Subject(s)
Seizures , Tachycardia, Ventricular , Anticonvulsants/therapeutic use , Arrhythmias, Cardiac , Electroencephalography , Humans , Seizures/diagnosis , Seizures/drug therapy , Seizures/etiology , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/drug therapy , Tachycardia, Ventricular/etiologyABSTRACT
We report a 3-year-old boy with giant and atypical coronary artery aneurysms in the acute phase of Kawasaki disease, despite appropriate therapeutic intervention, in Noonan syndrome with a novel heterozygous PTPN11 mutation, c. 907 G>A (p.Asp303Asn). We hypothesised that this PTPN11 mutation might affect both hyperinflammation caused by Kawasaki disease and vascular fragility in the coronary artery, resulting in coronary artery aneurysms.
Subject(s)
Coronary Aneurysm/etiology , Coronary Vessels/diagnostic imaging , Mucocutaneous Lymph Node Syndrome/complications , Mutation , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Child, Preschool , Coronary Aneurysm/diagnosis , Coronary Aneurysm/genetics , Coronary Angiography , DNA Mutational Analysis , Humans , Male , Noonan Syndrome/complications , Noonan Syndrome/diagnosis , Noonan Syndrome/geneticsABSTRACT
Poly (ADP-ribose) polymerase (PARP) is an indispensable component of the DNA repair machinery. PARP inhibitors are used as cutting-edge treatments for patients with homologous recombination repair (HRR)-defective breast cancers harboring mutations in BRCA1 or BRCA2. Other tumors defective in HRR, including some hematological malignancies, are predicted to be good candidates for treatment with PARP inhibitors. Screening of leukemia-derived cell lines revealed that lymphoid lineage-derived leukemia cell lines, except for those derived from mature B cells and KMT2A (MLL)-rearranged B-cell precursors, were relatively sensitive to PARP inhibitors. By contrast, acute myelogenous leukemia cell lines, except for RUNX1-RUNXT1 (AML1-ETO)-positive lines, were relatively resistant. Intriguingly, TCF3 (E2A)-HLF-positive leukemia was sensitive to PARP inhibitors. TCF3-HLF expression suppressed HRR activity, suggesting that PARP inhibitor treatment induced synthetic lethality. Furthermore, TCF3-HLF expression decreased levels of MCPH1, which regulates the expression of BRCA1, resulting in attenuation of HRR activity. The PARP inhibitor olaparib was also effective in an in vivo xenograft model. Our results suggest a novel therapeutic approach for treating refractory leukemia, particularly the TCF3-HLF-positive subtype.
