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p27(KIP1) and PTEN cooperate in myeloproliferative neoplasm tumor suppression in mice

Jingchen Shao1, Susann Li1, Lars Palmqvist1

  • 1Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ; Laboratory of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.

Experimental Hematology & Oncology
|July 2, 2016
PubMed

Insights

Combined inactivation of PTEN and p27(KIP1) genes in mice leads to a more severe myeloproliferative neoplasm, accelerating leukemia development and reducing lifespan. These findings highlight the cooperative tumor suppressive roles of PTEN and p27(KIP1) in blood cancers.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • PTEN negatively regulates the PI3K/AKT pathway by dephosphorylating PIP3.
  • p27(KIP1), a cyclin-dependent kinase inhibitor, controls cell cycle progression from G1 to S phase.
  • Genetic alterations in PTEN and CDKN1B (p27(KIP1)) are frequent in hematological malignancies.

Purpose of the Study:

  • To investigate the cooperative roles of PTEN and p27(KIP1) in leukemogenesis.
  • To determine the impact of combined PTEN and p27(KIP1) inactivation in the hematopoietic system.

Main Methods:

  • Inactivation of Pten and Cdkn1b genes in the hematopoietic compartment of mice.
  • Phenotypic analysis including blood counts, organ size, and survival.
  • Assessment of molecular markers such as p-AKT, cyclin D1, and cyclin D3.

Main Results:

  • Combined Pten and Cdkn1b inactivation resulted in a more severe myeloproliferative neoplasm (MPN) phenotype.
  • Mice with combined gene inactivation exhibited lower hemoglobin levels, enlarged spleen and liver, and reduced lifespan compared to Pten-deficient mice.
  • Accelerated disease progression was associated with severe anemia, increased myeloid infiltration, and splenic destruction.

Conclusions:

  • PTEN and p27(KIP1) exhibit cooperative tumor suppressor functions in the hematopoietic system.
  • The combined loss of PTEN and p27(KIP1) exacerbates MPN development and progression.
  • Elevated p-AKT, cyclin D1, and cyclin D3 signaling pathways may contribute to the observed phenotype.
Keywords:
Myeloproliferative neoplasmsPTENp27KIP1

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