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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 [Cancer Cell] 2015 Mar 09; Vol. 27 (3), pp. 409-25. - Publication Year :
- 2015
-
Abstract
- 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.<br /> (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Subjects :
- Basic Helix-Loop-Helix Transcription Factors metabolism
Basic Helix-Loop-Helix Transcription Factors physiology
Clinical Trials as Topic
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Humans
Intracellular Signaling Peptides and Proteins metabolism
Molecular Sequence Data
Phosphatidylinositol 3-Kinase metabolism
Pre-B-Cell Leukemia Transcription Factor 1
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Protein-Tyrosine Kinases metabolism
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins physiology
Proto-Oncogene Proteins c-bcl-6
Signal Transduction
Syk Kinase
Up-Regulation
src-Family Kinases metabolism
DNA-Binding Proteins physiology
Gene Expression Regulation, Neoplastic
Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism
Precursor Cells, B-Lymphoid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 27
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 25759025
- Full Text :
- https://doi.org/10.1016/j.ccell.2015.02.003