Depsipeptide (FK228) preferentially induces apoptosis in BCR/ABL-expressing cell lines and cells from patients with chronic myelogenous leukemia in blast crisis

Seiichi Okabe, Tetsuzo Tauchi, Akihiro Nakajima, Goro Sashida, Akihiko Gotoh, Hal Broxmeyer, Junko H. Ohyashiki, Kazuma Ohyashiki

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Abstract

Resistance to imatinib can occur in patients with chronic myelogenous leukemia (CML). In this study, we report mechanisms of action of histone deacetylase (HDAC) inhibitor, depsipeptide (FK228) in BCR/ABL-expressing cell lines and its effectiveness in imatinib-resistant cells from patients with blast crisis of CML. FK228 potently induced apoptosis of TF-1 BCR/ABL, K562, and H7 BCR/ABL cells. We found that histone H4, BCR/ABL, heat shock protein 90 (HSP-90), p53, focal adhesion kinase (FAK), paxillin, and retinoblastoma protein (Rb) were acetylated in the treated cells. Cells were also blocked in G 2/M phase of the cell cycle and activity of mitogen-activated protein kinase (MAPK) was blocked, but p38MAPK (p38) was activated. Inhibitor of apoptosis proteins (IAPs) were suppressed, and common results of apoptotic induction were observed, such as caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP) activation. Although p38 was phosphorylated after FK228 treatment, histone H4 acetylation, caspase-3 activation, and apoptosis were not inhibited by treatment with the p38 inhibitor SB203580. We also found that human telomerase reverse transcriptase (hTERT) ShRNA-transfected cells demonstrated decreased FK228-induced apoptosis. Of clinical relevance, FK228-induced apoptosis of imatinib-resistant primary cells from patients with CML, who had progressed to blast crisis (BC) while receiving therapy with imatinib. In conclusion, FK228 potently induces apoptosis of CML cells by acetylation and degradation of BCR/ABL protein. Our study suggests how FK228 may mediate its effects on imatinib-resistant CML cells.

Original languageEnglish
Pages (from-to)503-514
Number of pages12
JournalStem Cells and Development
Volume16
Issue number3
DOIs
StatePublished - Jun 2007

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Depsipeptides
Blast Crisis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Apoptosis
Cell Line
Acetylation
Caspase 3
Histones
Paxillin
Inhibitor of Apoptosis Proteins
HSP90 Heat-Shock Proteins
Focal Adhesion Protein-Tyrosine Kinases
Retinoblastoma Protein
Histone Deacetylase Inhibitors
Poly(ADP-ribose) Polymerases
romidepsin
Caspase 9
Mitogen-Activated Protein Kinases
Cell Division
Cell Cycle

ASJC Scopus subject areas

  • Hematology

Cite this

Depsipeptide (FK228) preferentially induces apoptosis in BCR/ABL-expressing cell lines and cells from patients with chronic myelogenous leukemia in blast crisis. / Okabe, Seiichi; Tauchi, Tetsuzo; Nakajima, Akihiro; Sashida, Goro; Gotoh, Akihiko; Broxmeyer, Hal; Ohyashiki, Junko H.; Ohyashiki, Kazuma.

In: Stem Cells and Development, Vol. 16, No. 3, 06.2007, p. 503-514.

Research output: Contribution to journalArticle

Okabe, Seiichi ; Tauchi, Tetsuzo ; Nakajima, Akihiro ; Sashida, Goro ; Gotoh, Akihiko ; Broxmeyer, Hal ; Ohyashiki, Junko H. ; Ohyashiki, Kazuma. / Depsipeptide (FK228) preferentially induces apoptosis in BCR/ABL-expressing cell lines and cells from patients with chronic myelogenous leukemia in blast crisis. In: Stem Cells and Development. 2007 ; Vol. 16, No. 3. pp. 503-514.
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AU - Okabe, Seiichi

AU - Tauchi, Tetsuzo

AU - Nakajima, Akihiro

AU - Sashida, Goro

AU - Gotoh, Akihiko

AU - Broxmeyer, Hal

AU - Ohyashiki, Junko H.

AU - Ohyashiki, Kazuma

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N2 - Resistance to imatinib can occur in patients with chronic myelogenous leukemia (CML). In this study, we report mechanisms of action of histone deacetylase (HDAC) inhibitor, depsipeptide (FK228) in BCR/ABL-expressing cell lines and its effectiveness in imatinib-resistant cells from patients with blast crisis of CML. FK228 potently induced apoptosis of TF-1 BCR/ABL, K562, and H7 BCR/ABL cells. We found that histone H4, BCR/ABL, heat shock protein 90 (HSP-90), p53, focal adhesion kinase (FAK), paxillin, and retinoblastoma protein (Rb) were acetylated in the treated cells. Cells were also blocked in G 2/M phase of the cell cycle and activity of mitogen-activated protein kinase (MAPK) was blocked, but p38MAPK (p38) was activated. Inhibitor of apoptosis proteins (IAPs) were suppressed, and common results of apoptotic induction were observed, such as caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP) activation. Although p38 was phosphorylated after FK228 treatment, histone H4 acetylation, caspase-3 activation, and apoptosis were not inhibited by treatment with the p38 inhibitor SB203580. We also found that human telomerase reverse transcriptase (hTERT) ShRNA-transfected cells demonstrated decreased FK228-induced apoptosis. Of clinical relevance, FK228-induced apoptosis of imatinib-resistant primary cells from patients with CML, who had progressed to blast crisis (BC) while receiving therapy with imatinib. In conclusion, FK228 potently induces apoptosis of CML cells by acetylation and degradation of BCR/ABL protein. Our study suggests how FK228 may mediate its effects on imatinib-resistant CML cells.

AB - Resistance to imatinib can occur in patients with chronic myelogenous leukemia (CML). In this study, we report mechanisms of action of histone deacetylase (HDAC) inhibitor, depsipeptide (FK228) in BCR/ABL-expressing cell lines and its effectiveness in imatinib-resistant cells from patients with blast crisis of CML. FK228 potently induced apoptosis of TF-1 BCR/ABL, K562, and H7 BCR/ABL cells. We found that histone H4, BCR/ABL, heat shock protein 90 (HSP-90), p53, focal adhesion kinase (FAK), paxillin, and retinoblastoma protein (Rb) were acetylated in the treated cells. Cells were also blocked in G 2/M phase of the cell cycle and activity of mitogen-activated protein kinase (MAPK) was blocked, but p38MAPK (p38) was activated. Inhibitor of apoptosis proteins (IAPs) were suppressed, and common results of apoptotic induction were observed, such as caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP) activation. Although p38 was phosphorylated after FK228 treatment, histone H4 acetylation, caspase-3 activation, and apoptosis were not inhibited by treatment with the p38 inhibitor SB203580. We also found that human telomerase reverse transcriptase (hTERT) ShRNA-transfected cells demonstrated decreased FK228-induced apoptosis. Of clinical relevance, FK228-induced apoptosis of imatinib-resistant primary cells from patients with CML, who had progressed to blast crisis (BC) while receiving therapy with imatinib. In conclusion, FK228 potently induces apoptosis of CML cells by acetylation and degradation of BCR/ABL protein. Our study suggests how FK228 may mediate its effects on imatinib-resistant CML cells.

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