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Absence of microsatellite instability in human chronic lymphocytic leukaemia B cells

Leukemia volume 22, pages 186–189 (2008)Cite this article

Tumours with microsatellite instability (MSI) exhibit a mutator phenotype and consequently disclose inactivating mutations or epigenetic silencing of post-replicative DNA mismatch repair (MMR) genes, predominantly MSH2 and MLH1.1 Microsatellite (MS)-repeated motifs are highly prone to insertion or deletion during DNA replication. In MMR-deficient tumours, oncogenesis has been attributed to the accumulation of frame shift mutations in coding MS located in genes playing a role in cell proliferation, cell cycle checkpoints and apoptosis. MSI may also occur through an excess in the activity of 3-methyladenine DNA glycosylase and apurinic endonuclease (APE1), enzymes involved in base-excision repair.2 Numerous MSI target genes are essential in DNA repair such as DNA-PKcs, ATR, RAD50 and MRE11,3 and some are involved in non-homologous end-joining repair (NHEJ), a DNA repair pathway that we previously showed to be altered in the aggressive subset of chronic lymphocytic leukaemia (CLL).4

MSI phenotyping could be adequately performed since germline DNA was successfully amplified with the five markers of the pentaplex assay: NR27, NR21, NR24, BAT25 and BAT26. Polymorphisms at these loci are rare and have been well-characterized among different populations worldwide in a study showing that tumour MSI can be determined for all human populations using this panel of markers without the need for matching normal DNA.12 Because the five mononucleotide repeats are all located outside the coding sequences, being in the 5′UTR sequences (NR21 and NR27), 3′UTR sequences (NR24) or introns (BAT25 and BAT26), their mutations are unlikely to be selected in MSI tumours. Thus, these markers should display high levels of instability in tumours originating from other tissues, making this method appropriate to detect MSI in haematological tumours, as previously shown with the BAT25 and BAT26 markers.8 The fact that several genes targeted by MSI in haematological tumours are also inactivated in MSI gastrointestinal tumours, including BAX, further strengthens the possibility to use the pentaplex method to efficiently detect MSI in CLL. Inactivating mutations of BAX occurring in half of colorectal MSI tumours decrease apoptosis in these tumours, which frequently overexpress Bcl-2.13 Likewise, MSI-driven BAX mutations could have been expected in CLL overexpressing Bcl-2.

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Acknowledgements

We thank the leukaemia patients who voluntarily gave blood samples. We also thank Sylvie Baudet for her technical assistance. Our research work is supported by grants from ARC to FP and JD and CEA and EDF to JD.

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Authors and Affiliations

  1. INSERM, U762, Paris, France

    F Praz

  2. Université Pierre et Marie Curie-Paris6, Paris, France

    F Praz, L Vallat, F Davi, F Nguyen-Khac & H Merle-Béral

  3. Laboratoire d'Onco-Hematologie, CEA/iRCM, Fontenay aux Roses, France

    F Le Page & J Delic

  4. Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière, Paris, France

    L Vallat, F Davi, F Nguyen-Khac, K Maloum & H Merle-Béral

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Correspondence to J Delic or H Merle-Béral.

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Praz, F., Le Page, F., Vallat, L. et al. Absence of microsatellite instability in human chronic lymphocytic leukaemia B cells. Leukemia 22, 186–189 (2008). https://doi.org/10.1038/sj.leu.2404889

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