Differential genomics and transcriptomics between tyrosine kinase inhibitor-sensitive and -resistant BCR-ABL-dependent chronic myeloid leukemia
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Neetu Singh1,*, Anil Kumar Tripathi2,*, Dinesh Kumar Sahu1,*, Archana Mishra3, Margaret Linan4, Bianca Argente4, Julia Varkey4, Niranjan Parida1, Rebecca Chowdhry5, Hari Shyam1, Nawazish Alam1, Shivani Dixit1, Pratap Shankar1, Abhishek Mishra1, Avinash Agarwal6, Chris Yoo4, Madan Lal Brahma Bhatt7 and Ravi Kant8
1Molecular Biology Unit, Center for Advance Research, King George’s Medical University, Lucknow, India
2Department of Clinical Hematology, King George’s Medical University, Lucknow, India
3Department of Cardio Thoracic and Vascular Surgery, King George’s Medical University, Lucknow, India
4Systems Imagination, Scottsdale, Arizona, USA
5Department of Periodontics, King George’s Medical University, Lucknow, India
6Department of Medicine, King George’s Medical University, Lucknow, India
7Department of Radiotherapy, King George's Medical University, Lucknow, India
8All India Institute of Medical Sciences, Rishikesh, India
*These authors have contributed equally to this work
Neetu Singh, email: email@example.com
Keywords: tyrosine kinase inhibitors; chronic myeloid leukemia; molecular-inversion-probe based array; human-transcriptome array 2.0; axiom biobank array
Received: February 01, 2018 Accepted: May 28, 2018 Published: July 13, 2018
Previously, it has been stated that the BCR-ABL fusion-protein is sufficient to induce Chronic Myeloid Leukemia (CML), but additional genomic-changes are required for disease progression. Hence, we profiled control and tyrosine kinase inhibitors (TKI) alone or in combination with other drug-treated CML-samples in different phases, categorized as drug-sensitive and drug-resistant on the basis of BCR-ABL transcripts, the marker of major molecular-response. Molecular-profiling was done using the molecular-inversion probe-based-array, Human Transcriptomics-Array2.0, and Axiom-Biobank genotyping-arrays. At the transcript-level, clusters of control, TKI-resistant and TKI-sensitive cases were correlated with BCR-ABL transcript-levels. Both at the gene- and exon-levels, up-regulation of MPO, TPX2, and TYMS and down-regulation of STAT6, FOS, TGFBR2, and ITK lead up-regulation of the cell-cycle, DNA-replication, DNA-repair pathways and down-regulation of the immune-system, chemokine- and interleukin-signaling, TCR, TGF beta and MAPK signaling pathways. A comparison between TKI-sensitive and TKI-resistant cases revealed up-regulation of LAPTM4B, HLTF, PIEZO2, CFH, CD109, ANGPT1 in CML-resistant cases, leading to up-regulation of autophagy-, protein-ubiquitination-, stem-cell-, complement-, TGFβ- and homeostasis-pathways with specific involvement of the Tie2 and Basigin signaling-pathway. Dysregulated pathways were accompanied with low CNVs in CP-new and CP-UT-TKI-sensitive-cases with undetectable BCR-ABL-copies. High CNVs (previously reported gain of 9q34) were observed in BCR-ABL-independent and -dependent TKI, non-sensitive-CP-UT/AP-UT/B-UT and B-new samples. Further, genotyping CML-CP-UT cases with BCR-ABL 0-to-77.02%-copies, the identified, rsID239798 and rsID9475077, were associated with FAM83B, a candidate for therapeutic resistance. The presence of BCR-ABL, additional genetic-events, dysregulated-signaling-pathways and rsIDs associated with FAM83B in TKI-resistant-cases can be used to develop a signature-profile that may help in monitoring therapy.
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