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Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia
- Source :
- Cancer cell, vol 27, iss 3
- Publisher :
- Elsevier Inc.
-
Abstract
- SummaryStudying 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.
- Subjects :
- Cancer Research
Precursor Cells
Pediatric Cancer
Childhood Leukemia
Oncology and Carcinogenesis
Molecular Sequence Data
Biology
Tonic (physiology)
Vaccine Related
Rare Diseases
Downregulation and upregulation
Precursor cell
Proto-Oncogene Proteins
hemic and lymphatic diseases
Basic Helix-Loop-Helix Transcription Factors
Pre-B-Cell Leukemia Transcription Factor 1
Humans
Syk Kinase
Oncology & Carcinogenesis
B-Lymphoid
Cancer
Pediatric
Regulation of gene expression
Neoplastic
Clinical Trials as Topic
Precursor Cells, B-Lymphoid
Neurosciences
Intracellular Signaling Peptides and Proteins
Hematology
Cell Biology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Protein-Tyrosine Kinases
BCL6
3. Good health
Up-Regulation
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
src-Family Kinases
Gene Expression Regulation
Oncology
Immunology
Cancer research
Proto-Oncogene Proteins c-bcl-6
Signal transduction
Phosphatidylinositol 3-Kinase
Tyrosine kinase
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 15356108
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cancer Cell
- Accession number :
- edsair.doi.dedup.....c83e54ba07409d1f257f98562e3da1b6
- Full Text :
- https://doi.org/10.1016/j.ccell.2015.02.003