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Activating mutation in the TSLPR gene in B-cell precursor lymphoblastic leukemia

Leukemia volume 24, pages 642–645 (2010)Cite this article

Genomic and expression analyses of human B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have uncovered several oncogenic events that contribute to the transformation of B-cell progenitors.1 Besides BCR-ABL1, mutations and rearrangements detected in BCP-ALL predominantly affect genes coding for transcriptional regulators involved in the control of early hematopoietic differentiation, B-cell development or both. Activating mutations in the JAK2 gene that targets the R683 residue2, 3, 4 have been recently suggested to cooperate with the transcriptional activation of the gene coding for the cytokine receptor chain gene TSLPR/CRLF2.5 TSLPR codes for a cytokine receptor chain related to γc/IL2Rc. Both chains are able to interact with IL7R to constitute the receptor for IL7 (γc+IL7R) or TSLP (TSLPR+IL7R). Signaling from the IL7 receptor is known to involve JAK1 and JAK3 whereas intracellular signaling by the TSLP receptor is poorly characterized.6 In BCP-ALL, aberrant expression of TSLPR itself occurs through either a cryptic chromosomal translocation between the TSLPR locus (Xp22/Yp11) and the immunoglobulin heavy-chain locus (14q32) or through a deletion of chromosome X or Y pseudoautosomal sequences juxtaposing the P2RY8 gene to TSLPR.5 Sox5 upregulation through juxtaposition to the P2RY8 promoter has been previously reported in lymphoma.7

Activation of the JAK–STAT pathway through an activating mutation of the JAK2 gene, JAK2V617F, has been described in human myeloproliferative neoplasms (MPN).8 In a proportion of MPN patients, primitive myelofibrosis and essential thrombocytemia, mutations targeting the W515 residue of MPL, the homodimeric receptor chain for TPO, have been observed.9 Wild-type (WT) MPL intracellular signaling activates the JAK–STAT pathway through JAK2. The mutant MPL experimentally leads to a constitutive activation of the JAK–STAT pathway. In a subset of patients, MPL mutations are associated to JAK2V617F. This situation presumably represents oncogenic cooperation leading to a stronger JAK–STAT activity than either JAK2 or MPL mutation alone.9

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Acknowledgements

This work was supported by INSERM, INCa, Leukaemia Research UK, ANR MRAR and the Ligue Nationale Contre le Cancer (Equipe labellisée, PD and OAB). We thank Dr Kitamura for gifting the TSLPR cDNA.

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Author notes

  1. E Chapiro, L Russell and E Lainey: These authors contributed equally to this work

Authors and Affiliations

  1. INSERM E210, Hôpital Necker, Paris, France

    E Chapiro, E Lainey, S Kaltenbach, C Ragu, V Della-Valle, I Radford-Weiss, T Mercher & O A Bernard

  2. Université Paris Descartes, Paris, France

    E Chapiro, S Kaltenbach, C Ragu, V Della-Valle, E A Macintyre, T Mercher & O A Bernard

  3. Service d’Hématologie Biologique, Hôpital Pitié-Salpêtrière,

    E Chapiro & F Nguyen-Khac

  4. INSERM U872, Université Pierre et Marie Curie-Paris 6, Paris, France

    E Chapiro & F Nguyen-Khac

  5. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle, UK

    L Russell & C J Harrison

  6. APHP, Service d’Hématologie Biologique, Hôpital Robert Debré, Université Paris 7-Denis Diderot, Paris, France

    E Lainey

  7. INSERM U891, Laboratoire de Signalisation, Hématopoïèse et Mécanisme de l’Oncogenèse, Centre de Recherche en Cancérologie de Marseille, Marseille, France

    K Hanssens & P Dubreuil

  8. Centre de référence des mastocytoses, Marseille, France

    K Hanssens & P Dubreuil

  9. Institut Paoli-Calmettes, Marseille, France

    K Hanssens & P Dubreuil

  10. Université de la Méditerranée, Marseille, France

    K Hanssens & P Dubreuil

  11. Hôpital Necker-Enfants Malades, Paris, France

    E A Macintyre

  12. Service de cytogénétique, Hôpital Necker-Enfants Malades, Paris, France

    I Radford-Weiss

  13. Laboratoire d’Hématologie, INSERM U563, Université Toulouse III, CHU Purpan, Toulouse, France

    E Delabesse

  14. Département de Génétique, APHP, Hôpital Robert Debré, Université Paris 7-Denis Diderot, Paris, France

    H Cavé

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  1. E Chapiro
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Correspondence to O A Bernard.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Chapiro, E., Russell, L., Lainey, E. et al. Activating mutation in the TSLPR gene in B-cell precursor lymphoblastic leukemia. Leukemia 24, 642–645 (2010). https://doi.org/10.1038/leu.2009.231

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