Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia
Copyright policy )Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia
Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR(+) ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR(+) ALL.
- University of Pennsylvania United States
- University of Oxford United Kingdom
- Cornell University United States
- The University of Texas System United States
- The University of Texas MD Anderson Cancer Center United States
Cancer Research, Childhood Leukemia, Pediatric Cancer, Precursor Cells, Oncology and Carcinogenesis, Molecular Sequence Data, Vaccine Related, Rare Diseases, Proto-Oncogene Proteins, Basic Helix-Loop-Helix Transcription Factors, Humans, Syk Kinase, Oncology & Carcinogenesis, Cancer, B-Lymphoid, Pediatric, Neoplastic, Clinical Trials as Topic, Biomedical and Clinical Sciences, Precursor Cells, B-Lymphoid, Pre-B-Cell Leukemia Transcription Factor 1, Neurosciences, Intracellular Signaling Peptides and Proteins, Oncology and carcinogenesis, Hematology, Cell Biology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Protein-Tyrosine Kinases, Up-Regulation, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, src-Family Kinases, Gene Expression Regulation, Oncology, Biochemistry and cell biology, Proto-Oncogene Proteins c-bcl-6, Phosphatidylinositol 3-Kinase, Signal Transduction
Cancer Research, Childhood Leukemia, Pediatric Cancer, Precursor Cells, Oncology and Carcinogenesis, Molecular Sequence Data, Vaccine Related, Rare Diseases, Proto-Oncogene Proteins, Basic Helix-Loop-Helix Transcription Factors, Humans, Syk Kinase, Oncology & Carcinogenesis, Cancer, B-Lymphoid, Pediatric, Neoplastic, Clinical Trials as Topic, Biomedical and Clinical Sciences, Precursor Cells, B-Lymphoid, Pre-B-Cell Leukemia Transcription Factor 1, Neurosciences, Intracellular Signaling Peptides and Proteins, Oncology and carcinogenesis, Hematology, Cell Biology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Protein-Tyrosine Kinases, Up-Regulation, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, src-Family Kinases, Gene Expression Regulation, Oncology, Biochemistry and cell biology, Proto-Oncogene Proteins c-bcl-6, Phosphatidylinositol 3-Kinase, Signal Transduction
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