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

Pre-BCR–independent activation of spleen tyrosine kinase plays a pathogenic role in high-risk B cell acute lymphoblastic leukemia. 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. Intensified and central nervous system (CNS)–directed chemotherapy has improved outcomes for pediatric B cell acute lymphoblastic leukemia (B-ALL) but confers treatment-related morbidities. Moreover, many patients suffer relapses, underscoring the need to develop new molecular targeted B-ALL therapies. Using a mouse model, we show that leukemic B cells require pre–B cell receptor (pre-BCR)–independent spleen tyrosine kinase (SYK) signaling in vivo for survival and proliferation. In diagnostic samples from human pediatric and adult B-ALL patients, SYK and downstream targets were phosphorylated regardless of pre-BCR expression or genetic subtype. Two small-molecule SYK inhibitors, fostamatinib and BAY61-3606, attenuated the growth of 69 B-ALL samples in vitro, including high-risk (HR) subtypes. Orally administered fostamatinib reduced heavy disease burden after xenotransplantation of HR B-ALL samples into immunodeficient mice and decreased leukemia dissemination into spleen, liver, kidneys, and the CNS of recipient mice. Thus, SYK activation sustains the growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL.