Integrated Genomic Analysis Identifies ANKRD36 Gene as a Novel and Common Biomarker of Disease Progression in Chronic Myeloid Leukemia

Version 1 : Received: 19 August 2021 / Approved: 25 August 2021 / Online: 25 August 2021 (16:03:46 CEST)
Version 2 : Received: 19 December 2023 / Approved: 3 January 2024 / Online: 3 January 2024 (12:14:25 CET)

A peer-reviewed article of this Preprint also exists.

Iqbal, Z.; Absar, M.; Akhtar, T.; Aleem, A.; Jameel, A.; Basit, S.; Ullah, A.; Afzal, S.; Ramzan, K.; Rasool, M.; et al. Integrated Genomic Analysis Identifies ANKRD36 Gene as a Novel and Common Biomarker of Disease Progression in Chronic Myeloid Leukemia. Biology 2021, 10, 1182, doi:10.3390/biology10111182. Iqbal, Z.; Absar, M.; Akhtar, T.; Aleem, A.; Jameel, A.; Basit, S.; Ullah, A.; Afzal, S.; Ramzan, K.; Rasool, M.; et al. Integrated Genomic Analysis Identifies ANKRD36 Gene as a Novel and Common Biomarker of Disease Progression in Chronic Myeloid Leukemia. Biology 2021, 10, 1182, doi:10.3390/biology10111182.

Abstract

Background: Chronic Myeloid Leukemia (CML) is initiated in bone marrow due to chromosomal translocation t(22;9) leading to fusion oncogene BCR-ABL. Targeting BCR-ABL by tyrosine kinase inhibitors (TKI) have changed fatal CML into an almost curable disease. Despite that, TKIs lose their effectiveness due to disease progression. Unfortunately, mechanism of CML progression is poorly understood and common biomarkers for CML progression are unavailable. This study was conducted to find out 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 was carried out using Illumina platforms. Statistical analysis was carried out using [SAS/STAT] software version 9.4 and R package employed to find mutations shared exclusively by all AP-/BC-CML. Confirmation of mutations was carried out using Sanger sequencing and protein structure modelling 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 modelling 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 human. It has the highest expression in bone marrow, specifically myeloid cells. We recommend carrying out further studies to explore the role of ANKRD36 in biology and progression of CML.

Keywords

CML; Disease progression; common biomarker; drug target; ANRD36.

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Comments (1)

Comment 1

Received: 3 January 2024
Commenter: Zafar Iqbal
Commenter's Conflict of Interests: Author

Comment: Chronic myeloid leukemia is a type of blood cancer that is regarded as a success story in determining the exact biological origin, pathogenesis and development of a molecularly targeted (mutation-specific) therapy that has led to successful treatment of this fatal cancer. It is caused by the BCR-ABL fusion gene, which is formed from the translocation between chromosomes 9 and 22. Anti-BCR-ABL drugs, known as tyrosine kinase inhibitors (TKIs), have led to long-term remissions in more than 80% of CML patients and even cure in about one-third of patients. Nevertheless, many patients face drug resistance, and disease progression occurs in about 30% of CML patients, leading to morbidities and mortality. Unfortunately, no biomarkers of CML progression are available due to a poor understanding of the mechanism of progression. Therefore, finding reliable molecular biomarkers of CML progression is one of the most attractive research areas in 21st-century cancer research. In this study, we report novel genomic variants exclusively found in all our advanced-phase CML patients. This study will help in identifying CML patients at risk of disease progression and timely therapeutic interventions to avoid or at least delay fatal disease progression in this cancer.

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