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ETV6 Mutations and Loss in AML-M0 Letters to the Editor 1639 individuals. This was performed in a number of studies for flow patient) is too low due to false positive healthy and regenerating cytometry (Kern et al.;6 San Miguel et al.;8 Venditti et al.;9 and bone marrows. others) and also for leukemia-specific genes (Lapillone et al.;3 If we use, for instance, a threshold of 10À3 for clinical Steinbach et al.;4 Matsushita et al.;5 and others). decision-making, it does not matter whether the LPT is 10À4 or However, such analyses can still produce misleading results. 10À6. What really matters is the sensitivity and specificity of the In clinical practice, we do not compare samples that contain diagnostic test at the threshold of 10À3. residual leukemic cells with steady-state healthy bone marrow. We should put less effort into determining LPTs and more Instead, we look at bone marrows that are regenerating after effort into determining sensitivity and specificity of our methods heavy chemotherapy. The expression of presumed leukemia- at the clinically relevant thresholds. specific genes or the frequency of presumed leukemia specific Because of the many issues that influence the quality of each phenotypes can be very different in such samples compared to method of monitoring MRD, the best way of really comparing steady-state healthy bone marrow. two methods is to simultaneously apply both of them in one For instance, the gene CSPG4 was identified as a possible clinical trial. Such studies are strongly needed. MRD marker.4 It was highly expressed in AML samples but not in healthy bone marrow. However, we found that it was useless D Steinbach and K-M Debatin as an MRD marker because expression of CSPG4 was also high Department of Pediatric Oncology, University Hospital Ulm, Ulm, Germany in bone marrow that was free of leukemia but was regenerating E-mail: [email protected] after chemotherapy.4 Therefore, to determine the real sensitivity and specificity of an MRD analysis, it is mandatory to analyze a large number of References leukemia-free, regenerating bone marrows. A second problem of analyzing serial dilutions of leukemic 1 Yin JA, Grimwade D. Minimal residual disease evaluation in acute myeloid leukaemia. Lancet 2002; 360: 160–162. cells in samples of healthy bone marrow is that this does not really 2 Campana D. Minimal residual disease studies in acute leukemia. simulate the situation of minimal residual disease. The important Am J Clin Pathol 2004; 122 (Suppl): S47–S57. clinical question is the amount of leukemic stem cells that is still 3 Lapillonne H, Renneville A, Auvrignon A, Flamant C, Blaise A, Perot C present in the patient. If the leukemic phenotype that is used for et al. High WT1 expression after induction therapy predicts high risk flow cytometry is present on the majority of leukemic cells but not of relapse and death in pediatric acute myeloid leukemia. J Clin on leukemic stem cells, the sensitivity could be lower than Oncol 2006; 24: 1507–1515. 4 Steinbach D, Schramm A, Eggert A, Onda M, Dawczynski K, Rump A anticipated. If the expression of a leukemia-associated gene, like et al. Identification of a set of seven genes for the monitoring WT1, is particularly high in leukemic stem cells, the sensitivity of minimal residual disease in pediatric acute myeloid leukemia. might be much better than anticipated and vice versa. Clin Cancer Res 2006; 12: 2434–2441. 5 Matsushita M, Ikeda H, Kizaki M, Okamoto S, Ogasawara M, Ikeda Y et al. Quantitative monitoring of the PRAME gene for the detection of minimal residual disease in leukaemia. Br J Haematol 2001; 112: Conclusions 916–926. 6 Kern W, Danhauser-Riedl S, Ratei R, Schnittger S, Schoch C, Kolb HJ et al. Detection of minimal residual disease in unselected patients Monitoring MRD has become a strong diagnostic tool in acute with acute myeloid leukemia using multiparameter flow cytometry leukemia. It is widely used for clinical decision-making in acute for definition of leukemia-associated immunophenotypes and lymphoblastic leukemia, chronic myeloid leukemia and acute determination of their frequencies in normal bone marrow. Haema- promyelocytic leukemia. Various methods have been developed tologica 2003; 88: 646–653. to monitor MRD in AML and we should proceed to put them 7 van der Velden VH, Cazzaniga G, Schrauder A, Hancock J, Bader P, into clinical practice. Panzer-Grumayer ER, et al., European Study Group on MRD Sensitivity is an important issue in the comparison of these detection in ALL (ESG-MRD-ALL). Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation methods. When the term is used, it should always be clear of real-time quantitative PCR data. Leukemia 2007; 21: 604–611. whether we are talking about the LPT or the real sensitivity and 8 San Miguel JF, Vidriales MB, Lopez-Berges C, Diaz-Mediavilla J, specificity of our diagnostic test. Gutierrez N, Canizo C et al. Early immunophenotypical evaluation The LPT is easy to determine and for most methods of of minimal residual disease in acute myeloid leukemia identifies monitoring MRD, is in the range of 10À4–10À6. These figures different patient risk groups and may contribute to postinduction have a very limited meaning because for clinical decision- treatment stratification. Blood 2001; 98: 1746–1751. 9 Venditti A, Buccisano F, Del Poeta G, Maurillo L, Tamburini A, making LPT cannot be used as the cutoff for high versus low Cox C et al. Level of minimal residual disease after consolidation MRD. At such a low threshold, the specificity of monitoring therapy predicts outcome in acute myeloid leukemia. Blood 2000; MRD (likelihood of a negative test result in a truly negative 96: 3948–3952. ETV6 mutations and loss in AML-M0 Leukemia (2008) 22, 1639–1643; doi:10.1038/leu.2008.34; belonging to the E26 transforming specific (ETS) family of DNA- published online 28 February 2008 binding proteins. ETV6 is known as a proto-oncogene involved in translocation with over 40 partners.1 In acute myeloid leukemia (AML) only a few rare translocations result in transforming fusion ETV6 (ETS translocation-variant gene 6, located on chromosome proteins,1 indicating that the oncogenic role of ETV6 does not 12p), also known as TEL, encodes a transcription repressor play a major part in AML. However, abnormalities of the short Leukemia Letters to the Editor 1640 Figure 1 Single-nucleotide polymorphism analysis of patients with chromosome 12 abnormalities. (a) Loss-of-heterozygosity values based on haplotype, using the paired normal. Each box represents the combined call between tumor sample and respective control (T cells). Black boxes represent loss of heterozygosity, dark gray boxes no loss and light gray boxes non-informative markers. Boxes are displayed proportionally to the position of the SNP that they represent in relation to the cytogenetic band to the left of the panel. (b) Chromosome copy number calculated for the common region showing loss of heterozygosity in panel a (amplified). Copy number for the tumor samples was inferred using the paired normal as reference and a median smoothing. Gray boxes represent two copies and black boxes one copy (deletion) for each chromosome locus. (c) Schematic representation of the genes present in the minimal deleted overlapping region defined in (b) based on the UCSC Genome Browser (http://genome.ucsc.edu/). Solid black boxes represent clusters of related genes. SNP, single-nucleotide polymorphism. Table 1 Clinical, hematological, cytogenetic features and mutational status of ETV6 Patient Age Diagnoses Karyotype ETV6 Allele 1 Allele 2 1a 65 AML-M0 46,XX,del(16)(q22?),i(17)(q10),del(20)(q?) Deleted WT 2a 67 sAML-M0 47,XX,t(4;12)(q12;p13),À21,+der21del(q?)x2 Translocated WT 6a 37 AML-M0 46,XY S107DfsX21 V345_Y346insR 9a 47 sAML-M0 52,XX,t(1;4)(p13;p12),+6,+8,t(10;12)(q11;p11),+18,+19,+20,+21 Deleted WT 21 59 AML-M0 46,XY R360X WT 43 64 AML-M0 46,XY,t(4;12)(q12;p13) Translocated WT 45 F AML-M0 ND Deleted WT 58 50 AML-M0 46,XY,idic(21)(p11.2) F103LfsX11 WT Abbreviations: AML, acute myeloid leukemia; ETV6, ETS translocation-variant gene 6; ND, not done; s, secondary; WT, wild type. aPatients in the study by Silva et al.7 Leukemia Letters to the Editor 1641 arm of chromosome 12 (12p) are found in about 5% of AML and investigated specifically in this subtype.4,6 To better understand myelodysplastic syndromes. Most abnormalities consist of total or the role of ETV6 in AML-M0, we studied 52 M0 patients using partial loss of 12p usually affecting ETV6 and CDKN1B, cytogenetic techniques complemented with single-nucleotide implicating these genes as tumor-suppressor genes.1–4 Recently, polymorphism (SNP) arrays and sequencing of ETV6,as heterozygous mutations of ETV6, resulting in loss of repressor described in the Supplementary Information. The cohort was activity, were found in AML, adding to the view that ETV6 might not selected for any parameter rather than being AML-M0, had a have tumor-suppressor characteristics.5 median age of 61 years (one patient was a child) and consisted Whereas translocations and deletions involving ETV6 have of de novo, therapy-related (1 case) and secondary leukemia been reported in AML-M0, ETV6 mutations were never (4 cases). Figure 2 Schematic representation of FISH analysis of the breakpoints in t(10;12) in patient 9 and t(4;12) in patient 2, and fusion transcripts in patients 2 and 43. (a) Determination of the deletion and translocation break points in patient 9. The deleted region in chromosome 12 is localized between SNP rs252027 to SNP rs747726 (SNPs present in a single copy are not underlined) as determined using the GeneChip 10K array (Figure 1b).
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