Differential genomics and transcriptomics between tyrosine kinase inhibitor-sensitive and -resistant BCR-ABL-dependent chronic myeloid leukemia

// Neetu Singh 1, * , Anil Kumar Tripathi 2, * , Dinesh Kumar Sahu 1, * , Archana Mishra 3 , Margaret Linan 4 , Bianca Argente 4 , Julia Varkey 4 , Niranjan Parida 1 , Rebecca Chowdhry 5 , Hari Shyam 1 , Nawazish Alam 1 , Shivani Dixit 1 , Pratap Shankar 1 , Abhishek Mishra 1 , Avinash Agarwal 6 , Chris Yoo 4 , Madan Lal Brahma Bhatt 7 and Ravi Kant 8 1 Molecular Biology Unit, Center for Advance Research, King George’s Medical University, Lucknow, India 2 Department of Clinical Hematology, King George’s Medical University, Lucknow, India 3 Department of Cardio Thoracic and Vascular Surgery, King George’s Medical University, Lucknow, India 4 Systems Imagination, Scottsdale, Arizona, USA 5 Department of Periodontics, King George’s Medical University, Lucknow, India 6 Department of Medicine, King George’s Medical University, Lucknow, India 7 Department of Radiotherapy, King George's Medical University, Lucknow, India 8 All India Institute of Medical Sciences, Rishikesh, India * These authors have contributed equally to this work Correspondence to: Neetu Singh, email: neetusingh@kgmcindia.edu 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 ABSTRACT 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.