title: Disrupting BCR-ABL in combination with secondary leukemia-specific pathways in CML cells leads to enhanced apoptosis and decreased proliferation.
abstract: Chronic myeloid leukemia (CML) is a myeloproliferative disorder caused by expression of the fusion gene BCR-ABL following a chromosomal translocation in the hematopoietic stem cell. Therapeutic management of CML uses tyrosine kinase inhibitors (TKIs), which block ABL-signaling and effectively kill peripheral cells with BCR-ABL. However, TKIs are not curative, and chronic use is required in order to treat CML. The primary failure for TKIs is through the development of a resistant population due to mutations in the TKI binding regions. This led us to develop the mutant coiled-coil, CC(mut2), an alternative method for BCR-ABL signaling inhibition by targeting the N-terminal oligomerization domain of BCR, necessary for ABL activation. In this article, we explore additional pathways that are important for leukemic stem cell survival in K562 cells. Using a candidate-based approach, we test the combination of CC(mut2) and inhibitors of unique secondary pathways in leukemic cells. Transformative potential was reduced following silencing of the leukemic stem cell factor Alox5 by RNA interference. Furthermore, blockade of the oncogenic protein MUC-1 by the novel peptide GO-201 yielded reductions in proliferation and increased cell death. Finally, we found that inhibiting macroautophagy using chloroquine in addition to blocking BCR-ABL signaling with the CC(mut2) was most effective in limiting cell survival and proliferation. This study has elucidated possible combination therapies for CML using novel blockade of BCR-ABL and secondary leukemia-specific pathways.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah College of Pharmacy, Salt Lake City, Utah 84108, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Woessner
authors.forename: Carol S
authors.initials: CS
authors.lastname: Lim
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C060192:MUC1 protein, human; D018396:Mucin-1; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl