ABSTRACT
Therapy-related acute myeloid leukemia (t-AML) caused by MLL rearrangements (rMLL) can arise from topoisomerase II agents. However, whether rMLL-related leukemogenesis is inextricably linked to drug cytotoxicity remains controversial. We therefore compared (i) rMLL in children with acute lymphoblastic leukemia (ALL) who developed t-AML and those who did not, (ii) epipodophyllotoxin toxicity in patients with t-AML and in controls, and (iii) rMLL in cells sensitive to etoposide and in those resistant to etoposide. In children with ALL, rMLL appeared to be more frequent in children who developed t-AML than in those who did not (seven pairs, P = 0.04), although independent of the cumulative etoposide dose (P = 0.5). Similarly, the frequency of epipodophyllotoxin-related toxicities did not differ between patients with t-AML and controls (26 pairs, P > 0.17). Moreover, in 25 cell lines, etoposide-induced MLL fusions did not differ in sensitive vs. resistant lines at equitoxic concentrations (P = 0.65). Together, these results indicate that epipodophyllotoxin-mediated leukemogenesis is not directly linked to drug cytotoxicity.
Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Etoposide/adverse effects , Leukemia, Myeloid, Acute/chemically induced , Myeloid-Lymphoid Leukemia Protein/drug effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Agents, Phytogenic/administration & dosage , Case-Control Studies , Child , Child, Preschool , Drug Hypersensitivity , Etoposide/therapeutic use , Female , Humans , Leukemia, Myeloid, Acute/physiopathology , Male , Myeloid-Lymphoid Leukemia Protein/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Predictive Value of Tests , Reference Values , Risk AssessmentSubject(s)
Germ-Line Mutation , Ligases/genetics , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , von Hippel-Lindau Disease/genetics , Brazil , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Family Health , Gene Frequency , Genotype , Humans , Phenotype , Von Hippel-Lindau Tumor Suppressor Protein , von Hippel-Lindau Disease/pathologyABSTRACT
INTRODUCTION: We present herein clinical, histological and magnetic resonance imaging (MRI) findings in a patient with Fukuyama-type congenital muscular dystrophy (FCMD). He is the first case report in the Japanese population living in Brazil. CASE REPORT: The child presented with neonatal hypotonia, delayed motor abilities and speech, seizures, cerebral and cerebellar gyrus abnormalities with signal intensity change in the white matter by MRI, high serum level of creatinephosphokinase (CK), and dystrophic skeletal muscle with normal merosin, alpha-sarcoglycan and dystrophin expression. The fukutin gene study showed one founder 3-kb retrotransposal insertion in the 3'-non-coding region, and in the other allele no mutation was detected after screening all exons and flanking introns by sequencing. DISCUSSION: This case report emphasizes the importance to consider FCMD in Japanese people living in other countries.
