title: Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression.
abstract: BCR-ABL kinase domain (KD) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-KDmutations in chronic phase (n = 41), late chronic phase (n = 33) and accelerated phase (n = 16) imatinib responders. Direct sequencing analysis was used for this purpose. Eleven patients (12.22%) in late-CP CML were detected having total 24 types of point mutations, out of which 8 (72.72%) harbored compound mutated sites. SH2 contact site mutations were dominant in our study cohort, with E355G (3.33%) being the most prevalent. Five patients (45%) all having compound mutated sites, progressed to advanced phases of disease during follow up studies. Two novel silent mutations G208G and E292E/E were detected in combination with other mutants, indicating limited tolerance for BCR-ABL1 kinase domain for missense mutations. However, no patient in early CP of disease manifested mutated ABL-KD. Occurrence of mutations was found associated with elevated platelet count (p = 0.037) and patients of male sex (p = 0.049). The median overall survival and event free survival of CML patients (n = 90) was 6.98 and 5.8 y respectively. The compound missense mutations in BCR-ABL kinase domain responsible to elicit disease progression, drug resistance or disease relapse in CML, can be present in yet Imatinib sensitive patients. Disease progression observed here, emphasizes the need of ABL-KDmutation screening in late chronic phase CML patients for improved clinical management of disease.
authors.affiliation: a Institute of Molecular Biology and Biotechnology, The University of Lahore , Lahore , Pakistan.|b Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Research Laboratories , Department of Zoology, University of the Punjab , Lahore , Pakistan.
authors.forename: Afia Muhammad
authors.initials: AM
authors.lastname: Akram
authors.affiliation: b Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Research Laboratories , Department of Zoology, University of the Punjab , Lahore , Pakistan.|c Cancer and Medical Genetics, CAMS-A, King Saud Bin Abdulaziz University for Health Sciences & King Abdullah International Medical Research Centre (KAIMRC), King Abdulaziz Medical City, National Guard Health Affairs , Al Ahsa , Saudi Arabia.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: b Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Research Laboratories , Department of Zoology, University of the Punjab , Lahore , Pakistan.
authors.forename: Tanveer
authors.initials: T
authors.lastname: Akhtar
authors.affiliation: a Institute of Molecular Biology and Biotechnology, The University of Lahore , Lahore , Pakistan.
authors.forename: Ahmed Mukhtar
authors.initials: AM
authors.lastname: Khalid
authors.affiliation: d Centre for Applied Molecular Biology (CAMB), University of the Punjab , Lahore , Pakistan.
authors.forename: Muhammad Farooq
authors.initials: MF
authors.lastname: Sabar
authors.affiliation: a Institute of Molecular Biology and Biotechnology, The University of Lahore , Lahore , Pakistan.
authors.forename: Mahmood Hussain
authors.initials: MH
authors.lastname: Qazi
authors.affiliation: e Department of Oncology , Hameed Latif Hospital , Lahore , Pakistan.
authors.forename: Zeba
authors.initials: Z
authors.lastname: Aziz
authors.affiliation: f Department of Hematology and Oncology , Institute of Nuclear Medicine and Oncology , Lahore , Pakistan.
authors.forename: Nadia
authors.initials: N
authors.lastname: Sajid
authors.affiliation: g College of Medicine and King Khalid University Hospital, King Saud University , Riyadh , Saudi Arabia.
authors.forename: Aamer
authors.initials: A
authors.lastname: Aleem
authors.affiliation: h Centre of Excellence in Genomic Medicine Research, King Abdulaziz University , Jeddah , Saudi Arabia.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Rasool
authors.affiliation: i Department of Biotechnology , Office of Research Innovation and Commercialization, Balochistan University of Information Technology, Engineering and Management Sciences , Quetta , Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Asif
authors.affiliation: j College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, National Guard- Health Affairs , Riyadh , Saudi Arabia.
authors.forename: Saleh
authors.initials: S
authors.lastname: Aloraibi
authors.affiliation: k Division of Pediatric Hematology/Oncology, Department of Oncology/King Saud Bin Abdulaziz University for Health Sciences , King Abdulaziz Medical City, National Guard Health Affairs , Riyadh , Saudi Arabia.
authors.forename: Khaled
authors.initials: K
authors.lastname: Aljamaan
authors.affiliation: b Hematology Oncology and Pharmacogenetic Engineering Sciences (HOPES) Group, Health Sciences Research Laboratories , Department of Zoology, University of the Punjab , Lahore , Pakistan.|l Asian Medical Institute, Kant City, & National Surgical Centre , Bishkek , Kyrgyzstan.
authors.forename: Mudassar
authors.initials: M
authors.lastname: Iqbal
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D010976:Platelet Count; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: BCR-ABL; chronic myeloid leukemia; compound mutations; disease progression; late chronic phase