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Cyclin D1 depletion induces DNA damage in mantle cell lymphoma lines

Suchismita Mohanty1, Atish Mohanty1, Natalie Sandoval1

  • 1a Division of Hematopoietic Stem Cell and Leukemia Research , Beckman Research Institute , Duarte , CA , USA.

Leukemia & Lymphoma
|June 25, 2016
PubMed

Insights

Depleting cyclin D1 (CCND1) in mantle cell lymphoma (MCL) induces cancer cell death and DNA damage, enhancing sensitivity to chemotherapy. This suggests CCND1 is a potential therapeutic target for MCL patients resistant to standard treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Elevated cyclin D1 (CCND1) expression in mantle cell lymphoma (MCL) correlates with aggressive disease and chemoresistance.
  • The precise mechanisms by which CCND1 promotes MCL chemoresistance remain largely unexplored.

Purpose of the Study:

  • To investigate the role of CCND1 in MCL chemoresistance.
  • To explore CCND1 depletion as a potential therapeutic strategy for MCL.

Main Methods:

  • RNA interference (RNAi) was used to deplete CCND1 in human MCL cell lines (UPN-1, JEKO-1).
  • Assays included caspase-3 activity, apoptosis, histone H2AX phosphorylation (DNA damage marker), and DNA fiber analysis.
  • In vitro and xenotransplant studies were conducted.
  • Chemosensitivity to hydroxyurea and cytarabine was assessed after CCND1 depletion.

Main Results:

  • CCND1 depletion significantly increased caspase-3 activity and induced apoptosis in MCL cells.
  • CCND1 depletion led to increased histone H2AX phosphorylation, indicating DNA damage.
  • DNA fiber analysis suggested deregulated replication initiation as a cause of DNA damage.
  • CCND1 depletion enhanced MCL cell chemosensitivity to replication inhibitors hydroxyurea and cytarabine.

Conclusions:

  • CCND1 depletion induces DNA damage and apoptosis in MCL cells, contributing to their death.
  • Targeting CCND1 may overcome chemoresistance in MCL.
  • CCND1 represents a promising therapeutic target for refractory MCL patients.
Keywords:
ChemoresistanceDNA damagecyclin D1mantle cell lymphomareplication stress

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