CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737.
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.
Institute for Advanced Research, Nagoya University, Nagoya, Japan. kshimada@med.nagoya-u.ac.jp
Kazuyuki
K
Shimada
Akihiro
A
Tomita
Yosuke
Y
Minami
Akihiro
A
Abe
Charlotte K
CK
Hind
Hitoshi
H
Kiyoi
Mark S
MS
Cragg
Tomoki
T
Naoe
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001549:Benzamides; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D020014:K562 Cells; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D009596:Nitrophenols / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D011519:Proto-Oncogenes / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic; D051025:bcl-Associated Death Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D000970:Antineoplastic Agents; D001549:Benzamides; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; D000068877:Imatinib Mesylate; D000074008:MDS1 and EVI1 Complex Locus Protein; D009596:Nitrophenols; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D050783:Proto-Oncogene Proteins c-ets; D011743:Pyrimidines; D012097:Repressor Proteins; D013449:Sulfonamides; D014157:Transcription Factors; D051025:bcl-Associated Death Protein; D000097764:ETS Translocation Variant 6 Protein; C501332:ABT-737; C494819:BAD protein, human; C063575:MECOM protein, human