ArrayExpress Uploader0mouseC57B/6pre-B cellswild typeC57B/6pre-B cellswild typeC57B/6pre-B cellswild typemixed 129/Sv and BALB/CB-cell leukemia cells, arrested in pre-B-like stagep53 -/-; Prkdc scid/scid double-mutantmixed 129/Sv and BALB/CB-cell leukemia cells, arrested in pre-B-like stagep53 -/-; Prkdc scid/scid double-mutantmixed 129/Sv and BALB/CB-cell leukemia cells, arrested in pre-B-like stagep53 -/-; Prkdc scid/scid double-mutantC57B/6pro-B cellswild typeC57B/6pro-B cellswild typeC57B/6pro-B cellswild type7601arrayexpress_sid6This study revealed pathogenic role of pre-BCR-independent SYK activation in high-risk B-ALL. Intensified and central nervous system...E-GEOD-56345/profile/8773/arrayexpressuploader39acute lymphoblastic leukemiacellcentraldiseaseleukemialiverlymphoblastic leukemianervous systemspleentyrosineDec.12, 2014Falsetherapeutic-potential-of-spleen-tyrosine-kinase-inE-GEOD-56345_A-AFFY-45Therapeutic potential of spleen tyrosine kinase inhibition for treatment of high-risk precursor B-cell acute lymphoblastic leukemiaNov.12, 2014This 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.http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-56345http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-56345/samples/