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Titolo:
Spleen tyrosine kinase (Syk) deficiency in childhood pro-B cell acute lymphoblastic leukemia
Autore:
Goodman, PA; Wood, CM; Vassilev, A; Mao, C; Uckun, FM;
Indirizzi:
Parker Hughes Inst, Dept Mol Oncol, St Paul, MN 55113 USA Parker Hughes Inst St Paul MN USA 55113 Mol Oncol, St Paul, MN 55113 USA Parker Hughes Inst, Dept Mol Genet, St Paul, MN 55113 USA Parker Hughes Inst St Paul MN USA 55113 Mol Genet, St Paul, MN 55113 USA Parker Hughes Canc Ctr, St Paul, MN 55113 USA Parker Hughes Canc Ctr St Paul MN USA 55113 nc Ctr, St Paul, MN 55113 USA Parker Hughes Inst, Dept Biochem, St Paul, MN 55113 USA Parker Hughes Inst St Paul MN USA 55113 pt Biochem, St Paul, MN 55113 USA Parker Hughes Inst, Dept Biol Struct, St Paul, MN 55113 USA Parker Hughes Inst St Paul MN USA 55113 iol Struct, St Paul, MN 55113 USA
Titolo Testata:
ONCOGENE
fascicolo: 30, volume: 20, anno: 2001,
pagine: 3969 - 3978
SICI:
0950-9232(20010705)20:30<3969:STK(DI>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
CHILDRENS CANCER GROUP; SEVERE COMBINED IMMUNODEFICIENCY; MOLECULAR-CLONING; CLINICAL-SIGNIFICANCE; RECEPTOR STIMULATION; MEDIATED ACTIVATION; IKAROS ISOFORMS; MESSENGER-RNA; SH2 DOMAINS; PROTEIN;
Keywords:
pro-B cell; B-cell ontogeny; SYK; exon skipping; acute lymphoblastic leukemia;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Uckun, FM Parker Hughes Inst, Dept Mol Oncol, St Paul, MN 55113 USA ParkerHughes Inst St Paul MN USA 55113 , St Paul, MN 55113 USA
Citazione:
P.A. Goodman et al., "Spleen tyrosine kinase (Syk) deficiency in childhood pro-B cell acute lymphoblastic leukemia", ONCOGENE, 20(30), 2001, pp. 3969-3978

Abstract

The cytoplasmic spleen tyrosine kinase (SYK) is a key regulator of signal transduction events, apoptosis and orderly cell cycle progression in B-lineage lymphoid cells, Although SYK has not been linked to a human disease, defective expression of the closely related T-cell tyrosine kinase ZAP-70 hasbeen associated with severe combined immunodeficiency. Childhood CD19(+)CD10(-) pro-B cell acute lymphoblastic leukemia (ALL) is thought to originatefrom B-cell precursors with a maturational arrest at the pro-B cell stage and it is associated with poor prognosis, Since lethally irradiated mice reconstituted with SYK-deficient fetal liver-derived lymphohematopoietic progenitor cells show a block in B-cell ontogeny at the pro-B to pre-B cell transition, we examined the SYK expression profiles of primary leukemic cells from children with pro-B cell ALL, Here we report that leukemic cells from pediatric CD19(+)CD10(-) pro-B cell ALL patients (but not leukemic cells from patients with CD19(+)CD10(+) common pre-pre-B cell ALL) have markedly reduced SYK activity, Sequencing of the reverse transcriptase-polymerase chain reaction (RT-PCR) products of the Syk mRNA in these pro-B leukemia cells revealed profoundly aberrant coding sequences with deletions or insertions,These mRNA species encode abnormal SYK proteins with a missing or truncated catalytic kinase domain, In contrast to pro-B leukemia cells, pre-pre-B leukemia cells from children with CD19+CD10+ common B-lineage ALL and EBV-transformed B-cell lines from healthy volunteers expressed wild-type Syk coding sequences, Examination of the genomic structure of the Syk gene by inter-exonic PCR and genomic cloning demonstrated that the deletions and insertions in the abnormal mRNA species of pro-B leukemia cells are caused by aberrant splicing resulting in either missplicing, exon skipping or inclusion of alternative exons, consistent with an abnormal posttranscriptional regulation of alternative splicing of Syk pre-mRNA, Our findings link for the first time specific molecular defects involving the Syk gene to an immunophenotypically distinct category of childhood ALL, To our knowledge, this is thefirst discovery of a specific tyrosine kinase deficiency in a human hematologic malignancy.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 10/07/20 alle ore 12:18:50