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Pb1896: Whole Exome Sequencing Identifies a Novel Transcription Factor Associated With Fatal Disease Progression in Chronic Myeloid Leukemia

Year: 2022

Type: article

Abstract: Background: Chronic Myeloid Leukemia (CML) primarily develops as a result of t(22;9) that creates Philadelphia chromosome and oncogenic BCR-ABL fusion transcript (1). Discovery of BCR-ABL paved the way for designing signal transduction inhibitor drugs called tyrosine kinase inhibitors (TKIs) that have revolutionized CML treatment in 21st century, by making survival of CML equal to general population (2). Nevertheless, TKIs are minimally effective CML patients progressed to blast crisis (BC-CML). Unfortunately mechanism of CML progression is poorly understood (2). Various transcription factors (TFs) are associated with different diseases and progression of many cancers (3). Although a large number of TFs are involved in pathogenesis of acute leukemias, very little is known about role of TFs in CML progression. Aims: Therefore, objective of this study was to find about novel TFs associated with CML progression. Methods: Patient selection: Whole-exome sequencing (WES) was employed to find out mutations in novel TF-genes associated with accelerated phase (AP-CML) and blast crisis phase CML (BC-CML) patients (Experimental groups 1 & 2, respectively). Chronic phase treatment-naïve CML patients (CP-CML) were used as control 1, CP-CML CML long-term TKI responders (at least 3 continuous years of MMR) as control group 2 and TK-resistant CML patients as control group 3, along with healthy controls. Sample collection: DNA extraction and Clinical follow-up: 10 ml peripheral blood was collected from all study subjects. DNA was extracted and patient follow-up was carried out during course of this study. All treatment criteria per ENL guidelines were adopted. Whole Exome Sequencing (WES): WES was carried out using Illumina NGS instrument (HiSeq). bcl files 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 TF-gene mutants to disease phenotypes (5). TF-genes mutated in all AP/BC-CML patients but not mutated in any of control groups were selected. Variants were confirmed using Sanger sequencing. Results: We found ZNF208 as a novel TF-gene mutated in all AP/BC-CML but in none of the controls. Summary/Conclusion: ZNF208, a member of zing-finger binding transcription factor family, has been reported to be play role as tumor suppressor gene in various cancers through distant signaling pathways (3,6,7). Further studies are required to find exact role of ZNF208 in CML progression and its evaluation as potential biomarker and novel drug target in AP-and BC-CML. References: 1: Schwarz A, Roeder I, Seifert M. Cancers (Basel). 2022 Jan 5;14(1):256. 2: Annunziata M, Bonifacio M, Breccia M, Castagnetti F, Gozzini A, Iurlo A, et al. Front Oncol. 2020;10:883. 3: Hauffe L, Picard D, Musa J, Remke M, Grünewald TGP, Rotblat B, et al. Cell Death Discov. 2022 Feb 28;8(1):91. 4: Hashmi JA, Albarry MA, Almatrafi AM, Albalawi AM, Mahmood A, Basit S. Congenit Anom (Kyoto). 2017 Apr 16. doi: 10.1111/cga.12225. [Epub ahead of print]. 5: R Core Team (2012). R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URLhttp://www.R-project.org/ 6: Roy Choudhury S, Ashby C, Zhan F, van Rhee F. Cancers (Basel). 2021 Dec 17;13(24):6348. 7: Liu B, Li H, Liu X, Li F, Chen W, Kuang Y, et al. CCell Signal. 2021 Aug;84:110012.

Source: HemaSphere

DOI: 10.1097/01.hs9.0000850436.67961.dd