Low-level expression of proapoptotic Bcl-2-interacting mediator in leukemic cells in patients with chronic myeloid leukemia: Role of BCR/ABL, characterization of underlying signaling pathways, and reexpression by novel pharmacologic compounds

Karl J. Aichberger, Matthias Mayerhofer, Maria Theresa Krauth, Anja Vales, Rudin Kondo, Sophia Derdak, Winfried F. Pickl, Edgar Selzer, Michael Deininger, Brian Druker, Christian Sillaber, Harald Esterbauer, Peter Valent

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative disease in which BCR/ABL enhances survival of leukemic cells through modulation of proapoptotic and antiapoptotic molecules. Recent data suggest that proapoptotic Bcl-2-interacting mediator (Bim) plays a role as a tumor suppressor in myeloid cells, and that leukemic cells express only low amounts of this cell death activator. We here show that primary CML cells express significantly lower amounts of bim mRNA and Bim protein compared with normal cells. The BCR/ABL inhibitors imatimib and AMN107 were found to promote expression of Bim in CML cells. To provide direct evidence for tine role of BCR/ABL in Bim modulation, we employed Ba/F3 cells with doxycycline-indncible expression of BCR/ABL and found that BCR/ABL decreases expression of him mRNA and Bim protein in these cells. The BCR/ABL-induced decrease in expression of Bim was found to be a posttranscriptional event that depended on signaling through the mitogen-activated protein kinase pathway and was abrogated by the proteasome inhibitor MG132. Interestingly, MGI32 up-regulated the expression of bim mRNA and Bim protein and suppressed the growth of Ba/F3 cells containing wild-type BCR/ABL or imatinib-resistant mutants of BCR/ABL. To show functional significance of "Bim reexpression," a Bim-specific small interfering RNA was applied and found to rescue BCR/ABL-transformed leukemic cells from imatinib-induced cell death. In summary, our data identify BCR/ABL as a Bim suppressor in CML cells and suggest that reexpression of Bim by novel tyrosine kinase inhibitors, proteasome inhibition, or by targeting signaling pathways downstream of BCR/ABL may be an attractive therapeutic approach in imatinib-resistant CML.

Original languageEnglish (US)
Pages (from-to)9436-9444
Number of pages9
JournalCancer Research
Volume65
Issue number20
DOIs
StatePublished - Oct 15 2005
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Myeloid Cells
Proteasome Inhibitors
Messenger RNA
Cell Death
Proteins
Doxycycline
Mitogen-Activated Protein Kinases
Protein-Tyrosine Kinases
Small Interfering RNA
Cell Survival
Growth
Imatinib Mesylate
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Low-level expression of proapoptotic Bcl-2-interacting mediator in leukemic cells in patients with chronic myeloid leukemia : Role of BCR/ABL, characterization of underlying signaling pathways, and reexpression by novel pharmacologic compounds. / Aichberger, Karl J.; Mayerhofer, Matthias; Krauth, Maria Theresa; Vales, Anja; Kondo, Rudin; Derdak, Sophia; Pickl, Winfried F.; Selzer, Edgar; Deininger, Michael; Druker, Brian; Sillaber, Christian; Esterbauer, Harald; Valent, Peter.

In: Cancer Research, Vol. 65, No. 20, 15.10.2005, p. 9436-9444.

Research output: Contribution to journalArticle

Aichberger, Karl J. ; Mayerhofer, Matthias ; Krauth, Maria Theresa ; Vales, Anja ; Kondo, Rudin ; Derdak, Sophia ; Pickl, Winfried F. ; Selzer, Edgar ; Deininger, Michael ; Druker, Brian ; Sillaber, Christian ; Esterbauer, Harald ; Valent, Peter. / Low-level expression of proapoptotic Bcl-2-interacting mediator in leukemic cells in patients with chronic myeloid leukemia : Role of BCR/ABL, characterization of underlying signaling pathways, and reexpression by novel pharmacologic compounds. In: Cancer Research. 2005 ; Vol. 65, No. 20. pp. 9436-9444.
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abstract = "Chronic myeloid leukemia (CML) is a myeloproliferative disease in which BCR/ABL enhances survival of leukemic cells through modulation of proapoptotic and antiapoptotic molecules. Recent data suggest that proapoptotic Bcl-2-interacting mediator (Bim) plays a role as a tumor suppressor in myeloid cells, and that leukemic cells express only low amounts of this cell death activator. We here show that primary CML cells express significantly lower amounts of bim mRNA and Bim protein compared with normal cells. The BCR/ABL inhibitors imatimib and AMN107 were found to promote expression of Bim in CML cells. To provide direct evidence for tine role of BCR/ABL in Bim modulation, we employed Ba/F3 cells with doxycycline-indncible expression of BCR/ABL and found that BCR/ABL decreases expression of him mRNA and Bim protein in these cells. The BCR/ABL-induced decrease in expression of Bim was found to be a posttranscriptional event that depended on signaling through the mitogen-activated protein kinase pathway and was abrogated by the proteasome inhibitor MG132. Interestingly, MGI32 up-regulated the expression of bim mRNA and Bim protein and suppressed the growth of Ba/F3 cells containing wild-type BCR/ABL or imatinib-resistant mutants of BCR/ABL. To show functional significance of {"}Bim reexpression,{"} a Bim-specific small interfering RNA was applied and found to rescue BCR/ABL-transformed leukemic cells from imatinib-induced cell death. In summary, our data identify BCR/ABL as a Bim suppressor in CML cells and suggest that reexpression of Bim by novel tyrosine kinase inhibitors, proteasome inhibition, or by targeting signaling pathways downstream of BCR/ABL may be an attractive therapeutic approach in imatinib-resistant CML.",
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T2 - Role of BCR/ABL, characterization of underlying signaling pathways, and reexpression by novel pharmacologic compounds

AU - Aichberger, Karl J.

AU - Mayerhofer, Matthias

AU - Krauth, Maria Theresa

AU - Vales, Anja

AU - Kondo, Rudin

AU - Derdak, Sophia

AU - Pickl, Winfried F.

AU - Selzer, Edgar

AU - Deininger, Michael

AU - Druker, Brian

AU - Sillaber, Christian

AU - Esterbauer, Harald

AU - Valent, Peter

PY - 2005/10/15

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N2 - Chronic myeloid leukemia (CML) is a myeloproliferative disease in which BCR/ABL enhances survival of leukemic cells through modulation of proapoptotic and antiapoptotic molecules. Recent data suggest that proapoptotic Bcl-2-interacting mediator (Bim) plays a role as a tumor suppressor in myeloid cells, and that leukemic cells express only low amounts of this cell death activator. We here show that primary CML cells express significantly lower amounts of bim mRNA and Bim protein compared with normal cells. The BCR/ABL inhibitors imatimib and AMN107 were found to promote expression of Bim in CML cells. To provide direct evidence for tine role of BCR/ABL in Bim modulation, we employed Ba/F3 cells with doxycycline-indncible expression of BCR/ABL and found that BCR/ABL decreases expression of him mRNA and Bim protein in these cells. The BCR/ABL-induced decrease in expression of Bim was found to be a posttranscriptional event that depended on signaling through the mitogen-activated protein kinase pathway and was abrogated by the proteasome inhibitor MG132. Interestingly, MGI32 up-regulated the expression of bim mRNA and Bim protein and suppressed the growth of Ba/F3 cells containing wild-type BCR/ABL or imatinib-resistant mutants of BCR/ABL. To show functional significance of "Bim reexpression," a Bim-specific small interfering RNA was applied and found to rescue BCR/ABL-transformed leukemic cells from imatinib-induced cell death. In summary, our data identify BCR/ABL as a Bim suppressor in CML cells and suggest that reexpression of Bim by novel tyrosine kinase inhibitors, proteasome inhibition, or by targeting signaling pathways downstream of BCR/ABL may be an attractive therapeutic approach in imatinib-resistant CML.

AB - Chronic myeloid leukemia (CML) is a myeloproliferative disease in which BCR/ABL enhances survival of leukemic cells through modulation of proapoptotic and antiapoptotic molecules. Recent data suggest that proapoptotic Bcl-2-interacting mediator (Bim) plays a role as a tumor suppressor in myeloid cells, and that leukemic cells express only low amounts of this cell death activator. We here show that primary CML cells express significantly lower amounts of bim mRNA and Bim protein compared with normal cells. The BCR/ABL inhibitors imatimib and AMN107 were found to promote expression of Bim in CML cells. To provide direct evidence for tine role of BCR/ABL in Bim modulation, we employed Ba/F3 cells with doxycycline-indncible expression of BCR/ABL and found that BCR/ABL decreases expression of him mRNA and Bim protein in these cells. The BCR/ABL-induced decrease in expression of Bim was found to be a posttranscriptional event that depended on signaling through the mitogen-activated protein kinase pathway and was abrogated by the proteasome inhibitor MG132. Interestingly, MGI32 up-regulated the expression of bim mRNA and Bim protein and suppressed the growth of Ba/F3 cells containing wild-type BCR/ABL or imatinib-resistant mutants of BCR/ABL. To show functional significance of "Bim reexpression," a Bim-specific small interfering RNA was applied and found to rescue BCR/ABL-transformed leukemic cells from imatinib-induced cell death. In summary, our data identify BCR/ABL as a Bim suppressor in CML cells and suggest that reexpression of Bim by novel tyrosine kinase inhibitors, proteasome inhibition, or by targeting signaling pathways downstream of BCR/ABL may be an attractive therapeutic approach in imatinib-resistant CML.

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