BCL6 Enables Ph+ Acute Lymphoblastic Leukaemia Cells to Survive BCR-ABL1 Kinase Inhibition

Nature. 2011 May 19;473(7347):384-8. doi: 10.1038/nature09883.

Abstract

Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.

Publication types

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

MeSH terms

  • ADP-Ribosylation Factor 1 / metabolism
  • Animals
  • Cell Survival / drug effects
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drug Resistance, Neoplasm*
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-bcl-6
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • BCL6 protein, human
  • Bcl6 protein, mouse
  • DNA-Binding Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-6
  • Tumor Suppressor Protein p53
  • Fusion Proteins, bcr-abl
  • ADP-Ribosylation Factor 1

Associated data

  • GEO/GSE10086
  • GEO/GSE11794
  • GEO/GSE15179
  • GEO/GSE20987
  • GEO/GSE23743
  • GEO/GSE24400
  • GEO/GSE24426