IKB kinase B inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL cells

Chronic myelogenous leukemia is a malignant disease of the hematopoietic stem cell compartment, which is characterized by expression of the BCR-ABL fusion protein. Expression of BCR-ABL allows myeloid cells to grow in the absence of the growth factors interleukin-3 and granulocyte-macrophage colony-stimulating factor. The tyrosine kinase activity of BCR-ABL constitutively activates signaling pathways associated with Ras and its downstream effectors and with the Jak/STAT pathway. Additionally, we reported previously that BCR-ABL activates the transcription factor nuclear factor-KB (NF-KB) in a manner dependent on Ras and that inhibition of NF-KB by expression of a modified form of IKBA blocked BCRABL-driven tumor growth in a xenograft model. Here, we show that a highly specific inhibitor of IKB kinase B, a key upstream regulator of the NF-KB pathway, induces growth suppression and death in cells expressing wild-type, Imatinib-resistant, or the T315I Imatinib/Dasatinibresistant forms of BCR-ABL. Cell cycle variables were not affected by this compound. These data indicate that blockage of BCR-ABL-induced NF-KB activation via IKB kinase B inhibition represents a potential new approach for treatment of Imatinibor Dasatinib-resistant forms of chronic myelogenous leukemia. [Mol Cancer Ther 2008;7(2):391–7]