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

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

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subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS HETEROGENEITY OF _IKZF1_ GENOMIC ALTERATIONS AND RISK OF RELAPSE IN CHILDHOOD B-CELL PRECURSOR

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Open access 22 December 2022 PROGNOSTIC IMPACT OF CHROMOSOMAL ABNORMALITIES AND COPY NUMBER ALTERATIONS IN ADULT B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKAEMIA: A UKALL14 STUDY Article Open

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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. AUTHOR INFORMATION Author notes * 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 * INSERM U563, Toulouse, France J Familiades, M Bousquet, N Dastugue, E

Coyaud, C Quelen, N Prade-Houdellier, P Brousset, C Broccardo & É Delabesse * 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 * Department of Genetics, CHU Timone, Marseilles, France M Lafage-Pochitaloff *

Department of Immunology, CHU Nancy, Nancy, France M-C Béné * Department of Hematology, CHU Necker, Paris, France K Beldjord & E A Macintyre * INSERM U847, Montpellier, France J De Vos *

Biothérapie des cellules souches normales et cancéreuses, Université Montpellier I, Montpellier, France J De Vos * Department of Hematology, CHU Toulouse, Toulouse, France N Dastugue, S

Struski, S Dobbelstein, F Huguet & É Delabesse * Department of Hematology, CHU Saint-Louis, Paris, France J-M Cayuela, J Soulier & H Dombret * Department of Hematology, CHU Lille,

Lille, France N Grardel & C Preudhomme * Department of Genetics, CHU Robert-Debré, Paris, France H Cavé * Department of Hematology, CHU Angers, Angers, France O Blanchet & N Ifrah *

GRAALL, CHU Lyon, Lyons, France V Lhéritier * Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium A Delannoy * Division of Hematology, Hôpital Universitaire,

Geneva, Switzerland Y Chalandon * Department of Hematology, CHU Bordeaux, Bordeaux, France A Pigneux * Department of Pathology, CHU Toulouse, Toulouse, France P Brousset Authors * J

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FIGURE S5 (DOC 31 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 04 September 2008 * Revised: 17 March 2009 * Accepted: 05 May 2009 * Published: 09 July 2009 * Issue

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shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * BCP-ALL * oncogenesis * BCR-ABL1

* PAX5 * TCF3-PBX1