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Acute Leukemias

PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study

Leukemia volume 23, pages 1989–1998 (2009)Cite this article

Abstract

Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count.

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Acknowledgements

We thank the financial support of the association Laurette-Fugain. JF was supported by an ARC fellowship. CB and NPH were supported by a grant of Institut National du Cancer. ED, CB and PB were supported by the CITTIL (Cooperacion de investigacion transpirenaica en la terapia innovadora de la leucemia).

This work would not have been possible without the help of all the people who take care of the patients involved in the GRAALL studies, especially the centers that contributed directly to this study. Amiens: Damaj, Royer, Dubus, Capiod, Marolleau; Angers: Francois, Hunault, Ifrah, Marie, Genevieve, Baranger, Chassevent, Blanchet; Avignon: Boulat, Derre; Bayonne: Banos, Bauduer, Burtin; Bobigny: Gardin, Fenaux, Beve, Boulalam, Eclache, Fenaux; Bordeaux: Boiron, Leguay, Pigneux, Bilhou-Nabera, Perry, Lacombe, Tabrizi, Lippert, Marit; Brest: Guillerme, Berthou, Lecalvez, De Braekeleer, Ugo; Caen: Reman, Lepesant, Salaun, Plessis, Naguib, Leporrier; Clamart: De Revel, Samson, Desangles; Clermont-Ferrand: Chaleteix, Villemagne, Latiere, Berger, Giollant, Tchirkov, Tournilhac; Dijon: Caillot, Casanovas, Grandjean, Menadier, Favre-Audry, Mugneret, Teyssier; Lens: Stalnikiewicz, Poulain; Lille: Darre, De Botton, Lepelley, Lai, Soenen, Preudhomme, Grardel, Bauters; Limoges: Turlure, Bordessoule, Chaury, Trimoreau, Gachard; Lyon: Le, Nicolini, Tavernier, Thiebaut, Thomas, Lheritier, Girard, Wattel, Tigaud, Hayette, Michallet; Marseille: Vey, Charbonnier, Stoppa, Mouton, Sainty, Moziconacci, Arnoulet, Lafage-Pochitaloff, Blaise; Meaux: Frayfer, Mossafa; Mulhouse: Arkam, Ojeda Uribe, Iglarz, Drenou, Jeandidier, Isaac; Nancy: Witz, Bene, Witz, Gregoire, Monhoven; Necker: Buzyn, Couderc, Asnafi, Valensi, Radford-Weiss, Delabesse, Macintyre, Varet; Paris Pitié-Salpétrière: Dhedin, Aliammar, Merle-Beral, Nguyen-Khac, Davi, Leblond, Vernant; Paris Saint-Louis: Raffoux, Treilhou, Maarek, Daniel, Soulier, Cayuela, Miclea, de Labarthe, Dombret; Reims: Himberlin, Baury, Daliphard, Luquet, Cornillet-Lefebvre, Delmer; Rennes: Escoffre-Barbe, Lamy, Picouleau, Roussel, Henry, Ly Sunnaram, Fest; Rouen: Lepretre, Contentin, Jardin, Lenain, Tilly, Tallon, Lenormand, Stamatoullas-Bastard, Penther, Bastard; Saint-Etienne: Cornillon, Jaubert, Guyotat, Marchand, Campos, Nadal, Flandrin; Toulon: De Jaurreguiberry; Toulouse: Huguet, Recher, Daniel, Kuhlein, Dastugue, Demas, Attal; Tours: Delain, Delepine, Degene, Barin, Colombat; Valenciennes: Fernandes, Poulain, Daudignon; Versailles: Choquet, Rousselot, Taksin, Pousset, Terre, Castaigne; Villejuif: Arnaud, Bayle, Bourhis, Auger, Bernheim.

Among these participants, we specially acknowledge the following cytogeneticists that provided cytogenetic pellets and data to perform PAX5 and TCF3 FISH analyses, Eric Lippert (Bordeaux), Odile Maarek (Paris Saint-Louis), Christian Bastard and Dominique Penther (Rouen), Isabelle Tigaud (Lyon), Florence Nguyen-Khac (Paris Pitié-Salpétrière), Christine Terré (Versailles) and Ghislaine Plessis (Caen). We thank the extended FISH analysis of Francesca Correia (Toulouse).

The design and analysis of the experiments were performed by ED and CB. JF performed the PAX5 quantitative PCR. MB cloned and analyzed the PAX5-ELN case. They cloned the PAX5 mutants helped by ND, SS, EC, CQ, NPH and SD. ED, CB and PB overviewed the results. The cytogenetic results were collected and analyzed by MLP and ND. FISH analyses were performed by MLP and CB. The immunophenotype results were collected by MCB. The molecular data were collected by EAM and ED. KB performed VHDHJH sequence analysis. JDV performed the microarray analysis. JMC, NG, CP, HC, OB, KB and EAM provided DNA samples. VL collected clinical data, reviewed by YC, NI, AD, AP, FH and HD. Paper was written by ED, CB, JF and HD.

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Author notes

  1. J Familiades, M Bousquet, C Broccardo and É Delabesse: J Familiades and M Bousquet contributed equally to this work as first authors; C Broccardo and É Delabesse contributed equally to this work as senior authors.

Authors and Affiliations

  1. INSERM U563, Toulouse, France

    J Familiades, M Bousquet, N Dastugue, E Coyaud, C Quelen, N Prade-Houdellier, P Brousset, C Broccardo & É Delabesse

  2. Centre de Physiopathologie Toulouse Purpan, Université Toulouse III Paul Sabatier, Toulouse, France

    J Familiades, M Bousquet, E Coyaud, C Quelen, N Prade-Houdellier, P Brousset, C Broccardo & É Delabesse

  3. Department of Genetics, CHU Timone, Marseilles, France

    M Lafage-Pochitaloff

  4. Department of Immunology, CHU Nancy, Nancy, France

    M-C Béné

  5. Department of Hematology, CHU Necker, Paris, France

    K Beldjord & E A Macintyre

  6. INSERM U847, Montpellier, France

    J De Vos

  7. Biothérapie des cellules souches normales et cancéreuses, Université Montpellier I, Montpellier, France

    J De Vos

  8. Department of Hematology, CHU Toulouse, Toulouse, France

    N Dastugue, S Struski, S Dobbelstein, F Huguet & É Delabesse

  9. Department of Hematology, CHU Saint-Louis, Paris, France

    J-M Cayuela, J Soulier & H Dombret

  10. Department of Hematology, CHU Lille, Lille, France

    N Grardel & C Preudhomme

  11. Department of Genetics, CHU Robert-Debré, Paris, France

    H Cavé

  12. Department of Hematology, CHU Angers, Angers, France

    O Blanchet & N Ifrah

  13. GRAALL, CHU Lyon, Lyons, France

    V Lhéritier

  14. Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    A Delannoy

  15. Division of Hematology, Hôpital Universitaire, Geneva, Switzerland

    Y Chalandon

  16. Department of Hematology, CHU Bordeaux, Bordeaux, France

    A Pigneux

  17. Department of Pathology, CHU Toulouse, Toulouse, France

    P Brousset

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  1. J Familiades
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  2. M Bousquet
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  3. M Lafage-Pochitaloff
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  4. M-C Béné
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  6. J De Vos
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  27. H Dombret
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  28. C Broccardo
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  29. É Delabesse
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Corresponding author

Correspondence to É Delabesse.

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

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Familiades, J., Bousquet, M., Lafage-Pochitaloff, M. et al. PAX5 mutations occur frequently in adult B-cell progenitor acute lymphoblastic leukemia and PAX5 haploinsufficiency is associated with BCR-ABL1 and TCF3-PBX1 fusion genes: a GRAALL study. Leukemia 23, 1989–1998 (2009). https://doi.org/10.1038/leu.2009.135

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