In a study reported in Science Translational Medicine, Perova and colleagues found that pre–B-cell receptor–independent spleen tyrosine kinase signaling was necessary for leukemic B-cell survival and proliferation in a mouse model. Investigation of samples from pediatric and adult B-cell acute lymphoblastic leukemia (ALL) showed that spleen tyrosine kinase and downstream targets were phosphorylated independently of pre–B-cell receptor expression or genetic subtype.
Studies with two small-molecule spleen tyrosine kinase inhibitors showed reduced growth in vitro of B-cell ALL subtypes, including high-risk subtypes. Treatment of immunodeficient mice with one of the inhibitors reduced disease burden in high-risk B-cell ALL xenografts and decreased dissemination of leukemia into the spleen, liver, kidney, and central nervous system.
The investigators concluded, “[Spleen tyrosine kinase] activation sustains the growth of multiple [high-risk] B-ALL subtypes, suggesting that [spleen tyrosine kinase] inhibitors may improve outcomes for [high-risk] and relapsed B-ALL.” ■