Original articleClinical implications of PRAME gene expression in childhood acute myeloid leukemia
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.
References (21)
- et al.
Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor
Immunity
(1997) - et al.
Simultaneous expression of different immunogenic antigens in acute myeloid leukemia
Experimental Hematology
(2000) - et al.
Clinical significance of surface antigen expression in children with acute myeloid leukemiaresult of study AML-BFM-87
Blood
(1995) - et al.
High frequency of immunophenotype changes in acute myeloid leukemia at relapseimplications for residual disease detection (Cancer and Leukemia Group B Study 8361)
Blood
(2001) - et al.
Persistence of AML1 rearrangement in peripheral blood cells in t(8; 21)
Cancer Genet Cytogenet
(1996) - et al.
Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels
Blood
(1996) - et al.
PRAME, a gene encoding an antigen recognized on a human melanoma by cytolytic T cells, is expressed in acute leukaemia cells
Br J Haematol
(1998) - et al.
Efficient identification of novel HLA-A(*)0201-presented cytotoxic T lymphocyte epitopes in widely expressed tumor antigen PRAME by proteasome-mediated digestion analysis
J of Experimental Medicine
(2001) - et al.
Therapie der akuten myeloischen leukämie bei kindern—ergebnisse der multizentrischen therapiestudie AML II/87
Kinderärztliche Praxis
(1991) - et al.
Idarubicin improves blast cell clearance during induction therapy in children with AMLresults of study AML-BFM 93. AML-BFM study group
Leukemia
(2001)
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