Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ∼67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1β and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+ cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.

Background/Objectives: Exclusive enteral nutrition (EEN) is a safe and effective treatment modality for inducing remission in paediatric Crohn’s disease (CD). The primary aim of this study was to compare the outcomes of EEN to corticosteroid (CS) therapy in newly diagnosed, treatment-naïve patients with CD. A secondary aim was to describe the outcomes of EEN in a national cohort of paediatric CD patients over a 10-year period. Subjects/Methods: A retrospective chart review was conducted at the Irish national referral centre for paediatric CD. A case-matched analysis was conducted on two cohorts matched for age, gender, disease location, disease behaviour and disease activity, who received CS or EEN as their initial treatment. Subsequently, cohort analysis was conducted on all patients who undertook a course of EEN therapy between 2004 and 2013. Results: The case-matched analysis found higher remission rates after treatment with EEN (24/28, 86%) compared with those with CS (15/28, 54%; P =0.02). Dietetic contacts were found to be pivotal to the success of treatment and the attainment of remission. In total, 59 patients completed EEN at some time-point in their disease course and were included in the cohort analysis. Sixty-nine per cent of this cohort entered clinical remission (41/59). EEN was found to be most effective when used as an initial treatment ( P =0.004) and less effective in patients aged under 10 years ( P =0.04). Conclusions: EEN should be strongly considered as a favourable primary treatment over CS, especially in those diagnosed over the age of 10 years.

A role for the IL-36 family of cytokines has been identified in the pathogenesis of psoriasis. Although significant mechanistic overlap can exist between psoriasis and inflammatory bowel disease (IBD), to date there have been no reports investigating the IL-36 family in gastrointestinal inflammation. Here we demonstrate that expression levels of IL-36α are specifically elevated in the colonic mucosa of ulcerative colitis patients. This elevated expression is mirrored in the inflamed colonic mucosa of mice, wherein IL-36 receptor deficiency confirmed this pathway as a mediator of mucosal inflammation. Il36r−/− mice exhibited reduced disease severity in an acute DSS-induced model of colitis in association with decreased innate inflammatory cell infiltration to the colon lamina propria. Consistent with these data, infection with the enteropathogenic bacteria Citrobacter rodentium, resulted in reduced innate inflammatory cell recruitment and increased bacterial colonization in the colons of il36r−/− mice. Il36r−/− mice also exhibited altered T helper cell responses in this model, with enhanced Th17 and reduced Th1 responses, demonstrating that IL-36R signaling also regulates intestinal mucosal T-cell responses. These data identify a novel role for IL-36 signaling in colonic inflammation and indicate that the IL-36R pathway may represent a novel target for therapeutic intervention in IBD.

Background: Recent 'omics'-based approaches have revealed that acute myeloid leukemia (AML) has significant genetic heterogeneity, and that clonal evolution in AML occurs through stepwise acquisition of somatic mutations. However, extrinsic factors may also influence this process. Here we provide strong evidence that inflammatory cytokines secreted in the AML microenvironment play a critical role in clonal expansion and disease progression. Specifically, we show that the proinflammatory cytokine IL-1 promotes in vitro clonal expansion in a large subset of primary AML samples and in vivo disease progression in a murine AML model.

General estimates suggest 9-47% of hospitalised children may be at risk of malnutrition1 and subsequently many organisations recommend formal nutrition screening of all children on admission to hospital2,3,4. The Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP©) was recently developed to identify nutrition risk in hospitalised children aged 2-16 years5. The aim of this pilot study was to evaluate the use of STAMP© in infants under 2 years of age. Infants, aged 2 weeks to 2 years, were recruited from February to May 2012 on admission to participating infant wards in two tertiary children’s hospitals in Dublin. STAMP© was completed by the admitting nurse or project assistant. A subset of patients underwent a full nutrition assessment by a registered dietitian, utilising an adapted version of the Subjective Global Nutritional Assessment (SGNA) tool6. The validity, sensitivity and specificity of STAMP© were assessed by comparing nutrition risk as identified by the tool against the classification of nutrition risk as determined by the full nutritional assessment. In total, 59 infants were recruited to undergo a full nutritional assessment following STAMP© nutrition risk screening. Evaluation of STAMP© demonstrated moderate reliability in predicting nutrition risk compared to that determined by the full nutritional assessment (= 0.808; 95% CI 0.317, 0.633). Strong inter-rater reliability (=0.658) was observed when STAMP© was completed by both a dietitian and nurse/project assistant.Table 1Calculation of the statistic, sensitivity, specificity, positive and negative predictive values for malnutrition risk agreement between a full nutrition assessment and STAMP©.STAMP© nutrition screening tool riskLow risk∗High riskFull nutrition assessmentLow risk345High risk019Total3424Sensitivity (%)100Specificity (%)87 (0.785, 0.955)†PPV (%)79 (0.687, 0.893)†NPV (%)100Statistic‡0.808 (0.317, 0.633) † Open table in a new tab The results of this pilot study suggest that STAMP© would be a valid nutrition screening tool for identifying malnutrition risk in a general inpatient population aged 2 weeks to 2 years. 1 Puntis J. (2010) 2 Royal College of Nursing (2006) 3 Brotherton A., et al. (2010) 4 Agostoni C, et al. (2005) 5 McCarthy H. et al. (2012) 6 Secker D. & Jeejeebhoy K. (2012)

Background: p38 mitogen-activated protein kinase (p38MAPK) is activated by various pro-inflammatory and stress-related stimuli, and has been an attractive therapeutic target for autoimmune diseases. p38MAPK (hereafter referred to as p38) signaling is also involved in cell proliferation, differentiation, apoptosis, and invasion, suggesting that it may be a potential therapeutic target for cancer. We found that inflammatory cytokines, including interleukin-1 (IL-1), promote growth and survival of more than half of the acute myeloid leukemia (AML) patient samples we tested. Since p38 is a downstream mediator of inflammatory pathways, we hypothesized that targeting p38 might be an effective therapeutic strategy in AML and other hematologic malignancies. To test this hypothesis, we evaluated the effectiveness of three p38 inhibitors using in vitro studies in primary AML patient samples. We found that targeting p38 blocks IL-1-activated extrinsic signaling and is a critical therapeutic target in a large subset of AML patients.

Weight and height measurements are fundamental in the monitoring of normal growth and development, identification of growth and endocrine disorders, examining disease impact, calculation and provision of nutrition support, calculating drug dosage, assessing fluid balance and choosing appropriate clinical and resuscitation equipment. Proxy measures for weight and height, such as mid upper arm circumference, arm span and knee height, have been suggested for use in clinical situations where weight and height cannot be easily measured1-5. The aim of this study was to identify valid proxy measures that can accurately predict weight and height in healthy school children. Participants, aged 11-18 years, were recruited from post primary schools throughout the island of Ireland. All participants with written parental consent were measured in minimal clothing by two researchers. Measurements recorded included weight, height, mid upper arm circumference, waist circumference, lower leg length, knee height, foot length, upper arm length and arm span. The strength of correlation between weight and height and their potential proxy measures were examined. Strong correlation was observed between weight and mid upper arm circumference (R2=0.713). Correlation coefficients between height and segmental proxy measures were as follows: upper arm length (R2=0.355), lower leg length (R2=0.712), knee height (R2=0.705), arm span (R2=0.653) and foot length (R2=0.605). Prediction equations for weight and height based on the strongest predictive proxy measures were determined.Table 1Prediction equations for weight and height estimation using MUAC, WC, AS, KH and FL (OC76).GenderDependent variableIndependent variableEquationSEER2MaleWeightMUAC-23.638 + 2.382 (MUAC) + 1.272 (Age∗)7.3800.591HeightAS34.343 + 0.561 (AS) + 2.726 (Age)5.1990.667KH23.529 + 2.135 (KH) + 2.273 (Age)4.6330.736FL19.790 + 4.819 (FL) + 2.121 (Age)5.6190.614FemaleWeightMUAC-39.698 + 3.127 (MUAC) + 1.346 (Age)4.9400.817HeightAS47.448 + 0.639 (AS) + 0.745 (Age)4.4470.683KH34.740 + 2.164 (KH) + 1.393 (Age)4.3700.693FL25.650 + 4.182 (FL) + 2.547 (Age)4.5440.668 Open table in a new tab SEE, Standard Error of the Mean; MUAC, Mid Upper Arm Circumference; LLL, Lower Leg Length; KH, Knee Height; UAL, Upper Arm Length; FL, Foot Length; AS, Arm Span Child’s actual age in decimal years The results of this current study support the potential use of mid upper arm circumference as a proxy measure for weight while knee height may provide a practical predictive proxy measure for height in children. The regression equations reported here could potentially be used in a number of clinical and dietetic settings to facilitate the estimation of weight and height in children for whom these measures are not easily attainable. 1Stallings et al., (1995) 2Stevenson et al., (1995) 3Kanchan et al. (2008) 4Mazicioglu et al., (2009) 5Yabanci et al., (2010)

Abstract Background: Acute myeloid leukemia (AML) represents the most common type of leukemia in adults and is associated with high morbidity and mortality. Targeted therapy represents a promising approach in AML with the potential for increased efficacy and reduced toxicity. Because recent studies have demonstrated that certain inflammatory cytokines known to suppress normal hematopoiesis have the opposite effect (ie. enhancing proliferation) on cell growth of AML cells, we systematically assessed the functional relevance of 90 cytokines and their receptors in primary human AML cells. Here we present a novel role of Interleukin-1 (IL-1) signaling in aberrant regulation of AML cell growth. Methods and Results: To identify functionally important cytokine signaling pathways in leukemia pathogenesis we took a two pronged approach. First, we quantified the growth of 45 primary AML patient samples against graded concentrations of 90 cytokines. Second, we employed a functional siRNA screen targeting 188 cytokine receptors that were found highly expressed in 140 primary leukemia samples by gene expression analysis. Using this approach we identified that IL-1 signaling had the most dramatic effect. Forty percent of AML samples exhibited a 5-25 fold increase in growth in the presence of IL-1α/β. Paradoxically, IL-1 suppressed growth of normal CD34+ cells. Silencing the IL-1 receptor, IL1R1, reduced the viability of these AML primary samples by 60%. Most IL-1 sensitive AML samples exhibit monocytic and myelomonocytic features; however, no correlation with specific somatic mutations has thus far been observed. IL-1 responsive samples are from patients with abnormally increased serum IL-1β levels (5 fold). Consistent with this, conditioned media from the mononuclear cells of these samples promote the growth of AML CD34+ cells. Deep sequencing of primary AML samples indicated that genes encoding signaling molecules of IL-1 pathway (IL1R1, IL1RAP, MYD88, TRAF6, IRAK, IKK, cJUN, NFκB and p38) are normal. We confirmed the importance of IL1R1 using a genetic model. We found that the absence of IL1R1 in murine bone marrow leads to significant ablation of clonogenic potential (80% reduction) of oncogene-induced leukemic cells (AML1-ETO9a, NRASG12D and MLL-ENL) when compared to oncogene-induced leukemic cells from wild type mice. However, no effect on colony growth was observed with empty vector controls. These results suggest that multiple genetic drivers of leukemia share a dysfunctional IL-1 pathway. Mechanistically, IL-1 promotes CD34+ AML cell survival by increasing p38 phosphorylation that is significantly inhibited with IL1R1 knockdown or p38 kinase inhibitors such as Doramapimod. No toxic effect of Doramapimod was observed on normal cell growth. Conclusion: These results demonstrate a novel role for IL-1 signaling in promoting oncogenesis in AML and provide evidence that targeting this pathway might be beneficial to AML patients. Citation Format: Anupriya Agarwal, Alyssa Carey, Elie Traer, Jeffrey Tyner, Grover C. Bagby, Brian J. Druker. Targeted suppression of interleukin-1 signaling inhibits growth of primary human acute myeloid leukemia cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5248. doi:10.1158/1538-7445.AM2014-5248

Recent studies have revealed that p27, a nuclear cyclin-dependent kinase (Cdk) inhibitor and tumor suppressor, can acquire oncogenic activities upon mislocalization to the cytoplasm. To understand how these antagonistic activities influence oncogenesis, we dissected the nuclear and cytoplasmic functions of p27 in chronic myeloid leukemia (CML), a well-characterized malignancy caused by the BCR-ABL1 tyrosine kinase. p27 is predominantly cytoplasmic in CML and nuclear in normal cells. BCR-ABL1 regulates nuclear and cytoplasmic p27 abundance by kinase-dependent and -independent mechanisms, respectively. p27 knockdown in CML cell lines with predominantly cytoplasmic p27 induces apoptosis, consistent with a leukemogenic role of cytoplasmic p27. Accordingly, a p27 mutant (p27(CK-)) devoid of Cdk inhibitory nuclear functions enhances leukemogenesis in a murine CML model compared with complete absence of p27. In contrast, p27 mutations that enhance its stability (p27(T187A)) or nuclear retention (p27(S10A)) attenuate leukemogenesis over wild-type p27, validating the tumor-suppressor function of nuclear p27 in CML. We conclude that BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. These findings suggest that cytoplasmic mislocalization of p27 despite BCR-ABL1 inhibition by tyrosine kinase inhibitors may contribute to drug resistance, and effective therapeutic strategies to stabilize nuclear p27 must also prevent cytoplasmic mislocalization.

Background: Despite the great strides that have been made in the treatment of AML, resistance to treatment is common and signaling pathways influencing leukemic cellular proliferation have not been comprehensively defined. Cytokines and growth factors play important roles in cell survival, proliferation, differentiation, senesence, and immune response in both normal and cancer cells. Recent studies have demonstrated that certain inflammatory cytokines known to suppress normal hematopoiesis can have the opposite effect (i.e. enhancement of proliferation) on cell growth of AML cells. To test the importance of this mechanism, we systematically assessed the functional relevance of 98 cytokines and their receptors in primary human AML cells and identified interleukin-1 (IL-1) and its receptor as critical determinants in aberrant regulation of AML cell growth. Methods: To identify functionally important cytokine signaling pathways in AML pathogenesis we first quantified the proliferation of 50 primary AML patient samples in the presence of graded concentrations of 98 cytokines. We then employed a functional siRNA screen targeting 188 cytokine and growth factor receptors found to be highly expressed in 140 primary leukemia samples by gene expression analysis. Cytokine pathways of interest were functionally tested for their role as potential therapeutic targets utilizing primary patient samples and in vivo murine models. Results: We found that 40% of primary AML samples exhibited a 3- to 20-fold increase in cellular growth and a 2-fold decrease in apoptosis in the presence of IL-1α/β. Paradoxically, IL-1 suppressed the growth of normal CD34+ cells. Silencing of the IL-1 receptor, IL1R1, reduced the viability of these AML primary samples by 60-80%. Notably, most of the IL-1-sensitive AML samples exhibited monocytic and myelomonocytic features. To demonstrate the importance of IL-1 signaling in the survival of AML cells, we utilized IL1R1-/- mice and oncogene-induced leukemic cells in vitro and in vivo. We observed that IL1R1-/- mice and wild-type mice showed a normal distribution of stem and progenitor populations in their marrow by FACS analysis. Further, the absence of IL1R1 in murine bone marrow leads to a significant ablation of clonogenic potential (80% reduction) of oncogene-induced leukemic cells (AML1-ETO9a, NRASG12D and MLL-ENL) when compared to oncogene-induced leukemic cells from wild-type mice in a ligand-dependent manner. No difference in colony growth was observed with empty vector-transduced marrow cells. In a murine bone marrow transplantation model, recipients of IL1R1-/- marrow transduced with AML1-ETO9a/NRASG12D survived significantly longer for a median of 39 days (range: 28-118) compared to 30 days (range: 27-61) for recipients of wild-type marrow (p=0.012). Mice transplanted with IL1R1-/- marrow or wild-type marrow showed comparable white blood cell and platelet counts. However, histopathological analysis showed a significant reduction in myeloid infiltrates in liver and lungs as well as reduced marrow cellularity and reticulin fibrosis in IL1R1-/- leukemic mice as compared to wild-type leukemic mice. To exclude the possibility that this difference was related to differences in homing and engraftment of wild-type and IL1R1-/- bone marrow cells, we compared short-term homing and long-term engraftment of empty vector-transduced wild-type and IL1R1-/- marrow cells and found no significant differences. These results demonstrate an in vivo role of IL1-receptor in AML cell proliferation and progression. Mechanistically, exogenous IL-1 promotes the growth and survival of primary CD34+ AML cells and AML cell lines by increasing p38 MAPK phosphorylation. Conversely, knocking down IL1R1 or treating AML cells with p38 kinase inhibitors such as doramapimod (n=10; median IC50: 70 nM) reduced the growth of AML cells by decreasing phosphorylation of p38 kinase. No toxic effect of doramapimod was observed on normal cell growth, suggesting that targeting p38 kinase might be therapeutically beneficial for a subset of AML patients dependent on IL-1 signaling. Conclusion: These results demonstrate a novel in vitro and in vivo role for IL-1 and its receptor in promoting leukemic cellular growth and progression in a large subset of AML patients and warrant further investigation of this pathway as a therapeutic opportunity. Disclosures No relevant conflicts of interest to declare.

63% female, 63% Chinese).Median (range) age at diagnosis was 3.5 (1 5) years.UC was more common (63%) in EO-IBD, with 60% having extensive involvement (E3).Pan-colonic involvement and proctitis were seen in 83% (6 11 year-olds) and 57% (12 18 year-olds).CD was more common in lateronset disease: 66.7% (6 11 year-olds) and 53.3% (12 18 yearolds).Upper gastrointestinal tract involvement was seen in 37% of CD. 32% of CD had growth delay at presentation.32.2% of children with CD achieved remission with enteral nutrition alone.All other patients required a combination of steroids and immunomodulators with one child needing Adalimumab & thalidomide.A higher proportion of younger patients experienced relapse requiring repeat steroid therapy. Conclusion:We have seen a four-fold rise in paediatric IBD over the last five years.Early onset IBD appears to exhibit more extensive disease. P-022What is the difference between early-onset pediatric ulcerative colitis and late-onset pediatric ulcerative colitis?A single center experience in Japan

Introduction The rise in the incidence of paediatric inflammatory bowel disease (IBD) in Ireland from 2000 to 2010 has been recently documented. Aims/Background The aim of this current study was to examine the phenotypic attributes of IBD among children diagnosed with new onset IBD in 2010 to 2011. Method A retrospective review of paediatric IBD was undertaken using nationally representative data from the National Centre for Paediatric Gastroenterology, Hepatology and Nutrition (NCPGHN) in Ireland. IBD was phenotyped using the Paris classification and compared against previous Irish data from 2000 and 2008 and international figures. Data was analysed using the Statistical Package for Social Sciences (SPSS). Results The incidence of IBD from October 2010 to October 2011 was 7.5/100,000/year. Seventy nine children were diagnosed with IBD during the defined review period (49 boys, 32 girls, median age of diagnosis 12.7 years). The phenotype of new onset IBD has changed significantly from historic cohorts (Table 1). There is a marked increase in the incidence of combined upper and lower gastrointestinal CD. Furthermore, there is a distinct increase in complex disease behaviour (27%) such as stricturing and penetrating disease. The incidence of UC (n=29) has increased three-fold in 10 years (16 boys, median age of diagnosis 13.1 years). Additionally, 59% of children were reported to have moderate to severe disease activity, similar to previously reported data. At one year, 21 (46%) children with CD and 19 (66%) children with UC children were in remission, with 91% of children steroid free. Conclusion The incidence of IBD in Ireland remains high. The phenotypic behaviour of CD is changing with more complex disease behaviour evident at presentation. The prevalence of UC has tripled over 10 years. Future prospective longitudinal studies are needed to fully elucidate the factors underlying IBD in Irish children.

ABSTRACT Conjugative plasmids are known to facilitate the acquisition and dispersal of genes contributing to the fitness of Pseudomonas spp. Here, we report the characterization of pA506, the 57-kb conjugative plasmid of Pseudomonas fluorescens A506, a plant epiphyte used in the United States for the biological control of fire blight disease of pear and apple. Twenty-nine of the 67 open reading frames (ORFs) of pA506 have putative functions in conjugation, including a type IV secretion system related to that of MOB P6 family plasmids and a gene cluster for type IV pili. We demonstrate that pA506 is self-transmissible via conjugation between A506 and strains of Pseudomonas spp. or the Enterobacteriaceae . The origin of vegetative replication ( oriV ) of pA506 is typical of those in pPT23A family plasmids, which are present in many pathovars of Pseudomonas syringae , but pA506 lacks repA , a defining locus for pPT23A plasmids, and has a novel partitioning region. We selected a plasmid-cured derivative of A506 and compared it to the wild type to identify plasmid-encoded phenotypes. pA506 conferred UV resistance, presumably due to the plasmid-borne rulAB genes, but did not influence epiphytic fitness of A506 on pear or apple blossoms in the field. pA506 does not appear to confer resistance to antibiotics or other toxic elements. Based on the conjugative nature of pA506 and the large number of its genes that are shared with plasmids from diverse groups of environmental bacteria, the plasmid is likely to serve as a vehicle for genetic exchange between A506 and its coinhabitants on plant surfaces.

Background Acute myeloid leukemia (AML) is one of the most common hematologic malignancies affecting both children and adults. Targeted therapy represents a promising approach in AML with the potential for increased efficacy and reduced toxicity. However, the molecular abnormalities in AML are extraordinarily heterogeneous. Numerous genetic changes are reported which require careful functional analyses to distinguish “driver mutations” from “passengers.” Because cytokine/growth factor receptors contribute to cancer pathogenesis by regulating growth, differentiation, senescence and survival, we designed a functional screen focusing on these molecules. This RNAi-based screen was designed to reveal the functional and prognostic relevance of cytokine/growth factor receptors in leukemia. Using this approach, we identified several interleukin receptors that play critical roles in promoting leukemia cell growth. Importantly, we show the novel roles of two interleukin receptors, IL2Rγ and IL1R1, in promoting AML cell growth. Methods and Results We designed an siRNA-based functional screen targeting 188 growth factor receptors that were found highly expressed in mononuclear cells of 140 primary leukemia samples by gene expression microarray analysis. We tested 72 leukemia patient samples with AML, ALL and MPN and 10 cell lines for dependence on these receptors. Cells were electroporated with siRNAs and cell viability was quantified after 72 hrs. Novel candidate targets found in AML patient samples include IL17R, IL9R, IL4R IL1R1, IL2Rγ, IL2Rα and IL15Rα. We found a variety of genetic abnormalities in these target genes, including splice variation (IL2Rα) and intron retention (IL15Rα). We found that IL2Rγ is a potential target in a JAK3A572V mutation positive AML cell line (CMK). Validation experiments demonstrated that knockdown of IL2Rγ significantly reduces the viability of CMK cells (90% decrease) and abrogates phosphorylation of JAK3 and downstream signaling molecules, JAK1, STAT5, MAPK and pS6 ribosomal protein. Intriguingly, the absence of IL2Rγ in murine bone marrow completely abrogated the clonogenic potential of JAK3A572V as compared to IL2Rγ wild-type marrow. These effects were rescued by co-expressing IL2Rγ with JAK3A572V but not by co-expressing IL2Rγ with JAK3Y100C, an inactivating mutation. Additionally, we found that IL2Rγ contributes to constitutive JAK3 mutant signaling by increasing JAK3 protein levels and phosphorylation. Conversely, mutant but not wild type JAK3 increased the expression of IL2Rγ, indicating IL2Rγ contributes to constitutive JAK3 signaling through a feedback mechanism. Similarly, IL2Rγ receptor is critical for transforming potential of additional JAK3 activating mutations such as JAK3M511I and JAK3A573V. Overall these results demonstrate an oncogenic potentiating role of IL2Rγ. Additionally, we found that silencing IL1R1 reduces the viability of 25% of AML primary samples. Most IL1R1 knockdown-sensitive AML samples exhibit monocytic and myelomonocytic features; however, no correlation with particular somatic mutations has thus far been observed. Confirming the importance of IL1R1 using a genetic model, we found that the absence of IL1R1 in murine bone marrow leads to the significant ablation of clonogenic potential (80% reduction) induced with AML1-ETO9a, NRASG12D and MLL-ENL oncogenes as compared to wild-type marrow in a ligand-dependent manner. Similarly knocking down IL1R1 in CD34+ AML cells reduces cell growth and phosphorylation of p38. Conversely, the presence of exogenous IL1 promotes AML cell survival by increasing p38 phosphorylation, which is significantly inhibited with p38 inhibitors such as Doramapimod. These results support a novel role for IL1R1-mediated signaling in promoting AML cell growth and targeting of this pathway in AML. Conclusions RNAi-based functional screening for leukemia cell dependence on cytokine/growth factor receptors led to the identification of novel oncogenic pathophysiological mechanisms. Specifically, (A) IL2Rγ is essential for the growth of leukemia cells harboring activating JAK3 mutations and (B) IL1R1 is involved in regulating growth and survival of AML cells, particularly with monocytic differentiation. These findings underscore the importance of interleukin receptors in leukemia pathogenesis and suggest that targeting these pathways in AML will be beneficial. Disclosures: Tyner: Incyte Corporation: Research Funding. Bagby:NIH: Membership on an entity’s Board of Directors or advisory committees.

Introduction The rise in the incidence of paediatric inflammatory bowel disease (IBD) in Ireland from 2000 to 2010 has been recently documented. Aims/Background The aim of this current study was to examine the phenotypic attributes of IBD among children diagnosed with new onset IBD in 2010 to 2011. Method A retrospective review of paediatric IBD was undertaken using nationally representative data from the National Centre for Paediatric Gastroenterology, Hepatology and Nutrition (NCPGHN) in Ireland. IBD was phenotyped using the Paris classification and compared against previous Irish data from 2000 and 2008 and international figures. Data was analysed using the Statistical Package for Social Sciences (SPSS). Results The incidence of IBD from October 2010 to October 2011 was 7.5/100,000/year. Seventy nine children were diagnosed with IBD during the defined review period (49 boys, 32 girls, median age of diagnosis 12.7 years). The phenotype of new onset IBD has changed significantly from historic cohorts (Table 1). There is a marked increase in the incidence of combined upper and lower gastrointestinal CD. Furthermore, there is a distinct increase in complex disease behaviour (27%) such as stricturing and penetrating disease. The incidence of UC (n=29) has increased three-fold in 10 years (16 boys, median age of diagnosis 13.1 years). Additionally, 59% of children were reported to have moderate to severe disease activity, similar to previously reported data. At one year, 21 (46%) children with CD and 19 (66%) children with UC children were in remission, with 91% of children steroid free. Table 1 Location of Crohns Disease and Ulcerative Colitis as defined by the Paris classification Location of Crohns Disease n (%) 2000 (n= 25) 2008 (n=31) 2010 (n=46) L1 2 (8) 6 (19) 4 (9) L2 11 (44) 6 (19) 8 (17) L3 9 (36) 10 (32) 6 (13) L1+L4 1 (4) 4 (13) 2 (4) L2+L4 4 (16) 1 (3) 9 (20) L3+L4 3 (12) 5 (16) 13 (28) Location of Ulcerative Colitis n (%) 2000 (n=13) 2008 (n=14) 2010 (n=29) E1 1 (8) 2 (14) 4 (14) E2 1 (8) 2 (14) 4 (14) E3 0 1 (7) 13 (45) E4 11 (84) 9 (64) 7 (24) Conclusion The incidence of IBD in Ireland remains high. The phenotypic behaviour of CD is changing with more complex disease behaviour evident at presentation. The prevalence of UC has tripled over 10 years. Future prospective longitudinal studies are needed to fully elucidate the factors underlying IBD in Irish children.

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