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BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Copland, Mhairi Pellicano, Francesca Richmond, Linda Hamilton, Ashley R. Weinmann, Roberto Simon Holyoake, Tessa L. |
| Copyright Year | 2008 |
| Abstract | Chronic myeloid leukemia (CML), a hematopoietic stem-cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor imatinib mesylate (IM). To target CML stem/progenitor cells, we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill nonproliferating tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML stem/progenitor cells without inducing apoptosis. In contrast, BMS-214662, alone or in combination with IM or dasatinib, potently induced apoptosis of both proliferating and quiescent CML stem/progenitor cells with less than 1% recovery of Philadelphia-positive long-term culture-initiating cells. Normal stem/progenitor cells were relatively spared by BMS-214662, suggesting selectivity for leukemic stem/progenitor cells. The ability to induce selective apoptosis of leukemic stem/progenitor cells was unique to BMS-214662 and not seen with a structurally similar agent BMS-225975. BMS-214662 was cytotoxic against CML blast crisis stem/progenitor cells, particularly in combination with a tyrosine kinase inhibitor and equally effective in cell lines harboring wild-type vs mutant BCR-ABL, including the T315I mutation. This is the first report of an agent with activity in resistant and blast crisis CML that selectively kills CML stem/progenitor cells through apoptosis and offers potential for eradication of chronic phase CML. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.bloodjournal.org/content/bloodjournal/111/5/2843.full.pdf?sso-checked=true |
| Alternate Webpage(s) | http://bloodjournal.hematologylibrary.org/content/111/5/2843.full.pdf |
| PubMed reference number | 18156496v1 |
| Volume Number | 111 |
| Issue Number | 5 |
| Journal | Blood |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Apoptosis BCR gene BMS 214662 BMS225975 Blast Phase Cardiac Arrest Chronic Lymphocytic Leukemia Fusion Proteins, bcr-abl Imatinib mesylate Leukemia, B-Cell Mesylates Mutation Myeloid Leukemia Myeloid Leukemia, Chronic Neoplasms Protein Tyrosine Kinase Protein-tyrosine kinase inhibitor Stem cells dasatinib |
| Content Type | Text |
| Resource Type | Article |
