Apoptosis in Chronic Myeloid Leukemia Cells Transiently Treated with Imatinib or Dasatinib Is Caused by Residual BCR-ABL Kinase Inhibition
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| Year of publication | 2012 |
| Type | Conference abstract |
| MU Faculty or unit | |
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| Description | Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hemopoietic stem cells. The constitutively active tyrosine kinase BCR-ABL causes defects in the proliferation and differentiation of blood cells. CML is currently treated with tyrosine kinase specific inhibitors (TKIs), such as imatinib, nilotinib, and dasatinib. Transient, potent BCR-ABL inhibition with TKIs was demonstrated to commit CML cells to apoptosis irreversibly (Shah et al., 2008; Snead et al., 2009; Hiwase et al. 2009). This mechanism would explain the clinical efficacy of once-daily dasatinib treatment, despite the rapid clearance of the drug from the plasma. The restoration of BCR-ABL activity after TKI washout was demonstrated using phosphorylated CRKL (p-CRKL) protein as a surrogate marker. Our in vitro data challenges this model. We suggest that apoptosis observed in the BCR-ABL-positive cell lines K562, KYO-1, LAMA-84 and progenitor cells from chronic phase CML patients with transient imatinib and dasatinib treatment is instead caused by residual kinase inhibition that persists as a consequence of intracellular drug retention. |
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