Concurrent CDX2 cis -deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL - Archive ouverte HAL Access content directly
Journal Articles Blood Year : 2022

Concurrent CDX2 cis -deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL

Marie Passet
  • Function : Author
Rathana Kim
  • Function : Author
Stéphanie Gachet
  • Function : Author
François Sigaux
  • Function : Author
Julie Chaumeil
  • Function : Author
Samuel Quentin
  • Function : Author
Lucie Hernandez
  • Function : Author
Lise Larcher
  • Function : Author
Hugo Bergugnat
  • Function : Author
Nezih Karasu
  • Function : Author
Aurélie Caye
  • Function : Author
Patrice Chevallier
  • Function : Author
Philippe Rousselot
  • Function : Author
Françoise Huguet
  • Function : Author
Thibaut Leguay
  • Function : Author
Mathilde Hunault
  • Function : Author
Françoise Pflumio
  • Function : Author
Camille Lobry
  • Function : Author
Véronique Lhéritier
  • Function : Author
Hervé Dombret
  • Function : Author
Jean Soulier
  • Function : Author
Nicolas Boissel
  • Function : Author
Emmanuelle Clappier
  • Function : Author

Abstract

Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing 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 2 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-sequencing 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- B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). 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% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10-4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .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.

Domains

Cancer
Fichier principal
Vignette du fichier
islandora_156419.pdf (3.17 Mo) Télécharger le fichier
Origin : Publication funded by an institution

Dates and versions

hal-03788702 , version 1 (04-10-2022)

Identifiers

Cite

Marie Passet, Rathana Kim, Stéphanie Gachet, François Sigaux, Julie Chaumeil, et al.. Concurrent CDX2 cis -deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL. Blood, 2022, 139 (24), pp.3505-3518. ⟨10.1182/blood.2021014723⟩. ⟨hal-03788702⟩
74 View
26 Download

Altmetric

Share

Gmail Facebook X LinkedIn More