title: A novel Leu153Ser mutation of the Fanconi anemia FANCD2 gene is associated with severe chemotherapy toxicity in a pediatric T-cell acute lymphoblastic leukemia.
abstract: Fanconi anemia (FA) is an autosomal recessive disease characterized by pancitopenia, congenital malformations, predisposition to cancers and chromosomal instability. We report the clinical and molecular features of a patient initially identified as a potential FA case only because of chemotherapy toxicity during the treatment of a T-lineage acute lymphoblastic leukemia (ALL). Cells from this patient showed a moderate chromosomal instability, increasing sensitivity to DNA crosslinking agents but normal response to ionizing radiation. The analysis of FA proteins demonstrated a marked reduction of FANCD2 (>95%), but normal levels of FANCA or FANCG. Interestingly, this defect was associated with a homozygous missense mutation of FANCD2, resulting in a novel amino-acid substitution (Leu153Ser) at residue Leu153, which is highly conserved through evolution. The FANCD2(L153S) protein, whose reduced expression was not due to impaired transcription, was detected also in its monoubiquitinated form in the nucleus, suggesting that the mutation does not affect post-translation modifications or subcellular localization but rather the stability of FANCD2. Therefore, the hypomorphic Leu153Ser mutation represents the first example of a FANCD2 defect that might promote clonal progression of tumors, such as T-ALL, and severe chemotherapy toxicity in patients without any clinical manifestations typical of FA.
authors.affiliation: Department of Biochemistry and Biophysics, F Cedrangolo II, University of Naples, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Borriello
authors.forename: A
authors.initials: A
authors.lastname: Locasciulli
authors.forename: A M
authors.initials: AM
authors.lastname: Bianco
authors.forename: M
authors.initials: M
authors.lastname: Criscuolo
authors.forename: V
authors.initials: V
authors.lastname: Conti
authors.forename: P
authors.initials: P
authors.lastname: Grammatico
authors.forename: S
authors.initials: S
authors.lastname: Cappellacci
authors.forename: A
authors.initials: A
authors.lastname: Zatterale
authors.forename: F
authors.initials: F
authors.lastname: Morgese
authors.forename: V
authors.initials: V
authors.lastname: Cucciolla
authors.forename: D
authors.initials: D
authors.lastname: Delia
authors.forename: F
authors.initials: F
authors.lastname: Della Ragione
authors.forename: A
authors.initials: A
authors.lastname: Savoia
mesh_terms: D019943:Amino Acid Substitution; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D018826:CD13 Antigens; D002648:Child; D043171:Chromosomal Instability; D018450:Disease Progression; D005199:Fanconi Anemia / Q000235:genetics; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D006801:Humans; D007239:Infections / Q000209:etiology / Q000235:genetics; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D010198:Pancytopenia / Q000139:chemically induced / Q000235:genetics; D012074:Remission Induction; D063268:Sialic Acid Binding Ig-like Lectin 3
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D063268:Sialic Acid Binding Ig-like Lectin 3; D018826:CD13 Antigens