TY - JOUR
T1 - CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737
AU - Shimada, Kazuyuki
AU - Tomita, Akihiro
AU - Minami, Yosuke
AU - Abe, Akihiro
AU - Hind, Charlotte K.
AU - Kiyoi, Hitoshi
AU - Cragg, Mark S.
AU - Naoe, Tomoki
N1 - Funding Information:
The authors gratefully acknowledge the Daiichi-Sankyo Foundation for Life Sciences for a grant to K.S., Grant-Aid for Scientific Research (B) 22390192 and a Health Labour Sciences Research Grant H22YE010-01 for T.N., and the Association for International Cancer Research (AICR) for a grant to M.S.C. and C.K.H.
PY - 2012/9
Y1 - 2012/9
N2 - Chronic myeloid leukemia is the first disease in which the potential of molecular targeted therapy with tyrosine kinase inhibitors (TKIs) was realized. Despite this success, a proportion of patients, particularly with advanced disease, are, or become, resistant to this treatment. Overcoming resistance and uncovering the underlying mechanisms is vital for further improvement of clinical outcomes. Here we report the identification, development, and characterization of a novel chronic myeloid leukemia cell line carrying the additional chromosomal aberration t(3;12)(q26;p13) resulting in expression of the TEL/MDS1/EVI1 fusion protein, which is resistant to TKIs. Resistance to TKIs was overcome by the co-administration of the BH3-mimetic, ABT-737. In addition, application of EVI1-specific small interfering RNA decreased expression of the TEL/MDS1/EVI1 fusion, reduced resistance to imatinib, and increased sensitivity to ABT-737. Subsequent studies revealed a role for the BH3-only protein BAD, probably via a phosphoinositide 3-kinase/AKT-dependent pathway, as pharmacological inhibition of AKT could also resensitize cells to death from TKIs. These findings indicate a novel pathway of TKI resistance regulated by EVI1 proteins and provide a promising means for overcoming resistance in chronic myeloid leukemia and other hematological malignancies displaying EVI1 overexpression.
AB - Chronic myeloid leukemia is the first disease in which the potential of molecular targeted therapy with tyrosine kinase inhibitors (TKIs) was realized. Despite this success, a proportion of patients, particularly with advanced disease, are, or become, resistant to this treatment. Overcoming resistance and uncovering the underlying mechanisms is vital for further improvement of clinical outcomes. Here we report the identification, development, and characterization of a novel chronic myeloid leukemia cell line carrying the additional chromosomal aberration t(3;12)(q26;p13) resulting in expression of the TEL/MDS1/EVI1 fusion protein, which is resistant to TKIs. Resistance to TKIs was overcome by the co-administration of the BH3-mimetic, ABT-737. In addition, application of EVI1-specific small interfering RNA decreased expression of the TEL/MDS1/EVI1 fusion, reduced resistance to imatinib, and increased sensitivity to ABT-737. Subsequent studies revealed a role for the BH3-only protein BAD, probably via a phosphoinositide 3-kinase/AKT-dependent pathway, as pharmacological inhibition of AKT could also resensitize cells to death from TKIs. These findings indicate a novel pathway of TKI resistance regulated by EVI1 proteins and provide a promising means for overcoming resistance in chronic myeloid leukemia and other hematological malignancies displaying EVI1 overexpression.
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U2 - 10.1016/j.exphem.2012.05.007
DO - 10.1016/j.exphem.2012.05.007
M3 - Article
C2 - 22634393
AN - SCOPUS:84865006559
SN - 0301-472X
VL - 40
SP - 724-737.e2
JO - Experimental Hematology
JF - Experimental Hematology
IS - 9
ER -
