2. Academic Validation
  3. CEBP and ZEB2 alterations define three distinct subtypes of B-cell acute lymphoblastic leukemia

CEBP and ZEB2 alterations define three distinct subtypes of B-cell acute lymphoblastic leukemia

  • Hemasphere. 2026 Jun 15;10(6):e70383. doi: 10.1002/hem3.70383.
Rathana Kim 1 2 3,  Marie Passet 1 2 3,  Hugo Bergugnat 1 3,  Loïc Vasseur 1 3 4,  Thibaut Leguay 5,  Françoise Huguet 6,  Mathilde Hunault 7,  Tom Sexton 8,  Melha Benlebna 1 3,  Julie Renard 2 3,  Emmanuel Raffoux 3 4,  Cédric Pastoret 9,  Cathie Erb 8,  Laureen Chat 1 2 3,  Eric Delabesse 10,  Stéphanie Gachet 1 3,  Caroline Bonmati 11,  Marie Balsat 12,  Thorsten Braun 13,  Audrey Bidet 14,  Nicolas Duployez 15,  Carlos Graux 16,  Yves Chalandon 17 18,  Philippe Rousselot 19,  Patrice Chevallier 20,  Jean Soulier 1 2 3,  Véronique Lhéritier 21,  Hervé Dombret 1 3 4,  Nicolas Boissel 1 3 4,  Emmanuelle Clappier 2
Affiliations

Affiliations

  • 1 Université Paris Cité, Inserm UMR 1342, Institut de Recherche Saint-Louis (IRSL) Paris France.
  • 2 Laboratoire d'Hématologie AP-HP, hôpital Saint-Louis Paris France.
  • 3 The Leukemia Institute Paris Saint-Louis Paris France.
  • 4 Service d'Hématologie AP-HP, hôpital Saint-Louis Paris France.
  • 5 Service d'Hématologie CHU de Bordeaux, hôpital du Haut-Levêque Pessac France.
  • 6 Service d'Hématologie Institut Universitaire de Cancer Toulouse-Oncopole, CHU de Toulouse Toulouse France.
  • 7 Service d'Hématologie CHU Angers, FHU GOAL, Université d'Angers, Université de Nantes, INSERM, CNRS, CRCI2NA, SFR ICAT Angers France.
  • 8 Université de Strasbourg, Institute of Genetics and Molecular and Cellular Biology (IGBMC), CNRS UMR 7104, INSERM U1258 Illkirch France.
  • 9 Laboratoire d'Hématologie Centre Hospitalier Universitaire de Rennes Rennes France.
  • 10 Laboratoire d'Hématologie Institut Universitaire du Cancer de Toulouse-Oncopole Toulouse France.
  • 11 Service d'Hématologie CHU de Nancy Nancy France.
  • 12 Service d'Hématologie Hospices Civils de Lyon, Hôpital Lyon Sud Pierre Benite France.
  • 13 Service d'Hématologie hôpital Avicenne, AP-HP Bobigny France.
  • 14 Laboratoire d'Hématologie CHU de Bordeaux, hôpital du Haut-Levêque Pessac France.
  • 15 Laboratoire d'Hématologie Centre Hospitalier Régional Universitaire de Lille Lille France.
  • 16 Service d'Hématologie CHU UCL Namur Godinne Yvoir Belgium.
  • 17 Division of Hematology, Department of Oncology Geneva University Hospitals and Faculty of Medicine University of Geneva Geneva Switzerland.
  • 18 Leukemia Project Group Swiss Group for Clinical Cancer Research (SAKK) Bern Switzerland.
  • 19 Service d'Hématologie Centre Hospitalier de Versailles, Unité mixte de recherche 1274 Commissariat à l'Energie Atomique, University de Versailles Paris-Saclay Le Chesnay France.
  • 20 Service d'Hématologie Hôtel-Dieu - CHU de Nantes Nantes France.
  • 21 Coordination du Groupe GRAALL, Member of the French Institute Carnot OPALE (the Organisation for Partnership in Leukemia Consortium), Hospices Civils de Lyon, Hôpital Lyon Sud Pierre Benite France.
PMID: 42306066 DOI: 10.1002/hem3.70383
Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous malignancy driven by diverse genetic alterations. Among these, CEBP family genes and ZEB2 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 CEBPA, CEBPB, CEBPD, and CEBPE, including IGH and several non-IGH fusions, as well as noncoding mutations in regulatory regions. Combined with gene expression analysis, we identified three distinct subtypes, defined by co-occurring CEBP and ZEB2 p.H1038R alterations (CEBP/ZEB2, n = 18 cases); isolated CEBP alterations (CEBPalt, n = 43), associated with frequent IKZF1 deletions and FLT3 deregulation; and isolated ZEB2 p.H1038R mutation (ZEB2alt, n = 15), associated with various additional genomic hits targeting ZEB2 and enhancing mutant ZEB2 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 CEBP and ZEB2 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.

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