TY - JOUR
T1 - Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells
AU - Heaney, Nicholas B.
AU - Pellicano, Francesca
AU - Zhang, Bin
AU - Crawford, Lisa
AU - Chu, Su
AU - Kazmi, Syed M.A.
AU - Allan, Elaine K.
AU - Jorgensen, Heather G.
AU - Irvine, Alexandra E.
AU - Bhatia, Ravi
AU - Holyoake, Tessa L.
PY - 2010/3/18
Y1 - 2010/3/18
N2 - Chronic myeloid leukemia (CML) is treated effectively with tyrosine kinase inhibitors (TKIs); however, 2 key problems remain - the insensitivity of CMLstem and progenitor cells to TKIs and the emergence of TKI-resistant BCR-ABL mutations. BCRABL activity is associated with increased proteasome activity and proteasome inhibitors (PIs) are cytotoxic against CML cell lines. We demonstrate that bortezomib is antiproliferative and induces apoptosis in chronic phase (CP) CD34+ CML cells at clinically achievable concentrations. We also show that bortezomib targets primitive CML cells, with effects on CD34 +38-, long-term culture-initiating (LTC-IC) and nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulating cells. Bortezomib is not selective for CML cells and induces apoptosis in normal CD34+38- cells. The effects against CML cells are seen when bortezomib is used alone and in combination with dasatinib. Bortezomib causes proteasome but not BCR-ABL inhibition and is also effective in inhibiting proteasome activity and inducing apoptosis in cell lines expressing BCR-ABL mutations, including T315I. By targeting both TKI-insensitive stem and progenitor cells and TKI-resistant BCR-ABL mutations, we believe that bortezomib offers a potential therapeutic option in CML. Because of known toxicities, including myelosuppression, the likely initial clinical application of bortezomib in CML would be in resistant and advanced disease.
AB - Chronic myeloid leukemia (CML) is treated effectively with tyrosine kinase inhibitors (TKIs); however, 2 key problems remain - the insensitivity of CMLstem and progenitor cells to TKIs and the emergence of TKI-resistant BCR-ABL mutations. BCRABL activity is associated with increased proteasome activity and proteasome inhibitors (PIs) are cytotoxic against CML cell lines. We demonstrate that bortezomib is antiproliferative and induces apoptosis in chronic phase (CP) CD34+ CML cells at clinically achievable concentrations. We also show that bortezomib targets primitive CML cells, with effects on CD34 +38-, long-term culture-initiating (LTC-IC) and nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulating cells. Bortezomib is not selective for CML cells and induces apoptosis in normal CD34+38- cells. The effects against CML cells are seen when bortezomib is used alone and in combination with dasatinib. Bortezomib causes proteasome but not BCR-ABL inhibition and is also effective in inhibiting proteasome activity and inducing apoptosis in cell lines expressing BCR-ABL mutations, including T315I. By targeting both TKI-insensitive stem and progenitor cells and TKI-resistant BCR-ABL mutations, we believe that bortezomib offers a potential therapeutic option in CML. Because of known toxicities, including myelosuppression, the likely initial clinical application of bortezomib in CML would be in resistant and advanced disease.
UR - http://www.scopus.com/inward/record.url?scp=77950432694&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77950432694&partnerID=8YFLogxK
U2 - 10.1182/blood-2008-06-164582
DO - 10.1182/blood-2008-06-164582
M3 - Article
C2 - 20068223
AN - SCOPUS:77950432694
SN - 0006-4971
VL - 115
SP - 2241
EP - 2250
JO - Blood
JF - Blood
IS - 11
ER -