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Free keywords:
Animals
Antineoplastic Agents/pharmacology/therapeutic use
B-Cell-Specific Activator Protein/genetics
Coculture Techniques
Cohort Studies
DNA Mutational Analysis
Drug Resistance, Neoplasm
Female
Gene Expression
Genetic Association Studies
Genomics
Humans
Immunoglobulin Light Chains, Surrogate/genetics
Inhibitory Concentration 50
Kaplan-Meier Estimate
Male
Mice, Inbred NOD
Mice, SCID
Mutation
Oncogene Proteins, Fusion/*genetics/metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics/mortality
Sequence Deletion
Xenograft Model Antitumor Assays
Abstract:
TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.
