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

Oncogene volume 20, pages 3969–3978 (2001)Cite this article

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 has been associated with severe combined immunodeficiency. Childhood CD19+CD10− 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 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 mis-splicing, 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 the first discovery of a specific tyrosine kinase deficiency in a human hematologic malignancy.

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Acknowledgements

We wish to thank Kim Herman-Hatten, Nicole Burkhardt, Brian Juran and Chris Larson for technical assistance. Presented in part as an oral presentation at the 42nd Annual Meeting of the American Society of Hematology, San Francisco, CA, December 2000.

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Authors and Affiliations

  1. Department of Molecular Genetics, Parker Hughes Institute & Parker Hughes Cancer Center, St Paul, 55113, Minnesota, MN, USA

    Patricia A Goodman & Carla M Wood

  2. Department of Biochemistry, Parker Hughes Institute & Parker Hughes Cancer Center, St Paul, 55113, Minnesota, MN, USA

    Alexei Vassilev

  3. Department of Structural Biology, Parker Hughes Institute & Parker Hughes Cancer Center, St Paul, 55113, Minnesota, MN, USA

    Chen Mao

  4. Department of Molecular Oncology, Parker Hughes Institute & Parker Hughes Cancer Center, St Paul, 55113, Minnesota, MN, USA

    Fatih M Uckun

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  1. Patricia A Goodman
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  2. Carla M Wood
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  5. Fatih M Uckun
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Correspondence to Fatih M Uckun.

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Goodman, P., Wood, C., Vassilev, A. et al. Spleen tyrosine kinase (Syk) deficiency in childhood pro-B cell acute lymphoblastic leukemia. Oncogene 20, 3969–3978 (2001). https://doi.org/10.1038/sj.onc.1204515

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