Disovery of Novel Mutations Exclusively Shared By Accelerated and Blast Crisis Phase CML Patients Using Whole Exome Sequencing: Implication in Hunt for Common Biomarker /Drug Target of CML Progression

作     者：Iqbal, Zafar Basit, Salman Jamil, Abid Absar, Muhammad Ullah, Anhar Afzal, Sibtain Mahmood, Aamer Ramzan, Khushnooda Aleem, Aamir Hashmi, Jamil Amjad Rehman, Noor Aljamaan, Khalid Aloraibi, Saleh Saglio, Giuseppe Alanazi, Nawaf Iqbal, Mudassar Akhtar, Tanveer 

作者机构：Pakistan Society for Molecular and Clinical Hematology Lahore Pakistan Centre for Advanced Molecular Biology University of the Punjab Lahore Pakistan Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group Department of Zoology University of the Punjab Lahore Pakistan CAMS-A (College of Applied Medical Sciences Al AHSA) King Saud Bin Abdulaziz University of Health Sciences National Guard Health Affairs Al Ahsa Saudi Arabia Centre for Genetics and Inherited Diseases (CGID) Taibah University Madinah Saudi Arabia Hayatabad Medical Complex Peshawar Pakistan PhD Student Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group Pakistan & HOPES Laboratory Department of Zoology University of the Punjab Lahore Pakistan College of Medicine & King Khalid University Hospital King Saud University (CoM KSU) Riyadh Saudi Arabia PhD Fellow Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group Pakistan & HOPES Laboratory Department of Zoology University of the Punjab Lahore Pakistan Immunology Research Chair College of Medicine & King Khalid University Hospital King Saud University (CoM KSU) Riyadh Saudi Arabia King Faisal Specialist Hospital and Research Centre Riyadh Saudi Arabia Hematology/Oncology (Dept of Medicine) College of Medicine & King Khalid University Hospital King Saud University (CoM KSU) Riyadh Saudi Arabia Center For Genetics and Inherited Diseases Madinah Saudi Arabia Department of Pathology Khyber Medical University Peshawar Pakistan King Saud Bin Abdulaziz University for Health Sciences Riyadh Saudi Arabia Department of Pediatric Hematology/Oncology King Abdullah Specialist Children Hospital King Abdulaziz Medical City Riyadh Saudi Arabia Department of Clinical and Biological Sciences University of Turin Orbassano Turin Italy University of Turin Dept. of Clinical and Biological Sciences Orbassano Italy University of Turin Dept of Clinical and Biological Sciences Orbassano Italy University of Turin Orbassano Italy CAMS-A (College of Applied Medical Sciences Al AHSA) King Saud Bin Abdulaziz University of Health Sciences & King Abdulaziz Hospital National Guard Health Affairs Al Ahsa Saudi Arabia Division of Pediatric Hematology /Oncology Department of Medicine King Abdulaziz Hospital National Guard Health Affairs Al Ahsa Pakistan Asian Medical Institute Bishkek Kyrgyzstan Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group Pakistan & HOPES Laboratory Department of Zoology University of the Punjab Lahore Pakistan 2Pakistan Society for Molecular and Clinical Hematology Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group Pakistan & HOPES Laboratory Department of Zoology University of the Punjab Lahore Pakistan 

出 版 物：《BLOOD》 

年 卷 期：2017年第130卷

页      面：2886-2886页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

摘      要：Introduction: Chronic Myeloid Leukemia (CML) is resulted due t (9;22) which leads to fusion oncogene BCR-ABL. Although chronic phase (CP) CML is treatable, accelerated (AP) and blast phases (BP) have high degrees of drug resistance and subsequent treat failures 1 . Mechanism of this disease progression in CML is poorly understood and few markers studied in this regard are found only in a subset of advanced phase CML patients 2,3 . Therefore, this study was designed to find out common gene mutations (trunk mutations) associated with all advanced phase CML patients. Material and Methods: We investigated imatinib responder AP (N=13), BC (10) and CP (5) CML patients along with age-sex matched healthy controls using whole exome sequencing (WES). Illumina NGS instrument (HiSeq) generated bcl files which were converted to fastq files by using bcl2fastqtool 4 . Raw reads were aligned to genome using BWA tools while whole exome variants were annotated using Illumina Variant Studio 4 . R package was employed to align specific gene mutants to disease phases 5 . In order find a common CML progression biomarkers, gene mutations shared by all patients at a CML phase (so called trunk mutations) were selected and confirmed using Sanger sequencing. Results: Whole exome sequencing revealed novel gene mutations associated with different disease phases in CML. CP CML patients with long term CML response harbored mutations in TTN, PDLIM4, CELF2, ANO5, DOK2, MYO16, RAI1, LTBP3, CNNM3. On the other hand, specific genes were found mutated in AP (EV15L, FAM120B, ZNF208, PML, TMEM145, ASXL1, ABL1) and BC (ATXN3)CML patients. Discussion & Conclusions: All the genes mutated in AP and BC CML were either involved in other cancers or cellular processes like DNA repair, regulation of gene expression (for instance ATXN3 gene mutated in all BC-CML is involved in DNA repair and in repressing expression of some other genes 6 which indicates role of damaged DNA repair in CML blast crisis). Mutations in