Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia

Oncogene. 2015 Oct 16;34(42):5341-51. doi: 10.1038/onc.2014.450. Epub 2015 Feb 2.

Abstract

The initiation and maintenance of a malignant phenotype requires complex and synergistic interactions of multiple oncogenic signals. The Hedgehog (HH)/GLI pathway has been implicated in a variety of cancer entities and targeted pathway inhibition is of therapeutic relevance. Signal cross-talk with other cancer pathways including PI3K/AKT modulates HH/GLI signal strength and its oncogenicity. In this study, we addressed the role of HH/GLI and its putative interaction with the PI3K/AKT cascade in the initiation and maintenance of chronic lymphocytic leukemia (CLL). Using transgenic mouse models, we show that B-cell-specific constitutive activation of HH/GLI signaling either at the level of the HH effector and drug target Smoothened or at the level of the GLI transcription factors does not suffice to initiate a CLL-like phenotype characterized by the accumulation of CD5(+) B cells in the lymphatic system and peripheral blood. Furthermore, Hh/Gli activation in Pten-deficient B cells with activated Pi3K/Akt signaling failed to enhance the expansion of leukemic CD5(+) B cells, suggesting that genetic or epigenetic alterations leading to aberrant HH/GLI signaling in B cells do not suffice to elicit a CLL-like phenotype in mice. By contrast, we identify a critical role of GLI and PI3K signaling for the survival of human primary CLL cells. We show that combined targeting of GLI and PI3K/AKT/mTOR signaling can have a synergistic therapeutic effect in cells from a subgroup of CLL patients, thereby providing a basis for the evaluation of future combination therapies targeting HH/GLI and PI3K signaling in this common hematopoietic malignancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / analysis
  • B-Lymphocytes / immunology
  • CD5 Antigens / analysis
  • Hedgehog Proteins / physiology*
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / etiology*
  • Mice
  • Mice, Inbred C57BL
  • Oncogene Proteins / antagonists & inhibitors
  • Oncogene Proteins / physiology*
  • PTEN Phosphohydrolase / physiology
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, G-Protein-Coupled / physiology
  • Signal Transduction / physiology*
  • Smoothened Receptor
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / physiology*
  • Zinc Finger Protein GLI1

Substances

  • Antigens, CD19
  • CD5 Antigens
  • Hedgehog Proteins
  • Oncogene Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, G-Protein-Coupled
  • Smo protein, mouse
  • Smoothened Receptor
  • Trans-Activators
  • Zinc Finger Protein GLI1
  • PTEN Phosphohydrolase