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 pro-apoptotic, 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.
Keywords:
Bcl-2; Nutlin3a; TKI; blast crisis CML; quiescent CD34+ cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-ribosyl Cyclase 1 / metabolism
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Antigens, CD34 / metabolism
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology
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Biphenyl Compounds / pharmacology
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Blast Crisis / pathology*
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Cell Proliferation
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Enzyme Activation / physiology
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Fusion Proteins, bcr-abl / antagonists & inhibitors*
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Gene Expression Regulation, Leukemic
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Humans
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Imatinib Mesylate / pharmacology
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Imidazoles / pharmacology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
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Membrane Glycoproteins / metabolism
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Nitrophenols / pharmacology
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Piperazines / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Pyrimidines / pharmacology
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Sulfonamides / pharmacology
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism*
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bcl-X Protein / antagonists & inhibitors
Substances
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ABT-737
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Antigens, CD34
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Antineoplastic Agents
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BCL2L1 protein, human
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BCR-ABL1 fusion protein, human
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Biphenyl Compounds
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Imidazoles
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Membrane Glycoproteins
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Nitrophenols
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Piperazines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Pyrimidines
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Sulfonamides
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TP53 protein, human
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Tumor Suppressor Protein p53
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bcl-X Protein
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nutlin 3
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Imatinib Mesylate
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Fusion Proteins, bcr-abl
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CD38 protein, human
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ADP-ribosyl Cyclase 1
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nilotinib