Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells

Blood. 2004 Jun 1;103(11):4268-75. doi: 10.1182/blood-2003-07-2193. Epub 2004 Feb 19.

Abstract

BCR-ABL and v-ABL are oncogenic forms of the Abl tyrosine kinase that can cause leukemias in mice and humans. ABL oncogenes trigger multiple signaling pathways whose contribution to transformation varies among cell types. Activation of phosphoinositide 3-kinase (PI3K) is essential for ABL-dependent proliferation and survival in some cell types, and global PI3K inhibitors can enhance the antileukemia effects of the Abl kinase inhibitor imatinib. Although a significant fraction of BCR-ABL-induced human leukemias are of B-cell origin, little is known about PI3K signaling mechanisms in B-lineage cells transformed by ABL oncogenes. Here we show that activation of class I(A) PI3K and downstream inactivation of FOXO transcription factors are essential for survival of murine pro/pre-B cells transformed by v-ABL or BCR-ABL. In addition, analysis of mice lacking individual PI3K genes indicates that products of the Pik3r1 gene contribute to transformation efficiency by BCR-ABL. These findings establish a role for PI3K signaling in B-lineage transformation by ABL oncogenes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / physiology*
  • Cell Division / immunology
  • Cell Lineage / immunology
  • Cell Transformation, Neoplastic / metabolism*
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Leukemia / physiopathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Pregnancy
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-abl / genetics*
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Transcription Factors
  • Protein Kinases
  • MTOR protein, human
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-abl
  • TOR Serine-Threonine Kinases