Recent genome-wide screens have identified genetic variations in ARID5B associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). We sought to determine the contribution of ARID5B single nucleotide polymorphisms (SNPs) to racial disparities in ALL susceptibility and treatment outcome.We compared the association between ARID5B SNP genotype and ALL susceptibility in whites (> 95% European genetic ancestry; 978 cases and 1,046 controls) versus in Hispanics (> 10% Native American ancestry; 330 cases and 541 controls). We determined the relationships between ARID5B SNP genotype and ALL relapse risk in 1,605 children treated on the Children's Oncology Group (COG) P9904/9905 clinical trials.Among 49 ARID5B SNPs interrogated, 10 were significantly associated with ALL susceptibility in both whites and Hispanics (P < .05), with risk alleles consistently more frequent in Hispanics than in whites. rs10821936 exhibited the most significant association in both races (P = 8.4 × 10(-20) in whites; P = 1 × 10(-6) in Hispanics), and genotype at this SNP was highly correlated with local Native American genetic ancestry (P = 1.8 × 10(-8)). Multivariate analyses in Hispanics identified an additional SNP associated with ALL susceptibility independent of rs10821936. Eight ARID5B SNPs were associated with both ALL susceptibility and relapse hazard; the alleles related to higher ALL incidence were always linked to poorer treatment outcome and were more frequent in Hispanics.ARID5B polymorphisms are important determinants of childhood ALL susceptibility and treatment outcome, and they contribute to racial disparities in this disease.
Ingestion of opsonized pathogens by professional phagocytes results in the generation and release of microbicidal products that are essential for normal host defense. Because these products can result in significant tissue injury, phagocytosis must be regulated to limit damage to the host while allowing for optimal clearance and destruction of opsonized pathogens. To pursue negative regulation of phagocytosis, we assessed the effect of the Src kinase family member, Fgr, on opsonin-dependent phagocytosis by mouse macrophages. We chose Fgr because it is present in high concentrations in circulating phagocytes but is not essential for Fcgamma receptor-mediated ingestion by mouse macrophages. Although expression of Fgr both in a macrophage cell line and in primary macrophages significantly attenuates ingestion mediated by Fcgamma receptors and CR3, it does not affect macropinocytosis or receptor-mediated endocytosis. This selective effect of Fgr is independent of its tyrosine kinase function. After Fcgamma receptor cross-linking, Fgr becomes associated with the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor, SIRPalpha (a member of the signal-regulatory protein family, also known as Src homology 2 domain-containing protein tyrosine phosphatase [SHP] substrate 1 [SHPS-1], brain immunoglobulin-like molecule with tyrosine-based activation motifs [BIT], and P84) and potentiates the association of the phosphatase SHP-1 with SIRPalpha. This association is responsible, at least in part, for decreasing positive signaling essential for optimal phagocytosis. These data demonstrate an important negative regulatory role for this Src kinase family member and suggest that this homeostatic function must be overcome for optimal uptake and clearance of opsonized pathogens.
<p>Supplementary Materials and Methods. Supplementary Table S1. QC of Affymetrix U133_Plus_2.0 Data. Supplementary Table S2. Summary of the Objective Response Measure (ORM) scoring methodology. Supplementary Table S3. Correlation of xenograft with parent U133_Plus_2.0 expression. Supplementary Table S4. Probe sets where parent expression is always greater than xenograft. Supplementary Table S5. Probe sets where xenograft expression is always greater than parent. Supplementary Table S6. Complete summary of in vivo AZD1480 single agent responses for individual mice. Supplementary Table S7. In vitro Combination Indices (CIs) for AZD1480 and selumetinib. Supplementary Table S8. In vivo responses of JAK-mutated ALL xenografts to AZD1480/selumetinib combination treatment. Supplementary Table S9. Complete summary of in vivo AZD1480 single agent and AZD1480/selumetinib combination responses for individual mice. Supplementary Figure S1. Chemical structures of (A) AZD1480 and (B) selumetinib. Supplementary Figure S2. Relationship between high CRLF2 expression and engraftment potential of the P9906 cohort. Supplementary Figure S3. Probe set expression by range. Supplementary Figure S4. Heatmap of microarray gene expression data corresponding to the qRT-PCR data shown in Figure 1. Supplementary Figure S5. In vitro cytotoxicity of AZD1480 against ALL xenograft cells. Supplementary Figure S6. In vivo efficacy of single agent AZD1480 against ALL xenografts. Supplementary Figure S7. Time of drug exposure affects synergistic interactions of AZD1480 and selumetinib against JAK-mutated ALL xenografts. Supplementary Figure S8. The extent of inhibition of the JAK/STAT and MAPK signaling pathways depends on the length of exposure to AZD1480/selumetinib.</p>
Abstract There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2 , CREBBP , WHSC1 , TP53 , USH2A , NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.
