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Integrated Genomic Sequencing in Myeloid Blast Crisis Chronic Myeloid Leukemia (Mbc-Cml), Identified Potentially Important Findings in the Context of Leukemogenesis Model Publisher Pubmed



Kazemisefat GE1, 2 ; Keramatipour M3 ; Vaezi M4 ; Razavi SM5 ; Kavousi K6 ; Talebi A7 ; Rostami S4 ; Yaghmaei M4 ; Chahardouli B4 ; Talebi S8 ; Mousavizadeh K2, 9
Authors
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Authors Affiliations
  1. 1. Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
  2. 2. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
  3. 3. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Oncopathology Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
  6. 6. Laboratory of Complex Biological Systems and Bioinformatics (CBB), Department of Bioinformatics, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
  7. 7. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  8. 8. Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
  9. 9. Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

Source: Scientific Reports Published:2022


Abstract

Chronic myeloid leukemia (CML) is a model of leukemogenesis in which the exact molecular mechanisms underlying blast crisis still remained unexplored. The current study identified multiple common and rare important findings in myeloid blast crisis CML (MBC-CML) using integrated genomic sequencing, covering all classes of genes implicated in the leukemogenesis model. Integrated genomic sequencing via Whole Exome Sequencing (WES), Chromosome-seq and RNA-sequencing were conducted on the peripheral blood samples of three CML patients in the myeloid blast crisis. An in-house filtering pipeline was applied to assess important variants in cancer-related genes. Standard variant interpretation guidelines were used for the interpretation of potentially important findings (PIFs) and potentially actionable findings (PAFs). Single nucleotide variation (SNV) and small InDel analysis by WES detected sixteen PIFs affecting all five known classes of leukemogenic genes in myeloid malignancies including signaling pathway components (ABL1, PIK3CB, PTPN11), transcription factors (GATA2, PHF6, IKZF1, WT1), epigenetic regulators (ASXL1), tumor suppressor and DNA repair genes (BRCA2, ATM, CHEK2) and components of spliceosome (PRPF8). These variants affect genes involved in leukemia stem cell proliferation, self-renewal, and differentiation. Both patients No.1 and No.2 had actionable known missense variants on ABL1 (p.Y272H, p.F359V) and frameshift variants on ASXL1 (p.A627Gfs*8, p.G646Wfs*12). The GATA2-L359S in patient No.1, PTPN11-G503V and IKZF1-R208Q variants in the patient No.3 were also PAFs. RNA-sequencing was used to confirm all of the identified variants. In the patient No. 3, chromosome sequencing revealed multiple pathogenic deletions in the short and long arms of chromosome 7, affecting at least three critical leukemogenic genes (IKZF1, EZH2, and CUX1). The large deletion discovered on the short arm of chromosome 17 in patient No. 2 resulted in the deletion of TP53 gene as well. Integrated genomic sequencing combined with RNA-sequencing can successfully discover and confirm a wide range of variants, from SNVs to CNVs. This strategy may be an effective method for identifying actionable findings and understanding the pathophysiological mechanisms underlying MBC-CML, as well as providing further insights into the genetic basis of MBC-CML and its management in the future. © 2022, The Author(s).