Spleen tyrosine kinase (Syk) deficiency in childhood pro-B cell acute lymphoblastic leukemia

Citation
Pa. Goodman et al., Spleen tyrosine kinase (Syk) deficiency in childhood pro-B cell acute lymphoblastic leukemia, ONCOGENE, 20(30), 2001, pp. 3969-3978
Citations number
52
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ONCOGENE
ISSN journal
09509232 → ACNP
Volume
20
Issue
30
Year of publication
2001
Pages
3969 - 3978
Database
ISI
SICI code
0950-9232(20010705)20:30<3969:STK(DI>2.0.ZU;2-U
Abstract
The cytoplasmic spleen tyrosine kinase (SYK) is a key regulator of signal t ransduction events, apoptosis and orderly cell cycle progression in B-linea ge lymphoid cells, Although SYK has not been linked to a human disease, def ective expression of the closely related T-cell tyrosine kinase ZAP-70 has been associated with severe combined immunodeficiency. Childhood CD19(+)CD1 0(-) pro-B cell acute lymphoblastic leukemia (ALL) is thought to originate from B-cell precursors with a maturational arrest at the pro-B cell stage a nd it is associated with poor prognosis, Since lethally irradiated mice rec onstituted with SYK-deficient fetal liver-derived lymphohematopoietic proge nitor cells show a block in B-cell ontogeny at the pro-B to pre-B cell tran sition, we examined the SYK expression profiles of primary leukemic cells f rom children with pro-B cell ALL, Here we report that leukemic cells from p ediatric CD19(+)CD10(-) pro-B cell ALL patients (but not leukemic cells fro m patients with CD19(+)CD10(+) common pre-pre-B cell ALL) have markedly red uced SYK activity, Sequencing of the reverse transcriptase-polymerase chain reaction (RT-PCR) products of the Syk mRNA in these pro-B leukemia cells r evealed 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 le ukemia cells from children with CD19+CD10+ common B-lineage ALL and EBV-tra nsformed B-cell lines from healthy volunteers expressed wild-type Syk codin g sequences, Examination of the genomic structure of the Syk gene by inter- exonic PCR and genomic cloning demonstrated that the deletions and insertio ns in the abnormal mRNA species of pro-B leukemia cells are caused by aberr ant splicing resulting in either missplicing, exon skipping or inclusion of alternative exons, consistent with an abnormal posttranscriptional regulat ion of alternative splicing of Syk pre-mRNA, Our findings link for the firs t time specific molecular defects involving the Syk gene to an immunophenot ypically distinct category of childhood ALL, To our knowledge, this is the first discovery of a specific tyrosine kinase deficiency in a human hematol ogic malignancy.