Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia

Cancer Cell. 2015 Mar 9;27(3):409-25. doi: 10.1016/j.ccell.2015.02.003.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • DNA-Binding Proteins / physiology*
  • Gene Expression Regulation, Neoplastic*
  • 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 / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Precursor Cells, B-Lymphoid / metabolism*
  • 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

Substances

  • BCL6 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • TCF3 protein, human
  • pbx1 protein, human
  • Phosphatidylinositol 3-Kinase
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • src-Family Kinases

Associated data

  • GEO/GSE59332
  • GEO/GSE59538