he treatment of CML, the persistence of residual disease and the occurrence of resistance have prompted investigations into the molecular effectors of BCR ABL. Here we show that BCRABL stimulates the proteasome dependent degradation of members of the Forkhead family of tumor suppressors in vitro, in an in vivo animal Mubritinib EGFR inhibitor model, and in samples from patients with BCR ABL positive CML or ALL. As several downstream mediators of BCR ABL , we also demonstrate that inhibition of this pathway, using bortezomib, causes regression of CML like disease. Bortezomib treatment led to inhibition of BCR ABL induced suppression of FoxO proteins and their pro apoptotic targets, TNF Related Apoptosis Inducing Ligand and BIM, thereby providing novel insights into the molecular effects of proteasome inhibitor therapy.
We additionally show sensitivity of imatinib resistant BCR ABL T315I cells to bortezomib. Our data delineates the involvement of FoxO proteins in BCR ABL induced evasion of apoptosis and provides evidence that bortezomib is a candidate therapeutic in the treatment of BCRABL induced leukemia. The BCR ABL oncoprotein plays a central role in the pathogenesis of virtually all chronic myeloid leukemia and 15 30% of acute lymphoblastic leukemia cases. A s a constitutively active tyrosine kinase, BCR ABL induces the hyperactivation of various signaling pathways that promote cell growth and suppress apoptosis, ultimately resulting in leukemogenesis. In recent years, there has been remarkable progress in the treatment of myeloproliferative diseases, especially with the development of the ABL kinase inhibitor, imatinib mesylate.
Whereas clinical data from imatinib treatment appears promising, the development of resistance due to primary or acquired point mutations in BCR ABL is a growing problem. Although highly potent kinase inhibitors, such as AMN107 and BMS 354825, have been recently developed to target imatinib resistance, these compounds do not inhibit all possible imatinib resistant mutants of BCR ABL, located within the kinase domain of BCR ABL. Alternative strategies, such as Aurora Kinase inhibitor, VX680, which also targets ABL, as well as combination therapies using chemotherapeutic agents and imatinib have shown some success in the treatment of the T315I mutant.
However, since these strategies also target the ABL kinase, a genetic pressure may promote the emergence of additional resistant mutants. Therefore, the identification of novel strategies for the treatment of leukemia are of high priority. As an alternative to targeting the ABL kinase, a promising approach involves the inhibition of downstream cellular pathways critical for BCR ABL mediated leukemogenesis. The activation of the PI3 K/Akt pathway plays a significant role in BCR ABL mediated leukemogenesis. One class of PI3 K/Akt effectors that are key regulators of cellular fate is the FoxO sub family of forkhead transcription factors, consisting of FoxO3a, FoxO1, FoxO4, and FoxO6. Recent evidence suggests that FoxO proteins function as tumor suppressors and promote their growth suppressive effects by up regulating the expression of cell cycle inhibitory genes and pro apoptotic genes, such as FasL TRAIL, and Bim. Therefore, the transcriptional