Abstract
BackgroundZinc-finger protein 384 (ZNF384) fusions are an emerging subtype of precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL) and here we further characterised their prevalence, survival outcomes and transcriptome.MethodsBone marrow mononuclear cells from 274 BCR-ABL1-negative pre-B-ALL patients were immunophenotyped and transcriptome molecularly characterised. Transcriptomic data was analysed by principal component analysis and gene-set enrichment analysis to identify gene and pathway expression changes.ResultsWe exclusively detect E1A-associated protein p300 (EP300)-ZNF384 in 5.7% of BCR-ABL1-negative adolescent/young adult (AYA)/adult pre-B-ALL patients. EP300-ZNF384 patients do not appear to be a high-risk subgroup. Transcriptomic analysis revealed that EP300-ZNF384 samples have a distinct gene expression profile that results in the up-regulation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) and cell adhesion pathways and down-regulation of cell cycle and DNA repair pathways.ConclusionsImportantly, this report contributes to a better overview of the incidence of EP300-ZNF384 patients and show that they have a distinct gene signature with concurrent up-regulation of JAK-STAT pathway, reduced expression of B-cell regulators and reduced DNA repair capacity.
Highlights
Many genomic lesions in precursor B-cell acute lymphoblastic leukaemia are associated with alterations of cytokine receptors or their signalling pathway mediators, transcription factors or regulators of differentiation.1,2 These lesions have prognostic significance, for example, ETV6-RUNX1 is associated with a relatively favourable outcome compared with poor-risk disease associated with BCR-ABL+ (Philadelphia-positive (Ph+)) orPh-like ALL
MATERIALS AND METHODS We studied 274 BCR-ABL1-negative pre-B-ALL patients (152 children, 54 adolescent/young adults (AYA, 16–39 years) and 68 adults) from the patient pool referred to us for Ph-like testing
In 7/9 patients the EP300ZNF384 fusion was detected at diagnosis, and in the one patient where matched diagnosis and relapse samples were available, the fusion was detected in both
Summary
Many genomic lesions in precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL) are associated with alterations of cytokine receptors or their signalling pathway mediators, transcription factors or regulators of differentiation. These lesions have prognostic significance, for example, ETV6-RUNX1 is associated with a relatively favourable outcome compared with poor-risk disease associated with BCR-ABL+ (Philadelphia-positive (Ph+)) orPh-like ALL. Many genomic lesions in precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL) are associated with alterations of cytokine receptors or their signalling pathway mediators, transcription factors or regulators of differentiation.. Many genomic lesions in precursor B-cell acute lymphoblastic leukaemia (pre-B-ALL) are associated with alterations of cytokine receptors or their signalling pathway mediators, transcription factors or regulators of differentiation.1,2 These lesions have prognostic significance, for example, ETV6-RUNX1 is associated with a relatively favourable outcome compared with poor-risk disease associated with BCR-ABL+ (Philadelphia-positive (Ph+)) or. CONCLUSIONS: Importantly, this report contributes to a better overview of the incidence of EP300-ZNF384 patients and show that they have a distinct gene signature with concurrent up-regulation of JAK-STAT pathway, reduced expression of B-cell regulators and reduced DNA repair capacity
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