TY - JOUR
T1 - Low-level expression of proapoptotic Bcl-2-interacting mediator in leukemic cells in patients with chronic myeloid leukemia
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 J.
AU - Sillaber, Christian
AU - Esterbauer, Harald
AU - Valent, Peter
PY - 2005/10/15
Y1 - 2005/10/15
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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U2 - 10.1158/0008-5472.CAN-05-0972
DO - 10.1158/0008-5472.CAN-05-0972
M3 - Article
C2 - 16230407
AN - SCOPUS:27144515283
SN - 0008-5472
VL - 65
SP - 9436
EP - 9444
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -