Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function

J Exp Med. 2009 Aug 3;206(8):1739-53. doi: 10.1084/jem.20090004. Epub 2009 Jul 20.

Abstract

B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre-B cell receptor-dependent stages. The Philadelphia chromosome-positive (Ph(+)) subtype of ALL accounts for 25-30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre-B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph(+) ALL cells. Pre-B cell receptor-mediated cell cycle arrest in Ph(+) ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre-B cell receptor signaling pathway, even if expression of the pre-B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre-B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph(+) ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre-B cell receptor-mediated tumor suppression.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology
  • Adult
  • Animals
  • Cell Cycle
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Down-Regulation
  • Gene Deletion
  • Genes, abl
  • Humans
  • Ikaros Transcription Factor / deficiency
  • Ikaros Transcription Factor / genetics
  • Ikaros Transcription Factor / physiology*
  • Leukemia, Prolymphocytic, B-Cell / genetics*
  • Leukemia, Prolymphocytic, B-Cell / pathology
  • Leukemia, Prolymphocytic, B-Cell / physiopathology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Philadelphia Chromosome*
  • Pre-B Cell Receptors / deficiency
  • Pre-B Cell Receptors / genetics
  • Pre-B Cell Receptors / physiology*
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • B cell linker protein
  • IKZF1 protein, human
  • Pre-B Cell Receptors
  • Ikaros Transcription Factor