Research ArticleLeukemia

Therapeutic Potential of Spleen Tyrosine Kinase Inhibition for Treating High-Risk Precursor B Cell Acute Lymphoblastic Leukemia

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Science Translational Medicine  14 May 2014:
Vol. 6, Issue 236, pp. 236ra62
DOI: 10.1126/scitranslmed.3008661

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Targeting the “SYK-ness” in B-ALL

Intensive chemotherapy in B cell acute lymphoblastic leukemia (B-ALL) provides improved outcomes for children and achieves remission in adults, but patients in both groups relapse, resulting in low survival rates. The discovery of aberrant signaling pathways in cancers has spurred development of targeted kinase inhibitors. In a mouse model of spontaneous B-ALL, Perova et al. demonstrate that aberrant activation of the spleen tyrosine kinase (SYK) was required for leukemic cell growth. SYK pathway activity and B-ALL cell survival were sensitive to two inhibitors of SYK signaling. Like the mouse model, the authors show that primary pediatric and adult human B-ALL samples exhibited basal SYK activation. Phosphorylation of SYK and its targets and leukemic cell proliferation were attenuated by in vitro treatment of the human leukemic cells with SYK inhibitors. Xenotransplantation of poor-prognosis primary human B-ALL samples into immunodeficient mice resulted in extensive bone marrow engraftment and dissemination to spleen, liver, and central nervous system. In vivo treatment of the transplanted animals with SYK inhibitors reduced human leukemia burden in these tissues. Thus, SYK activation regulates key signal transduction pathways of abnormal growth in multiple subtypes of B-ALL, suggesting that small-molecule SYK inhibitors may be promising agents for treating poor-prognosis and relapsed B-ALL.