Leukemia Research
Volume 36, Issue 6 , Pages 756-763, June 2012

Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML

  • Rajesh R. Nair

      Affiliations

    • Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA
    • ,
  • Joel H. Tolentino

      Affiliations

    • Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA
    • ,
  • Raul F. Argilagos

      Affiliations

    • Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA
    • ,
  • Ling Zhang

      Affiliations

    • Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
    • ,
  • Javier Pinilla-Ibarz

      Affiliations

    • Hematology Malignancies Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA
    • ,
  • Lori A. Hazlehurst

      Affiliations

    • Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA
    • Corresponding Author InformationCorresponding author at: Molecular Oncology Program, H. Lee Moffitt Cancer Center, 12905 Magnolia Dr., Tampa, FL 33612, USA. Tel.: +1 813 903 6807; fax: +1 813 979 7265.

Received 14 October 2011; received in revised form 22 November 2011; accepted 6 December 2011. published online 04 January 2012.

Abstract 

In this study, we show that conditioned media (CM) generated from bone marrow (BM)-derived mesenchymal stromal cells lead to BCR-ABL independent STAT3 activation. Activation of STAT3 is important not only for survival of CML cells but also for its protection against Nilotinib (NI), within the BM microenvironment. Reducing the expression of both JAK2 and TYK2 or utilizing a pan-JAK inhibitor blocked CM-mediated STAT3 activation and sensitized CML cells to NI-mediated cell death. Finally, we demonstrate that in patient-derived primitive leukemic cells, co-cultured with BM stromal cells, inhibition of BCR-ABL and JAK activity was a successful strategy to potentiate their elimination.

Keywords: STAT3, Conditioned media, Bone marrow microenvironment, Nilotinib, JAK, INC424

To access this article, please choose from the options below

Login to an existing account or Register a new account.

  • Purchase this article for 31.50 USD (You must login/register to purchase this article)

    Online access for 24 hours. The PDF version can be downloaded as your permanent record.

  • Subscribe to this title

    Get unlimited online access to this article and all other articles in this title 24/7 for one year.

  • Claim access now

    For current subscribers with Society Membership or Account Number.

  • Visit SciVerse ScienceDirect to see if you have access via your institution.
 

PII: S0145-2126(11)00580-7

doi:10.1016/j.leukres.2011.12.002

Leukemia Research
Volume 36, Issue 6 , Pages 756-763, June 2012

Article Tools

* Image Usage & Resolution