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Monitoring Minimal Residual Disease and Predicting Relapse in APL By Leukemia (2001) 15, 1060–1065 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu Monitoring minimal residual disease and predicting relapse in APL by quantitating PML-RARα transcripts with a sensitive competitive RT-PCR method K Tobal, H Moore, M Macheta and JA Liu Yin Molecular Oncology Group, University Department of Haematology, Manchester Royal Infirmary, Manchester M13 9WL, UK Qualitative RT-PCR methods used for monitoring minimal for diagnosis and in monitoring minimal residual disease residual disease (MRD) in APL patients fail to predict relapse (MRD).5–12 Serial negative tests for the PML-RARα transcripts in up to 25% of patients in remission. We report here the devel- opment and evaluation of a highly sensitive (10−5 and 10−6 with in post-chemotherapy patients are generally associated with one round and two rounds of PCR, respectively) competitive prolonged remission. However, up to 25% of those patients RT-PCR method to quantitate the PML-RARα fusion transcripts. can relapse within a short period of testing negative.10–13 This PML-RARα transcript’s levels were normalised to 105 copies of is due in part to the low level of sensitivity of these methods, ABL transcript. Serial BM and PB samples from 16 patients with approximately 10−4, which is 2 log lower than corresponding APL and t(15;17) were examined. Presentation samples from methods for other fusion genes such as AML1-MTG8.14 These three patients (three BM, one PB) showed levels in the range of 0.7 × 106–3.5 × 106 and 1.2 × 105 molecules in BM and PB methods lack the necessary sensitivity to detect the presence samples respectively. Serial quantitation of MRD in both BM of low levels of leukaemic cells present during stable and PB samples showed significantly lower levels of PML- remission. RARα transcripts in remission, although the majority of It is clear from the data reported by various groups on MRD samples remain positive for the PML-RARα transcripts even monitoring of APL that a sensitive quantitation of PML-RARα those in long-term remission (up to 94 months). Levels of PML- may provide a superior strategy for MRD monitoring in these RARα in remission samples were up to 2 × 102 and up to 5.2 × 1 patients. Recently, protocols for real-time quantitation of PML- 10 molecules in BM and PB respectively. BM and PB samples α taken from two patients 2–4 months before relapse showed sig- RAR have been developed, but these small studies have pro- nificantly higher levels of PML-RARα transcripts (1.2 × 104 mol- duced mixed results.15,16 Evaluation of real-time quantitation ecules in BM; 3.5 × 102, 1.2 × 102 and 1.2 × 103 in PB). The same of PML-RARα by various groups is in progress. samples, when tested with a standard qualitative RT-PCR for We have developed a highly sensitive competitive RT-PCR α −4 the amplification of PML-RAR (with a sensitivity of 10 ) pro- method for the quantitation of PML-RARα transcripts and have duced negative results. This indicates that the qualitative methods would not have predicted relapse in these patients. assessed its value in monitoring MRD in 16 patients with APL Our data show that quantitating PML-RARα transcripts with a and t(15;17). sensitive method may provide a superior approach for monitor- ing MRD in APL and identifying patients at high risk of relapse. Leukemia (2001) 15, 1060–1065. Keywords: APL; t(15;17); PML-RARα; minimal residual disease; competitive RT-PCR Materials and methods Introduction Patients Acute promyelocytic leukaemia (APL) is characterised by the α 1–3 t(15;17), which produces the PML-RAR fusion gene. Tran- Serial bone marrow (BM) and peripheral blood (PB) samples α scripts for PML-RAR are detected in all patients with t(15;17). were collected from 16 patients in complete remission (CR) The breakpoints on chromosome 17 were located in the of APL with a CR duration of 9–94 months (median 32 second intron of the RARA gene in all cases with t(15;17), months). Three of the patients were tested at presentation. whereas there are three different breakpoint cluster regions Diagnosis of APL (AML M3) was made according to FAB (BCR1, BCR2, BCR3) on chromosome 15. This leads to the classification17 and the presence of t(15;17) was confirmed by α formation of three types of PML-RAR transcripts. BCR1 and karyotypic analysis. All patients received standard intensive BCR3 are most frequently involved in APL (92–95% of cases) remission induction chemotherapy with an anthracycline/ α and produce a unique PML-RAR fusion gene, whereas BCR2 anthracenedione (daunorubicin or mitozantrone), cytosine leads to several different products due to different breakpoints arabinoside ± thioguanine and two courses of consolidation 4 within this cluster. The combination of all-trans retinoic acid chemotherapy with the same agents, followed by autologous (ATRA) and chemotherapy has made it possible for up to 90% or allogeneic bone marrow transplant (BMT) in four patients. of patients to achieve complete remission (CR). However, Patients who did not receive BMT received a fourth course of relapse still occurs in some 15–25% of patients, indicating the intensive chemotherapy with mitozantrone and an intermedi- need for an accurate protocol for the monitoring of minimal ate dose of cytosine arabinoside. Three patients received short residual disease (MRD) in these patients. Such a protocol may courses of ATRA 5–7 days prior to induction chemotherapy. enable the identification of patients at high risk of relapse and Five patients received concomitant ATRA with induction predict its onset at an early stage. RT-PCR methods developed chemotherapy until achievement of remission. Pre-BMT con- α for the amplification of PML-RAR transcripts have been used ditioning was comprised of daunorubicin (60 mg/m2), cyclo- phosphamide (120 mg/m2) and TBI (1000 cGy) in two frac- tions for allograft or melphalan (120 mg/m2) and TBI for Correspondence: K Tobal; Fax: 0161-2764088 autograft. The remission BM karyotypes were normal in all Received 26 October 2000; accepted 26 March 2001 patients. Monitoring MRD in APL with a competitive RT-PCR K Tobal et al 1061 Samples and RNA preparation fication parameters were 95°C for 12 min (one cycle); 93°C for 1 min, 56°C for 1 min and 72°C for 1 min (50 cycles); and Mononuclear cells (MNCs) from PB and BM samples were 72°C for 5 min (one cycle). Two µl of first round product were obtained by Ficoll–Hypaque density gradient centrifugation used in a 50 µl second round PCR reaction containing primers and either stored at −80°C or used immediately for RNA iso- NP32 and RAR for BCR1 and NP5 and RAR for BCR3. PCR lation. Between 1 × 106 and 2 × 106 cells from the NB4 cell parameters were 95°C for 12 min (one cycle); 93°C for 1 min, line or patients’ MNCs were used for RNA isolation by the 56°C for 1 min and 72°C for 1 min (40 cycles); and 72°C for guanidinium-phenol-chloroform method of Chomczynski and 5 min (one cycle). Second round products were electrophor- Sacchi18 with minor modifications as described previously.19 esed on a 2.5% agarose gel. RT reaction ABL competitive RT-PCR Four µl (1–5 µg) of RNA was heated at 72°C for 5 min and A competitive RT-PCR method was used to quantitate the ABL snap cooled on ice. RT reaction mixture (final concentration transcript.19 This quantitation was used to accurately estimate in a 20 µl reaction volume: 1× first strand buffer, 10 mM DTT, the level of amplifiable RNA present in samples. Two µlof 0.25 µg pd(N)6, 1 mM dNTPs, 200 U MMLV, 40 U RNAsin) cDNA were mixed with 2 µlofABL transcript competitor was then added to the RNA and incubated at room tempera- DNA and subjected to a one round PCR amplification as ture for 10 min. RT reaction was carried out at 37°C for 1 h, described above. The expected band sizes for ABL and 45°C for 30 min and 72°C for 5 min. competitor are 276 bp and 235 bp, respectively. Control gene (ABL RT-PCR) RARα competitive RT-PCR To assess the quality and estimate the quantity of amplifiable Competitors for BCR1 and BCR3 types of PML-RARα tran- RNA used for RT-PCR, qualitative and quantitative RT-PCR scripts were prepared by PCR amplification of the normal amplification of ABL gene transcripts was performed. PCR RARα transcripts with primers cpmr5 and 7 or cpmr3 and 7. amplification was performed as previously described;20 The sense primers, cpmr5 and cpmr3, have tails containing briefly, PCR amplification was performed in a 25 µl reaction sequences of primers NP3 and NP32 or NP51 and NP5 that containing primers CA3 and A2 at 97°C for 1 min 30 s, 64°C are used in PCR amplification respectively (Figure 1). None of for 50 s and 72°C for 1 min, (one cycle); 97°C for 30 s, 64°C our patients have a BCR2 fusion transcript, but a similar for 50 s and 72°C for 1 min (40 cycles) and 72°C for 5 min approach could be used to prepare BCR2 competitors. Three (one cycle). PCR products were electrophoresed on a 2% µlofPML-RARα positive samples’ cDNA were mixed with 2 agarose gel. µl of competitor DNA and subjected to PCR amplification as described above. Each sample was quantified at every order of magnitude and then at every half order of magnitude.
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