Integrated Genomic Analysis Identifies ANKRD36 Gene as a Novel and Common Biomarker of Disease Progression in Chronic Myeloid Leukemia
Zafar Iqbal,
Muhammad Absar,
Tanveer Akhtar,
Aamer Aleem,
Abid Jameel,
Sulman Basit,
Anhar Ullah,
Sibtain Afzal,
Khushnooda Ramzan,
Mahmood Rasool,
Sajjad Karim,
Zeenat Mirza,
Mudassar Iqbal,
Maryam AlMajed,
Buthinah AlShehab,
Sarah AlMukhaylid,
Nouf AlMutairi,
Nawaf Al-anazi,
Muhammad Farooq Sabar,
Muhammad Arshad,
Muhammad Asif,
Masood Shammas,
Amer Mahmood
Affiliations
Zafar Iqbal
Department of Clinical Laboratory Sciences (CLAB), College of Applied Medical Sciences (CoAMS-A), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC)/Kind Abdullah International Medical Research Centre (KAIMRC)/Saudi Society for Blood and Marrow Transplantation (SSBMT), National Guard Health Affairs (NGHA), Al-Ahsa 31982, Saudi Arabia
Muhammad Absar
Hematology, Oncology and Pharmaco-genetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories (HaSiL), Department of Zoology, University of the Punjab (ZPU), Lahore 54590, Pakistan
Tanveer Akhtar
Hematology, Oncology and Pharmaco-genetic Engineering Sciences (HOPES) Group, Health Sciences Laboratories (HaSiL), Department of Zoology, University of the Punjab (ZPU), Lahore 54590, Pakistan
Aamer Aleem
Division of Hematology/Oncology, Department of Medicine, King Khalid University Hospital (KKUH), College of Medicine, King Saud University, Riyadh 14800, Saudi Arabia
Abid Jameel
Hayatabad Medical Complex, Peshawar 25100, Pakistan
Sulman Basit
Center for Genetics and Inherited Diseases, Taibah University Madinah, Medina 30001, Saudi Arabia
Anhar Ullah
National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK
Sibtain Afzal
Biomedical Research Laboratory, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
Khushnooda Ramzan
Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh 11533, Saudi Arabia
Mahmood Rasool
Center of Excellence in Genomic Medicine Research (CEGMR), Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Sajjad Karim
Center of Excellence in Genomic Medicine Research (CEGMR), Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Zeenat Mirza
King Fahd Medical Research Center, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Mudassar Iqbal
Asian Medical Institute, Kant 725012, Kyrgyzstan
Maryam AlMajed
Department of Clinical Laboratory Sciences (CLAB), College of Applied Medical Sciences (CoAMS-A), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC)/Kind Abdullah International Medical Research Centre (KAIMRC)/Saudi Society for Blood and Marrow Transplantation (SSBMT), National Guard Health Affairs (NGHA), Al-Ahsa 31982, Saudi Arabia
Buthinah AlShehab
Department of Clinical Laboratory Sciences (CLAB), College of Applied Medical Sciences (CoAMS-A), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC)/Kind Abdullah International Medical Research Centre (KAIMRC)/Saudi Society for Blood and Marrow Transplantation (SSBMT), National Guard Health Affairs (NGHA), Al-Ahsa 31982, Saudi Arabia
Sarah AlMukhaylid
Department of Clinical Laboratory Sciences (CLAB), College of Applied Medical Sciences (CoAMS-A), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC)/Kind Abdullah International Medical Research Centre (KAIMRC)/Saudi Society for Blood and Marrow Transplantation (SSBMT), National Guard Health Affairs (NGHA), Al-Ahsa 31982, Saudi Arabia
Nouf AlMutairi
Department of Clinical Laboratory Sciences (CLAB), College of Applied Medical Sciences (CoAMS-A), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC)/Kind Abdullah International Medical Research Centre (KAIMRC)/Saudi Society for Blood and Marrow Transplantation (SSBMT), National Guard Health Affairs (NGHA), Al-Ahsa 31982, Saudi Arabia
Nawaf Al-anazi
Department of Clinical Laboratory Sciences (CLAB), College of Applied Medical Sciences (CoAMS-A), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC)/Kind Abdullah International Medical Research Centre (KAIMRC)/Saudi Society for Blood and Marrow Transplantation (SSBMT), National Guard Health Affairs (NGHA), Al-Ahsa 31982, Saudi Arabia
Muhammad Farooq Sabar
Centre for Applied Molecular Biology (CAMB), University of the Punjab, Lahore 54590, Pakistan
Muhammad Arshad
Department of Biological Sciences, International Islamic University, Islamabad 44000, Pakistan
Muhammad Asif
Research Operations and Development, BUITEMS, Quetta 87300, Balochistan, Pakistan
Masood Shammas
Department of Medical Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA 02115, USA
Amer Mahmood
Cancer Stem Cell Unit, Department of Anatomy, King Saud University, 11461 Riyadh, Saudi Arabia
Background: Chronic myeloid leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(9;22) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKIs) has changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, the mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find novel biomarkers of CML progression by employing whole-exome sequencing (WES). Materials and Methods: WES of accelerated phase (AP) and blast crisis (BC) CML patients was carried out, with chronic-phase CML (CP-CML) patients as control. After DNA library preparation and exome enrichment, clustering and sequencing were carried out using Illumina platforms. Statistical analysis was carried out using SAS/STAT software version 9.4, and R package was employed to find mutations shared exclusively by all AP-/BC-CML patients. Confirmation of mutations was carried out using Sanger sequencing and protein structure modeling using I-TASSER followed by mutant generation and visualization using PyMOL. Results: Three novel genes (ANKRD36, ANKRD36B and PRSS3) were mutated exclusively in all AP-/BC-CML patients. Only ANKRD36 gene mutations (c.1183_1184 delGC and c.1187_1185 dupTT) were confirmed by Sanger sequencing. Protein modeling studies showed that mutations induce structural changes in ANKRD36 protein. Conclusions: Our studies show that ANKRD36 is a potential common biomarker and drug target of early CML progression. ANKRD36 is yet uncharacterized in humans. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in the biology and progression of CML.
