Abstract
Abstract Previously it has been stated that BCR-ABL1 fusion protein is sufficient to induce CML, but additional genomic changes are required for disease progression. Based on this notion, we profiled control and Tyrosine Kinase Inhibitors (TKI)-treated-CML-samples in different-phases supported by copies of BCR-ABL-transcripts. Molecular-profiling was done through Molecular Inversion Probe (MIP) based array, Human Transcriptomics Array2.0, and Axiom Biobank genotyping-arrays. Transcriptionally, clusters of control, TKI-resistant and -sensitive cases were identified which showed correlation with BCR-ABL transcript-levels with the involvement of 228 pathways. On a comparison between TKI-sensitive versus resistant cases, at the exonic level Cassette Exon splicing event was observed in LAPTM4B (0.46), PIEZO2 (0.32), ANGPT1 (0.29), CFH (0.28), HLTF (0.28), SPTLC3 (0.26); Alternative 3' Acceptor Site splicing (0.22); and Junctional splicing in CD109 and ZNF711. These splicing events led to up-regulation of these transcripts. On further processing through Reactome Pathway, we identified over-expression of Hemostasis pathway in CML-resistant cases with specific involvement of Tie2 and Basigin signalling pathway. Based on CNV profiling, we identified low CNVs in CP-new and CP-UT-TKIs-sensitive cases with undetectable or <10% BCR-ABL copies. While, high CNVs (previously reported gain of 9q34) was observed in BCR-ABL-independent and -dependent TKIs-non-sensitive-CP-UT/AP-UT/B-UT and B-new samples. Further, genotyping CML-CP-UT cases with BCR-ABL 10 to 77.02% copies, we identified and validated rsIDs, rsID239798 and rsID9475077 in linkage with FAM83B which may act as potential therapeutic resistance candidate. BCR-ABL1, additional genetic events, over-expression of Tie-2 and Basigin signalling pathway and rsIDs in linkage with FAM83B in TKI resistant cases can be used for developing a signature profile which may help in monitoring therapy. Citation Format: Neetu Singh, Anil Kumar Tripathi, Dinesh Kumar Sahu, Archana Mishra, Margaret Linan, Bianca Argente, Julia Varkey, Rebecca Chowdhry, Avinash Agarwal, Chris Yoo, Ravi Kant, Madan Lal Bhatt. Differential genomics and transcriptomics between tyrosine kinase inhibitor sensitive versus resistant BCR-ABL dependent chronic myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3435.
Published Version
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