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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells

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Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition

H M Mehta1, M Futami2, T Glaubach1

  • 1Department of Pediatrics (Hematology-Oncology) and Cell and Molecular Biology, Lurie Children's Hospital of Chicago, Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Leukemia
|October 31, 2013
PubMed

Insights

Granulocyte colony-stimulating factor receptor (GCSFR) class IV isoform is elevated in AML and promotes leukemia by enhancing proliferation and impairing differentiation, yet remains sensitive to JAK2 inhibitors.

Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • Granulocyte colony-stimulating factor (GCSF) regulates neutrophil production via the GCSF receptor (GCSFR/CSF3R).
  • Mutations in GCSFR are linked to myelodysplasia/acute myeloid leukemia (AML) in children with severe congenital neutropenia.
  • Alternative splicing of CSF3R generates multiple isoforms, including class IV, whose biology is largely unknown.

Purpose of the Study:

  • To investigate the biological role and signaling of the alternatively spliced class IV GCSFR isoform.
  • To determine the impact of class IV GCSFR expression on cell proliferation, differentiation, and apoptosis in AML.
  • To assess the sensitivity of class IV GCSFR-mediated signaling to JAK2 inhibitors.

Main Methods:

  • Analysis of CSF3R isoform expression in adult myelodysplastic syndrome/AML patients.
  • Investigation of developmental regulation of CSF3R isoforms.
  • Phosphoprotein signaling analysis involving JAK-STAT pathways and cell cycle gene expression.
  • Assessment of proliferation, differentiation, and apoptosis in response to class IV GCSFR.

Main Results:

  • Class IV CSF3R expression is elevated in adult AML patients and is more representative of a progenitor cell stage.
  • Enhanced proliferation driven by class IV GCSFR is associated with diminished STAT3 and STAT5 activation.
  • Class IV GCSFR signaling remains sensitive to JAK2 inhibitors.
  • Alterations in the GCSFR C-terminal domain confer leukemic properties, including enhanced growth and resistance to apoptosis.

Conclusions:

  • The class IV GCSFR isoform may act as an oncogenic driver in AML.
  • Class IV GCSFR promotes leukemic properties through enhanced proliferation and impaired differentiation.
  • Targeting JAK2 may be a viable therapeutic strategy for AML patients with altered GCSFR.

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