RT Journal Article
SR Electronic
T1 Therapeutic Potential of Spleen Tyrosine Kinase Inhibition for Treating High-Risk Precursor B Cell Acute Lymphoblastic Leukemia
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 236ra62
OP 236ra62
DO 10.1126/scitranslmed.3008661
VO 6
IS 236
A1 Perova, Tatiana
A1 Grandal, Ildiko
A1 Nutter, Lauryl M. J.
A1 Papp, Eniko
A1 Matei, Irina R.
A1 Beyene, Joseph
A1 Kowalski, Paul E.
A1 Hitzler, Johann K.
A1 Minden, Mark D.
A1 Guidos, Cynthia J.
A1 Danska, Jayne S.
YR 2014
UL http://stm.sciencemag.org/content/6/236/236ra62.abstract
AB 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.