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