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Improving minimal residual disease detection in precursor B-ALL based on immunoglobulin-κ and heavy-chain gene rearrangements

Leukemia volume 22, pages 2265–2267 (2008)Cite this article

Patient-specific rearrangements of immunoglobulin and T-cell receptor genes (Ig/TCR) are currently used as markers of minimal residual disease (MRD) in patients with acute lymphoblastic leukaemia (ALL) enrolled on clinical trials in both Europe and Australia.1 Most laboratories in Europe utilize the generic Taqman probes published in Leukemia for the Junctional (J) region of the immunoglobulin heavy-chain gene (IGH) and the immunoglobulin-κ-deleting element (IGK-Kde) to provide effective real-time quantitative (RQ) PCR-based detection of these rearrangements.2, 3 Two MRD markers with high sensitivity (⩽10−4) are generally required in MRD intervention clinical trials to reduce false-negative results arising from clonal evolution,1, 4 and although IGK-Kde markers have been recommended for use as second markers,2 they have been under-utilized due to the lower sensitivity of some assays.1

We have trialled new MRD probes for both IGK and IGH with the aim of improving marker sensitivity and the efficiency of identifying suitable MRD markers (Table 1). These probes were designed to target the consensus Variable (V) region family sequences instead of the J or Kde gene segments and in most instances were based on minor groove binding or locked nucleic acid chemistry, which can provide better binding efficiency than the conventional Taqman probes. A comparison of the MRD probes was carried out in conjunction with the routine identification and optimization of MRD markers performed for a cohort of 400 patients enrolled on the Australian and New Zealand Children's Haematology Oncology Group Study 8. We compared the performance of the new probes with the published Taqman probes specific for IGH J1245, J3 and J6 sequences,3 which were used for some patients with IGH(V–J) rearrangements as well as all patients with IGH(VH5-J) or immature IGH(D–J) rearrangements. For IGK rearrangements, new probes, of which each bind a consensus sequence for a family of Vk sequences (VK1, VK2 and VK3) and an IGK(intron) probe were compared with the single generic IGK(Kde) probe used by most laboratories for all IGK-Kde rearrangements.2

Table 1 List of IGH and IGK probes assessed in patient-specific MRD tests
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Figure 1

References

  1. Flohr T, Schrauder A, Cazzaniga G, Panzer-Grümayer R, van der Velden V, Fischer S et al. Minimal residual disease (MRD)-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia (ALL). Leukemia 2008; 22: 771–782.

    Article  CAS  PubMed  Google Scholar 

  2. van der Velden VHJ, Willemse MJ, van der Schoot CE, Hahlen K, van Wering ER, van Dongen JJM et al. Immunoglobulin kappa deleting element rearrangements in precursor-B acute lymphoblastic leukemia are stable targets for detection of minimal residual disease by real-time quantitative PCR. Leukemia 2002; 16: 928–936.

    Article  CAS  PubMed  Google Scholar 

  3. Verhagen OJ, Willemse MJ, Breunis WB, Wijkhuijs AJ, Jacobs DC, Joosten SA et al. Application of germline IGH probes in real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia. Leukemia 2000; 14: 1426–1435.

    Article  CAS  PubMed  Google Scholar 

  4. Choi S, Henderson M, Kwan E, Beesley AH, Sutton R, Bahar AY et al. Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subclone. Blood 2007; 110: 632–639.

    Article  CAS  PubMed  Google Scholar 

  5. Kwan E, Norris MD, Zhu L, Ferrara D, Marshall GM, Haber M et al. Simultaneous detection and quantification of minimal residual disease in childhood acute lymphoblastic leukaemia using real-time polymerase chain reaction. Br J Haematol 2000; 109: 430–434.

    Article  CAS  PubMed  Google Scholar 

  6. van der Velden VHJ, Cazzaniga G, Schrauder A, Hancock J, Bader P, Panzer-Grümayer R et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: Guidelines for interpretation of real-time quantitative data. Leukemia 2007; 21: 604–611.

    Article  CAS  Google Scholar 

  7. Uchiyama M, Maesawa C, Yashima A, Itabashi T, Satoh T, Tarusawa M et al. Development of immunoglobulin variable heavy chain gene consensus probes with conjugated 3′ minor groove binder groups for monitoring minimal residual disease in childhood acute lymphoblastic leukaemia. J Clin Pathol 2003; 56: 952–955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. van der Velden VHJ, Wijkhuijs MJ, Jacobs DCH, van Wering ER, van Dongen JJM . T cell receptor gamma gene rearrangements as targets for detection of minimal residual disease in acute lymphoblastic leukemia by real-time quantitative PCR analysis. Leukemia 2002; 16: 1372–1380.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge the NH&MRC, the Cancer Council of NSW, private donors and the Leukaemia Foundation for their financial support of MRD studies and also the Australian and New Zealand Children's Haematology Oncology Group Study 8 committee and participating clinicians and the I-BFM-SG. Standardization and quality control for MRD testing is supported by the ESG-MRD-ALL. Children's Cancer Institute Australia for Medical Research is affiliated with both the University of New South Wales and Sydney Children's Hospital.

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Authors and Affiliations

  1. Children's Cancer Institute Australia for Medical Research, University of NSW, Sydney, Australia

    R Sutton, A Y Bahar, E Kwan, J E Giles, N C Venn, S Tran, N Hackenberg, G M Marshall, M Haber & M D Norris

  2. Oncology Unit, The Children's Hospital at Westmead, Sydney, Australia

    L Dalla Pozza

  3. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands

    V H J van der Velden

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  1. R Sutton
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  2. A Y Bahar
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  3. E Kwan
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  12. M D Norris
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Correspondence to R Sutton.

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Sutton, R., Bahar, A., Kwan, E. et al. Improving minimal residual disease detection in precursor B-ALL based on immunoglobulin-κ and heavy-chain gene rearrangements. Leukemia 22, 2265–2267 (2008). https://doi.org/10.1038/leu.2008.121

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