van Barren et al. [2] found in adult patients with AML (35%). This discrepancy might be due to differences between the AML in these age groups, but also to a more sensitive analysis in our study. The latter explanation would be consistent with the differences concerning the expression of PRAME in normal peripheral blood, bone marrow, and CD34+

Acknowledgements

We thank S. Below and S. Wittig for their excellent technical assistance.

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    T cells engineered to express T-cell receptors (TCRs) specific for tumor-associated antigens (TAAs) target Cancer-testis antigens (CTAs), normally expressed in germline tissues but aberrantly expressed in malignant cells. PRAME -one such CTA - is overexpressed on several solid cancers and hematologic malignancies [2,3] and two early phase clinical trials testing autologous T cells expressing PRAME/A* 02:01-specific TCRs for treatment of AML (NCT02743611, NCT03503968) are ongoing. The overall effect of cellular senescence - the irreversible arrest of cell proliferation [4] - on treatment efficacy for AML is still controversial, since senescence is associated with the secretion of proinflammatory cytokines, chemokines, proteases, and growth factors, characterized as the senescence-associated secretory phenotype (SASP).

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