Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A

Arelis Salas, Suriyan Ponnusamy, Can E. Senkal, Marisa Meyers-Needham, Shanmugam Panneer Selvam, Sahar A. Saddoughi, Elif Apohan, R. David Sentelle, Charles Smith, Christopher R. Gault, Lina M. Obeid, Hesham M. El-Shewy, Joshua Oaks, Ramasamy Santhanam, Guido Marcucci, Yusuf Baran, Sandeep Mahajan, Daniel Fernandes, Robert Stuart, Danilo PerrottiBesim Ogretmen

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Abstract

The mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinib-resistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1-/- MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib- or nilotinib-induced growth inhibition in primary CD34+ mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, expressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type- or mutant-Bcr-Abl1 thereby overcoming drug resistance.

Original languageEnglish (US)
Pages (from-to)5941-5952
Number of pages12
JournalBlood
Volume117
Issue number22
DOIs
StatePublished - Jun 2 2011

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Salas, A., Ponnusamy, S., Senkal, C. E., Meyers-Needham, M., Selvam, S. P., Saddoughi, S. A., Apohan, E., Sentelle, R. D., Smith, C., Gault, C. R., Obeid, L. M., El-Shewy, H. M., Oaks, J., Santhanam, R., Marcucci, G., Baran, Y., Mahajan, S., Fernandes, D., Stuart, R., ... Ogretmen, B. (2011). Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A. Blood, 117(22), 5941-5952. https://doi.org/10.1182/blood-2010-08-300772