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

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abstract

  • 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.

authors

  • Perova, T
  • Grandal, I
  • Nutter, LMJ
  • Papp, E
  • Matei, IR
  • Beyene, Joseph
  • Kowalski, PE
  • Hitzler, JK
  • Minden, MD
  • Guidos, CJ
  • Danska, JS

publication date

  • May 14, 2014

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