B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy and is driven by multiple genetic alteratio
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. Projection of the ALL cells along the normal hematopoietic differentiation axis revealed a diversity in the maturation pattern between the different BCP-ALL subtypes. Although the BCR::ABL1+, ETV6::RUNX1+, and high hyperdiploidy cells mainly showed similarities to normal pro-B cells, DUX4-r ALL cells also displayed transcriptional signatures resembling mature B cells. Focusing on the DUX4-r subtype, we found that the blast population displayed not only multilineage priming toward nonhematopoietic cells, myeloid, and T-cell lineages, but also an activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling that sensitized the cells to PI3K inhibition in vivo. Given the multilineage priming of DUX4-r blasts with aberrant expression of myeloid marker CD371 (CLL-1), we generated chimeric antigen receptor T cells, which effectively eliminated DUX4-r ALL cells in vivo. These results provide a detailed characterization of BCP-ALL at the single-cell level and reveal therapeutic vulnerabilities in the DUX4-r subtype, with implications for the understanding of ALL biology and new therapeutic strategies.
Lund University, Profile areas and other strong research environments, Other Strong Research Environments, LUCC: Lund University Cancer Centre, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Övriga starka forskningsmiljöer, LUCC: Lunds universitets cancercentrum, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, Translational Genomic and Functional Studies of Leukemia, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, Translationella genomiska och funktionella studier av leukemi, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, Targeted therapies in leukemia, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, Målinriktade behandlingar för leukemi, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, Aneuploidy in cancer, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, Aneuploidi i cancer, Originator, Lund University, Faculty of Medicine, WCMM-Wallenberg Centre for Molecular Medicine, Lunds universitet, Medicinska fakulteten, WCMM- Wallenberg center för molekylär medicinsk forskning, Originator, Lund University, Profile areas and other strong research environments, Strategic research areas (SRA), StemTherapy: National Initiative on Stem Cells for Regenerative Therapy, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Strategiska forskningsområden (SFO), StemTherapy: National Initiative on Stem Cells for Regenerative Therapy, Originator, Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Section V, Paediatrics (Lund), Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Sektion V, Pediatrik, Lund, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Molecular Hematology (DMH), Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för molekylär hematologi, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, Synthetic Immunology, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, Syntetisk immunologi, Originator, Lund University, Faculty of Medicine, Department of Laboratory Medicine, Division of Clinical Genetics, The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, Avdelningen för klinisk genetik, MLL-rearrangerad leukemi hos spädbarn, Originator, Lund University, Faculty of Engineering, LTH, LTH Profile areas, LTH Profile Area: Engineering Health, Lunds universitet, Lunds Tekniska Högskola, LTH profilområden, LTH profilområde: Teknik för hälsa, Originator
