Fiche publication
Date publication
mars 2022
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DOMON-DELL Claire
,
Dr DULUC Isabelle
,
Dr FREUND Jean-Noël
,
Dr SEXTON Thomas
,
Dr HEIZMANN Beate
Tous les auteurs :
Passet M, Kim R, Gachet S, Sigaux F, Chaumeil J, Galland A, Sexton T, Quentin S, Hernandez L, Larcher L, Bergugnat H, Ye T, Karasu N, Caye-Eude A, Heizmann B, Duluc I, Chevallier P, Rousselot P, Huguet F, Leguay TT, Hunault-Berger MM, Pflumio F, Freund JN, Lobry C, Lheritier V, Dombret H, Domon-Dell C, Soulier J, Boissel N, Clappier E
Lien Pubmed
Résumé
Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA-seq and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of two genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-seq and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n=26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph-negative B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n=17/723, 2.4%) were frequently young women (M/F ratio 0.2, P=0.002, median age 31 years). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% versus 3%, P=0.017) and higher post-induction MRD levels (MRD ≥ 10-4, 93%, versus 46%, P<0.001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% versus 32.4%, P=0.004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults. Study can be found on https://clinicaltrials.gov NCT00327678 and NCT02617004.
Référence
Blood. 2022 Mar 22;: