Published online November 27, 2006
doi:10.1084/jem.20060967
The Journal of Experimental Medicine, Vol. 203, No. 13, 2829-2840
The Rockefeller University Press, 0022-1007 $30.00
© 2006 Wossning et al.
Deregulated Syk inhibits differentiation and induces growth factor–independent proliferation of pre–B cells
Thomas Wossning1,2,
Sebastian Herzog1,2,
Fabian Köhler1,2,
Sonja Meixlsperger1,2,
Yogesh Kulathu1,2,
Gerhard Mittler3,
Akihiro Abe4,
Uta Fuchs5,
Arndt Borkhardt5, and
Hassan Jumaa1,2
1 Institute of Biology III, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany
2 Department of Molecular Immunology and 3 Department of Cellular and Molecular Immunology, Max-Planck-Institute of Immunobiology, 79108 Freiburg, Germany
4 Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Showa-Ku, Nagoya 466-8550, Japan
5 Department of Pediatric Hematology and Oncology, Children's Hospital, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany
CORRESPONDENCE Hassan Jumaa: jumaa{at}immunbio.mpg.de
The nonreceptor protein spleen tyrosine kinase (Syk) is a key mediator of signal transduction in a variety of cell types, including B lymphocytes. We show that deregulated Syk activity allows growth factor–independent proliferation and transforms bone marrow–derived pre–B cells that are then able to induce leukemia in mice. Syk-transformed pre–B cells show a characteristic pattern of tyrosine phosphorylation, increased c-Myc expression, and defective differentiation. Treatment of Syk-transformed pre–B cells with a novel Syk-specific inhibitor (R406) reduces tyrosine phosphorylation and c-Myc expression. In addition, R406 treatment removes the developmental block and allows the differentiation of the Syk-transformed pre–B cells into immature B cells. Because R406 treatment also prevents the proliferation of c-Myc–transformed pre–B cells, our data indicate that endogenous Syk kinase activity may be required for the survival of pre–B cells transformed by other oncogenes. Collectively, our data suggest that Syk is a protooncogene involved in the transformation of lymphocytes, thus making Syk a potential target for the treatment of leukemia.
Abbreviations used: Abl, Abelson kinase; ALL, acute lymphocytic leukemia; BCR, B cell receptor; IRES, internal ribosome entry sequence; ITAM, immunoreceptor tyrosine-based activation motif; ITK, inducible T cell kinase; PH, pleckstrin homology; PI3-K, phosphatidylinositol 3–kinase; PLC
, phospholipase C; RSS, recombination signal sequences; SH2, Src homology 2; SLP-65, SH2 domain–containing leukocyte protein of 65 kD; Syk, spleen tyrosine kinase; TEL, translocated ETS leukemia.
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