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Single-cell genomics details the maturation block in BCP-ALL and identifies therapeutic vulnerabilities in DUX4-r cases.
Blood
September 2024
Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy and is driven by multiple genetic alterations that cause maturation arrest and accumulation of abnormal progenitor B cells. Current treatment protocols with chemotherapy have led to favorable outcomes but are associated with significant toxicity and risk of side effects, highlighting the necessity for highly effective, less toxic, targeted drugs, even in subtypes with a favorable outcome. Here, we used multimodal single-cell sequencing to delineate the transcriptional, epigenetic, and immunophenotypic characteristics of 23 childhood BCP-ALLs belonging to the BCR::ABL1+, ETV6::RUNX1+, high hyperdiploid, and recently discovered DUX4-rearranged (DUX4-r) subtypes.
View Article and Find Full Text PDFDUX4-r exerts a neomorphic activity that depends on GTF2I in acute lymphoblastic leukemia.
Sci Adv
September 2023
Gene Expression and Muscular Dystrophy Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milano, Italy.
Translocations producing rearranged versions of the transcription factor double homeobox 4 (DUX4-r) are one of the most frequent causes of B cell acute lymphoblastic leukemia (B-ALL). DUX4-r retains the DNA binding domain of wild-type DUX4 but is truncated on the C-terminal transcription activation domain. The precise mechanism through which DUX4-r causes leukemia is unknown, and no targeted therapy is currently available.
View Article and Find Full Text PDFTranscription factor abnormalities in B-ALL leukemogenesis and treatment.
Trends Cancer
October 2023
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Rui-Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200025, China. Electronic address:
The biological regulation of transcription factors (TFs) and repressor proteins is an important mechanism for maintaining cell homeostasis. In B cell acute lymphoblastic leukemia (B-ALL) TF abnormalities occur at high frequency and are often recognized as the major driving factor in carcinogenesis. We provide an in-depth review of molecular mechanisms of six major TF rearrangements in B-ALL, including DUX4-rearranged (DUX4-R), MEF2D-R, ZNF384-R, ETV6-RUNX1 and TCF3-PBX1 fusions, and KMT2A-R.
View Article and Find Full Text PDFIntegrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial.
Leukemia
March 2023
Leukaemia Research Cytogenetics Group, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, UK.
Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003.
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