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.