Whole exome sequencing identifies a novel FANCD2 gene splice site mutation associated with disease progression in chronic myeloid leukemia: Implication in targeted therapy of advanced phase CML

Pak J Pharm Sci. 2020 May;33(3(Special)):1419-1426.

Abstract

Tyrosine Kinase Inhibitors (TKIs) have significantly improved the clinical outcome of BCR-ABL+ Chronic Phase-Chronic Myeloid Leukemia (CP-CML). Nonetheless, approximately one-third of the CP-CML patient's progress to advanced phases of CML (accelerated and blast phase). Impaired DNA repair including mutations in Fanconi anemia (FA) pathway genes are responsible for progression of many cancers. Nevertheless, FA-pathways genes have never been reported in myeloid cancers. Hence, this study was aimed to discover DNA repair genes associated with CML progression. AP-CML patients were subjected to whole exome sequencing along with appropriate controls. A novel splice site FANCD2 mutation was detected. FANCD2 is a well-known FA-pathway gene with established role in DNA repair. This is first report of FA-pathway DNA repair genes in myeloid cancers that can serve as a novel marker of CML progression to clinically intervene CML progression. Further studies are needed to establish the functional role of FANCD2 in CML progression that can provide novel insights into CML pathogenesis. This study also indicates that a combination TKIs and Poly (ADP-ribose) polymerase (PARP) inhibitors like Olaparib (FDA approved anti-cancer drug for FA-pathway gene mutations) could improve the clinical outcome CML patients in accelerated and blast-crisis phases of the disease.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / genetics*
  • Case-Control Studies
  • Child
  • Disease Progression
  • Exome Sequencing*
  • Fanconi Anemia Complementation Group D2 Protein / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / diagnosis
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Mutation*
  • Phenotype
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
  • Precision Medicine
  • Predictive Value of Tests
  • Protein Kinase Inhibitors / therapeutic use
  • RNA Splice Sites*
  • Young Adult

Substances

  • Biomarkers, Tumor
  • FANCD2 protein, human
  • Fanconi Anemia Complementation Group D2 Protein
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protein Kinase Inhibitors
  • RNA Splice Sites