Synergistic effects of p53 activation via MDM2 inhibition in combination with inhibition of Bcl-2 or Bcr-Abl in CD34+ proliferating and quiescent chronic myeloid leukemia blast crisis cells

Bing Z. Carter, Po Yee Mak, Duncan H. Mak, Vivian R. Ruvolo, Wendy Schober, Teresa McQueen, Jorge Cortes, Hagop M. Kantarjian, Richard E. Champlin, Marina Konopleva, Michael Andreeff

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

The Bcr-Abl tyrosine kinase regulates several Bcl-2 family proteins that confer resistance to apoptosis in chronic myeloid leukemia (CML) cells. Given p53's ability to modulate the expression and activity of Bcl-2 family members, we hypothesized that targeting Bcr-Abl, Bcl-2, and p53 concomitantly could have therapeutic benefits in blast crisis (BC) CML and in quiescent CML CD34+cells that are insensitive to tyrosine kinase inhibitors (TKI). We examined the effects of the MDM2 inhibitor nutlin3a and its combination with the dual Bcl-2 and Bcl-xL inhibitor ABT-737, and the Bcr-Abl inhibitor nilotinib on BC CML patient samples. We found that in quiescent CD34+progenitors, p53 expression is significantly lower, and MDM2 is higher, compared to their proliferating counterparts. Treatment with nutlin3a induced apoptosis in bulk and CD34+CD38- cells, and in both proliferating and quiescent CD34+progenitor CML cells. Nutlin3a synergized with ABT-737 and nilotinib, in part by inducing proapoptotic, and suppressing anti-apoptotic, Bcl-2 proteins. Nilotinib inhibited the expression of Bcl-xL and Mcl-1 in BC CML cells. These results demonstrate that p53 activation by MDM2 blockade can sensitize BC CML cells, including quiescent CD34+cells, to Bcl-2 inhibitor- and TKI-induced apoptosis. This novel strategy could be useful in the therapy of BC CML.

Original languageEnglish (US)
Pages (from-to)30487-30499
Number of pages13
JournalOncotarget
Volume6
Issue number31
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • Bcl-2
  • Blast crisis CML
  • Nutlin3a
  • Quiescent CD34cells
  • TKI

ASJC Scopus subject areas

  • Oncology

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    Carter, B. Z., Mak, P. Y., Mak, D. H., Ruvolo, V. R., Schober, W., McQueen, T., Cortes, J., Kantarjian, H. M., Champlin, R. E., Konopleva, M., & Andreeff, M. (2015). Synergistic effects of p53 activation via MDM2 inhibition in combination with inhibition of Bcl-2 or Bcr-Abl in CD34+ proliferating and quiescent chronic myeloid leukemia blast crisis cells. Oncotarget, 6(31), 30487-30499. https://doi.org/10.18632/oncotarget.5890