CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737

Kazuyuki Shimada, Akihiro Tomita, Yosuke Minami, Akihiro Abe, Charlotte K. Hind, Hitoshi Kiyoi, Mark S. Cragg, Tomoki Naoe

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalExperimental Hematology
Volume40
Issue number9
DOIs
Publication statusPublished - 01-01-2012

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Protein-Tyrosine Kinases
Apoptosis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Molecular Targeted Therapy
Proteins
1-Phosphatidylinositol 4-Kinase
Hematologic Neoplasms
Myeloid Cells
Chromosome Aberrations
Small Interfering RNA
Cell Death
ABT-737
Imatinib Mesylate
Pharmacology
Cell Line
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

Cite this

Shimada, Kazuyuki ; Tomita, Akihiro ; Minami, Yosuke ; Abe, Akihiro ; Hind, Charlotte K. ; Kiyoi, Hitoshi ; Cragg, Mark S. ; Naoe, Tomoki. / CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737. In: Experimental Hematology. 2012 ; Vol. 40, No. 9.
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CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737. / Shimada, Kazuyuki; Tomita, Akihiro; Minami, Yosuke; Abe, Akihiro; Hind, Charlotte K.; Kiyoi, Hitoshi; Cragg, Mark S.; Naoe, Tomoki.

In: Experimental Hematology, Vol. 40, No. 9, 01.01.2012.

Research output: Contribution to journalArticle

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