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Acute lymphoblastic leukemia

TCRα rearrangements identify a subgroup of NKL-deregulated adult T-ALLs associated with favorable outcome

Leukemia volume 32, pages 61–71 (2018)Cite this article

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) results from leukemic transformation of T-cell precursors arrested at specific differentiation stages, including an ‘early-cortical’ thymic maturation arrest characterized by expression of cytoplasmic TCRβ but no surface T-cell receptor (TCR) and frequent ectopic expression of the TLX1/3 NK-like homeotic proteins (NKL). We designed a TCRα VJC PCR to identify clonal TCRα rearrangements in 32% of 127 T-ALLs, including 0/52 immature/TCRγδ lineage cases and 41/75 (55%) TCRαβ lineage cases. Amongst the latter, TCRα rearrangements were not identified in 30/54 (56%) of IMβ/pre-αβ early-cortical T-ALLs, of which the majority (21/30) expressed TLX1/3. We reasoned that the remaining T-ALLs might express other NKL proteins, so compared transcript levels of 46 NKL in T-ALL and normal thymic subpopulations. Ectopic overexpression of 10 NKL genes, of which six are unreported in T-ALL (NKX2-3, BARHL1, BARX2, EMX2, LBX2 and MSX2), was detectable in 17/104 (16%) T-ALLs. Virtually all NKL overexpressing T-ALLs were TCRα unrearranged and ectopic NKL transcript expression strongly repressed Eα activity, suggesting that ectopic NKL expression is the major determinant in early-cortical thymic T-ALL maturation arrest. This immunogenetic T-ALL subtype, defined by TCRβ VDJ but no TCRα VJ rearrangement, is associated with a favorable outcome in GRAALL-treated adult T-ALLs.

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Acknowledgements

We thank all French, Swiss and Belgian participants, clinicians, biologists and clinical research assistants, in the GRAALL 2003-2005 trials for collecting and providing data and samples. We thank the IBiSA ‘Transcriptomics and Genomics Marseille-Luminy (TGML)’ platform for sequencing of RNAseq samples. We thank the tumorothèque plateform of Necker’s hospital APHP.

Author contributions

PV, EAM and VA wrote the manuscript. PV, CL, SLN, RBA, AC, AT, MB, ML, MT, AL and SP performed research and/or data analysis. NI, HD, AP and NB provided clinical material and data analysis from the GRAALL trials. VA oversaw conceptual development of the project.

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Author notes

  1. P Villarese and C Lours: These authors contributed equally to this work.

Authors and Affiliations

  1. Université Paris Descartes Sorbonne Cité, Institut Necker Enfants-Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, Paris, France,

    P Villarese, C Lours, A Trinquand, S Le Noir, M Belhocine, L Lhermitte, A Cieslak, M Tesio, E Macintyre & V Asnafi

  2. Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France

    P Villarese, C Lours, A Trinquand, M Belhocine, L Lhermitte & V Asnafi

  3. Aix Marseille Univ, INSERM, TAGC UMR1090, Marseille, France

    M Belhocine & S Spicuglia

  4. Department of Hematology and Oncologie Pédiatrique, Hôpital Trousseau Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France

    A Petit

  5. Laboratory of Cytogenetics, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France

    M LeLorch

  6. Department of Hematology, Centre Hospitalier, Angers, France

    N Ifrah

  7. Department of Hematology and Institut Universitaire d’Hématologie, University Paris 7, Hôpital Saint-Louis, AP-HP, Paris, France

    H Dombret & N Boissel

  8. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    A W Langerak

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  1. P Villarese
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Correspondence to V Asnafi.

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Villarese, P., Lours, C., Trinquand, A. et al. TCRα rearrangements identify a subgroup of NKL-deregulated adult T-ALLs associated with favorable outcome. Leukemia 32, 61–71 (2018). https://doi.org/10.1038/leu.2017.176

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