Fiche publication
Date publication
juin 2026
Journal
HemaSphere
Auteurs
Membres identifiés du Cancéropôle Est :
Dr SEXTON Thomas
Tous les auteurs :
Kim R, Passet M, Bergugnat H, Vasseur L, Leguay T, Huguet F, Hunault M, Sexton T, Benlebna M, Renard J, Raffoux E, Pastoret C, Erb C, Chat L, Delabesse E, Gachet S, Bonmati C, Balsat M, Braun T, Bidet A, Duployez N, Graux C, Chalandon Y, Rousselot P, Chevallier P, Soulier J, Lhéritier V, Dombret H, Boissel N, Clappier E
Lien Pubmed
Résumé
B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous malignancy driven by diverse genetic alterations. Among these, family genes and are recurrently involved, yet the spectrum of genomic mechanisms and their clinical impact remain incompletely defined. Integrated genomic analyses of a cohort of 992 Philadelphia-negative adult B-ALL patients revealed multiple mechanisms of enhancer hijacking-mediated deregulation of , , , and , including and several non- fusions, as well as noncoding mutations in regulatory regions. Combined with gene expression analysis, we identified three distinct subtypes, defined by co-occurring and p.H1038R alterations (CEBP/ZEB2, = 18 cases); isolated alterations (CEBPalt, = 43), associated with frequent deletions and deregulation; and isolated p.H1038R mutation (ZEB2alt, = 15), associated with various additional genomic hits targeting and enhancing mutant expression. The three subtypes exhibited distinct clinical features, including age distribution (patients with CEBP/ZEB2 and ZEB2alt B-ALL were younger) and sex bias (female and male predominance in CEBPalt and ZEB2alt, respectively). Early treatment responses and outcomes also differed: patients with CEBP/ZEB2 B-ALL had a favorable early response, in contrast to patients with ZEB2alt B-ALL, who had high levels of minimal residual disease and a dismal prognosis. Collectively, our findings define and alterations as drivers of genetically and clinically distinct subtypes of adult B-ALL and provide a rationale for subtype-specific risk stratification. Preclinical experiments in CEBPalt B-ALL patient-derived xenografts demonstrated sensitivity to FLT3 inhibition, highlighting a potential therapeutic vulnerability.
Référence
Hemasphere. 2026 06;10(6):e70383
