Therapeutic potential of spleen tyrosine kinase inhibition for treating high-risk precursor B cell acute lymphoblastic leukemia

Sci Transl Med. 2014 May 14;6(236):236ra62. doi: 10.1126/scitranslmed.3008661.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Animals
  • Cell Proliferation
  • Cell Survival
  • Child
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Leukemia / drug therapy
  • Male
  • Mice
  • Mice, SCID
  • Mutation
  • Neoplasm Transplantation
  • Niacinamide / analogs & derivatives
  • Niacinamide / chemistry
  • Oligonucleotide Array Sequence Analysis
  • Oxazines / chemistry
  • Phosphorylation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cells, B-Lymphoid / cytology*
  • Protein Kinase Inhibitors / chemistry*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism*
  • Pyridines / chemistry
  • Pyrimidines / chemistry
  • Recurrence
  • Signal Transduction
  • Spleen / enzymology*
  • Syk Kinase
  • Treatment Outcome

Substances

  • 2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide
  • Intracellular Signaling Peptides and Proteins
  • Oxazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Niacinamide
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse
  • fostamatinib