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Home › Dataset Library › Therapeutic potential of spleen tyrosine kinase inhibition for treatment of high-risk precursor B-cell acute lymphoblastic leukemia

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

This study revealed pathogenic role of pre-BCR-independent SYK activation in high-risk B-ALL. Intensified and central nervous system...

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This study revealed pathogenic role of pre-BCR-independent SYK activation in high-risk B-ALL. Intensified and central nervous system (CNS)-directed chemotherapy has significantly improved outcomes for pediatric B-acute lymphoblastic leukemia (B-ALL), but confers significant late-effect morbidities. Moreover, many patients suffer relapses, underscoring the need to develop novel, molecularly targeted B-ALL therapies. Using a mouse model, we showed that leukemic B-cells require pre-B-cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) signaling in vivo. In diagnostic samples from human 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 growth of 69 B-ALL samples, including high-risk (HR) subtypes. Orally administered fostamatinib significantly reduced high disease burden after xenotransplantation of HR B-ALL samples into immune-deficient mice, and decreased leukemia dissemination into spleen, liver, kidneys and the CNS of recipients. Thus, SYK activation sustains growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL. B-cell leukemia samples (3) from a mutant mouse model were compared to sorted or cultured preB or proB cells from normal mice using Affymetrix GeneChip arrays.

Species:
mouse

Samples:
9

Source:
E-GEOD-56345

Updated:
Dec.12, 2014

Registered:
Nov.12, 2014


Factors: (via ArrayExpress)
Sample STRAIN/BACKGROUND CELL TYPE GENOTYPE
GSM1359549 C57B/6 pre-B cells wild type
GSM1359549 C57B/6 pre-B cells wild type
GSM1359549 C57B/6 pre-B cells wild type
GSM1359552 mixed 129/Sv and BALB/C B-cell leukemia cells, arrested in pre-B-like stage p53 -/-; Prkdc scid/scid double-mutant
GSM1359552 mixed 129/Sv and BALB/C B-cell leukemia cells, arrested in pre-B-like stage p53 -/-; Prkdc scid/scid double-mutant
GSM1359552 mixed 129/Sv and BALB/C B-cell leukemia cells, arrested in pre-B-like stage p53 -/-; Prkdc scid/scid double-mutant
GSM1359555 C57B/6 pro-B cells wild type
GSM1359555 C57B/6 pro-B cells wild type
GSM1359555 C57B/6 pro-B cells wild type

Tags

  • acute lymphoblastic leukemia
  • cell
  • central
  • disease
  • leukemia
  • liver
  • lymphoblastic leukemia
  • nervous system
  • spleen
  • tyrosine

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