title: Imatinib sensitivity in BCR-ABL1-positive chronic myeloid leukemia cells is regulated by the remaining normal ABL1 allele.
abstract: Chronic myeloid leukemia in chronic phase (CML-CP) cells that harbor oncogenic BCR-ABL1 and normal ABL1 allele often become resistant to the ABL1 kinase inhibitor imatinib. Here, we report that loss of the remaining normal ABL1 allele in these tumors, which results from cryptic interstitial deletion in 9q34 in patients who did not achieve a complete cytogenetic remission (CCyR) during treatment, engenders a novel unexpected mechanism of imatinib resistance. BCR-ABL1-positive Abl1(-/-) leukemia cells were refractory to imatinib as indicated by persistent BCR-ABL1-mediated tyrosine phosphorylation, lack of BCR-ABL1 protein degradation, increased cell survival, and clonogenic activity. Expression of ABL1 kinase, but not a kinase-dead mutant, restored the antileukemic effects of imatinib in ABL1-negative chronic myelogenous leukemia (CML) cells and in BCR-ABL1-positive Abl1(-/-) murine leukemia cells. The intracellular concentration of imatinib and expression of its transporters were not affected, although proteins involved in BCR-ABL1 degradation were downregulated in Abl1(-/-) cells. Furthermore, 12 genes associated with imatinib resistance were favorably deregulated in Abl1(-/-) leukemia. Taken together, our results indicate that loss of the normal ABL1 kinase may serve as a key prognostic factor that exerts major impact on CML treatment outcomes.
authors.affiliation: Molecular Cytogenetics Laboratory, Academic Hematology, University College London Cancer Institute, Royal Free Campus, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Virgili
authors.forename: Mateusz
authors.initials: M
authors.lastname: Koptyra
authors.forename: Yashodhara
authors.initials: Y
authors.lastname: Dasgupta
authors.forename: Eliza
authors.initials: E
authors.lastname: Glodkowska-Mrowka
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stoklosa
authors.forename: Elisabeth P
authors.initials: EP
authors.lastname: Nacheva
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D002871:Chromosome Banding; D055028:Comparative Genomic Hybridization; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate