Abstract
Simple SummaryDUX4-rearrangement (DUX4r) is a recently discovered recurrent genomic lesion reported in 4–7% of childhood B cell acute lymphoblastic leukaemia (B-ALL) cases. This subtype has favourable outcomes, especially in children and adolescents treated with intensive chemotherapy. The fusion most commonly links the hypervariable IGH gene to DUX4 a gene located within the D4Z4 macrosatellite repeat on chromosome 4. DUX4r is cryptic to most standard diagnostic techniques, and difficult to identify even with next generation sequencing assays. This review summarises the clinical features and molecular genetics of DUX4r B-ALL and proposes prospective new diagnostic methods.DUX4-rearrangement (DUX4r) is a recently discovered recurrent genomic lesion reported in 4–7% of childhood B cell acute lymphoblastic leukaemia (B-ALL) cases. This subtype has favourable outcomes, especially in children and adolescents treated with intensive chemotherapy. The fusion most commonly links the hypervariable IGH gene to DUX4 a gene located within the D4Z4 macrosatellite repeat on chromosome 4, with a homologous polymorphic repeat on chromosome 10. DUX4r is cryptic to most standard diagnostic techniques, and difficult to identify even with next generation sequencing assays. This review summarises the clinical features and molecular genetics of DUX4r B-ALL and proposes prospective new diagnostic methods.
Highlights
B-cell acute lymphoblastic leukaemia (B-ALL) is a malignant disorder of the bone marrow resulting in over proliferation of immature B lymphoblasts
Cytogenetic analysis has proven adept at identifying several recurrent genomic alterations which result in diseases with distinct gene expression profiles (GEP) and defined prognosis
Similar experiments conducted with Reh cells transfected with patient-derived constructs of the DUX4-immunoglobulin heavy chain (IGH) fusion confirm this finding [43] and suggest that alteration of the C-terminus of DUX4-IGH attenuates the transcription inducing ability compared to wild-type DUX4 (WT DUX4)
Summary
B-cell acute lymphoblastic leukaemia (B-ALL) is a malignant disorder of the bone marrow resulting in over proliferation of immature B lymphoblasts. Cytogenetic analysis has proven adept at identifying several recurrent genomic alterations which result in diseases with distinct gene expression profiles (GEP) and defined prognosis. This includes high hyperdiploidy, hypodiploidy, and the translocations t(12;21) [ETV6-RUNX1], t(9;22) BCR-ABL1, t(1;19). Molecular studies involving GEP and next-generation sequencing (NGS) have subsequently identified a number of additional recurrent molecular alterations not detectable with standard cytogenetics, several of which may be targetable by precision medicine approaches This includes the newly recognized subtype of Philadelphia chromosome-like (Ph-like) ALL characterized by a gene expression profile similar to cases with a BCR-ABL1 translocation, but instead carrying one of multiple kinase activating lesions. We further explore the continued difficulties associated with detection of this alteration in new patient samples and discuss the impact this may have on the accurate assessment of prognosis and subsequent therapy options
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