ORCID Profile
0000-0002-8776-1472
Current Organisations
University of Adelaide
,
South Australian Health and Medical Research Institute
,
Institute of Dendrology
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Publications
Analysis of the Relationship Between Mannose‐Binding Lectin (MBL) Genotype, MBL Levels and Function in an Australian Blood Donor Population
Publisher: Wiley
Date: 12-2002
DOI: 10.1046/J.1365-3083.2002.01167.X
Abstract: The mannose-binding lectin (MBL) pathway of complement activation is an important component of innate host defence. Numerous studies have described associations between the MBL genotype, MBL levels and disease susceptibility. However, genotyping and quantitative assays used in these studies have frequently been limited, and comprehensive data examining the interaction between structural and coding MBL genetic variants, MBL antigenic levels and MBL functional activity are lacking. Such data may be important for accurate planning and interpretation of studies of MBL and disease. This study has examined MBL in a cohort of 236 Australian blood donors. Five MBL promoter and coding single nucleotide polymorphisms were genotyped using polymerase chain reaction-sequence-specific priming (PCR-SSP). Plasma levels of MBL antigen were quantified using a double-antibody enzyme-linked immunosorbent assay (ELISA), and functional MBL levels were quantified using a mannan-binding assay. Activation of the complement pathway by MBL was measured in a C4-deposition assay. Significant associations were found between both coding and promoter polymorphisms and MBL antigenic and functional levels. There was significant correlation between the results of MBL double-antibody, mannan-binding and C4-deposition assays. Comprehensive MBL genotyping and functional MBL quantitation using mannan-binding and C4-deposition assays have the potential to be highly informative in MBL disease association studies.
Polymorphisms in immunoregulatory genes and the risk of histologic chorioamnionitis in Caucasoid women: a case control study
Publisher: Springer Science and Business Media LLC
Date: 21-02-2005
Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2018
Crown structure and biomass allocation patterns modulate aboveground productivity in young loblolly pine and slash pine
Publisher: Elsevier BV
Date: 05-2007
Donor mannose-binding lectin deficiency increases the likelihood of clinically significant infection after liver transplantation.
Publisher: Oxford University Press (OUP)
Date: 15-02-2009
DOI: 10.1086/596313
Abstract: Mannose-binding lectin (MBL) is an important mediator of innate immunity and is synthesized primarily by the liver. Low MBL levels are common, are due primarily to polymorphisms in the gene encoding MBL (MBL2), and are associated with an increased risk of infection, particularly when immunity is compromised. We report a large, retrospective study that examined the association between MBL status and clinically significant infection following orthotopic liver transplantation. One hundred two donor-recipient orthotopic liver transplantation pairs were studied. Five polymorphisms in the promoter and coding regions of MBL2 were examined. MBL levels were measured, using the mannan-binding and C4-deposition assays, in serum s les obtained before and after transplantation. Associations between MBL status, as assessed by serum MBL levels and MBL2 genotype, and time to first clinically significant infection (CSI) after transplantation were examined in survival analysis with consideration of competing risks. The median duration of follow-up after orthotopic liver transplantation was 4 years. Thirty-six percent of recipients developed CSI after transplantation. The presence of MBL2 coding mutations in the donor was significantly associated with CSI in the recipient the cumulative incidence function of infection was 55% in recipients of deficient livers, compared with 32% for recipients of wild-type livers (P = .002). Infection was not associated with recipient MBL2 genotype. Low MBL levels after orthotopic liver transplantation levels (mannan-binding <1 microg/mL or C4 deposition <0.2 C4 U/microL) were also associated with CSI (cumulative incidence function, 52% vs. 20%, P = .003 and cumulative incidence function, 54% vs. 24%, P = .007, respectively). In multivariate analysis, mutation in the MBL2 coding region of the donor (hazard ratio, 2.8 P = .005) and the use of cytomegalovirus prophylaxis (hazard ratio, 2.6 P = .005) were independently associated with CSI. Recipients of MBL-deficient livers have almost a 3-fold greater likelihood of developing CSI and may benefit from MBL replacement.
Constitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia
Publisher: Elsevier BV
Date: 08-2021
Leaf traits in relation to crown development, light interception and growth of elite families of loblolly and slash pine
Publisher: Oxford University Press (OUP)
Date: 05-2008
DOI: 10.1093/TREEPHYS/28.5.729
Abstract: Crown architecture and size influence leaf area distribution within tree crowns and have large effects on the light environment in forest canopies. The use of selected genotypes in combination with silvicultural treatments that optimize site conditions in forest plantations provide both a challenge and an opportunity to study the biological and environmental determinants of forest growth. We investigated tree growth, crown development and leaf traits of two elite families of loblolly pine (Pinus taeda L.) and one family of slash pine (P. elliottii Mill.) at canopy closure. Two contrasting silvicultural treatments -- repeated fertilization and control of competing vegetation (MI treatment), and a single fertilization and control of competing vegetation treatment (C treatment) -- were applied at two experimental sites in the West Gulf Coastal Plain in Texas and Louisiana. At a common tree size (diameter at breast height), loblolly pine trees had longer and wider crowns, and at the plot-level, intercepted a greater fraction of photosynthetic photon flux than slash pine trees. Leaf-level, light-saturated assimilation rates (A(max)) and both mass- and area-based leaf nitrogen (N) decreased, and specific leaf area (SLA) increased with increasing canopy depth. Leaf-trait gradients were steeper in crowns of loblolly pine trees than of slash pine trees for SLA and leaf N, but not for A(max). There were no species differences in A(max), except in mass-based photosynthesis in upper crowns, but the effect of silvicultural treatment on A(max) differed between sites. Across all crown positions, A(max) was correlated with leaf N, but the relationship differed between sites and treatments. Observed patterns of variation in leaf properties within crowns reflected acclimation to developing light gradients in stands with closing canopies. Tree growth was not directly related to A(max), but there was a strong correlation between tree growth and plot-level light interception in both species. Growth efficiency was unaffected by silvicultural treatment. Thus, when coupled with leaf area and light interception at the crown and canopy levels, A(max) provides insight into family and silvicultural effects on tree growth.
Heteroligomeric forms of codon 54 mannose binding lectin (MBL) in circulation demonstrate reduced in vitro function
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.MOLIMM.2005.06.023
Abstract: Mannose binding lectin (MBL) is a pattern recognition molecule that plays a pivotal role in innate immunity. This liver derived, circulating plasma protein binds organisms displaying high-density carbohydrate structures and flags them for destruction via opsonisation and initiation of the lectin pathway of the complement cascade. The present study reveals native, oligomeric forms of human MBL in plasma from healthy blood donors of differing genotypes and correlates the relative abundance of observed molecular weight species with mannan binding activity and C4 deposition in vitro. Wild type (A/A) in iduals demonstrate predominately high molecular weight MBL that correlated with high mannan binding capacity and C4 deposition. A/C in iduals demonstrated predominantly low molecular weight MBL with decreased mannan binding and C4 deposition activity. A/D in iduals demonstrated both high molecular weight and low molecular weight MBL with reduced mannan binding and C4 deposition predominantly seen in combination with LX promoter. We identified A/B in iduals as a unique group with large variation in MBL level, mannan binding activity and C4 deposition and propose a model for C4 deposition based on differential binding of MASP.
Interleukins-1, -4, -6, -10, tumor necrosis factor, transforming growth factor-β, FAS, and mannose-binding protein C gene polymorphisms in Australian women: Risk of preterm birth
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1016/J.AJOG.2004.04.021
Abstract: The purpose of this study was to examine the relationship between preterm birth and 22 single nucleotide polymorphisms in genes that encode cytokines and mediators of apoptosis and host defense. Two hundred two white women with a spontaneous preterm birth of <35 weeks of gestation were compared with 185 white women with term births. Genotyping was performed with polymerase chain reaction and sequence specific primers. Multivariable analyses included demographic and genetic variables. Alcohol (multivariable odds ratio, 2.3 P = .001] and substance use (multivariable odds ratio, 3.7 P = .01) were associated with preterm birth at <35 weeks of gestation. Smoking (multivariable odds ratio, 2.3 P = .03), haplotypes IL10 -1082A/-819T/-592A (multivariable odds ratio, 2.1 P = .04), tumor necrosis factor ( TNF )+488A/-238G/-308G (multivariable odds ratio, 2.4 P = .04), and IL4 -509C/C (multivariable odds ratio, 3.4 P = .02), and the presence of MBL2 codon 54Asp (multivariable odds ratio, 2.3 P = .02) were associated independently with preterm birth at <29 weeks of gestation. Homozygosity for IL10 -1082G/-819C/-592C haplotype (multivariable odds ratio, 1.9 P = .02) was more common in women with preterm premature rupture of membranes. Polymorphisms in immunoregulatory genes may influence susceptibility to preterm birth or premature rupture of membranes.
Quantitative Phosphotyrosine Profiling of Patient-Derived Xenografts Identifies Therapeutic Targets in Pediatric Leukemia
Publisher: American Association for Cancer Research (AACR)
Date: 05-2016
DOI: 10.1158/0008-5472.CAN-15-2786
Abstract: Activating mutations in tyrosine kinases (TK) drive pediatric high-risk acute lymphoblastic leukemia (ALL) and confer resistance to standard chemotherapy. Therefore, there is urgent need to characterize dysregulated TK signaling axes in patients with ALL and identify actionable kinase targets for the development of therapeutic strategies. Here, we present the first study to quantitatively profile TK activity in xenografted patient biopsies of high-risk pediatric ALL. We integrated a quantitative phosphotyrosine profiling method with “spike-in” stable isotope labeling with amino acids in cell culture (SILAC) and quantified 1394 class I phosphorylation sites in 16 ALL xenografts. Moreover, hierarchical clustering of phosphotyrosine sites could accurately classify these leukemias into either B- or T-cell lineages with the high-risk early T-cell precursor (ETP) and Ph-like ALL clustering as a distinct group. Furthermore, we validated this approach by using specific kinase pathway inhibitors to perturb ABL1, FLT3, and JAK TK signaling in four xenografted patient s les. By quantitatively assessing the tyrosine phosphorylation status of activated kinases in xenograft models of ALL, we were able to identify and validate clinically relevant targets. Therefore, this study highlights the application and potential of phosphotyrosine profiling for identifying clinically relevant kinase targets in leukemia. Cancer Res 76(9) 2766–77. ©2016 AACR.
Woody plants optimise stomatal behaviour relative to hydraulic risk
Publisher: Wiley
Date: 23-04-2018
DOI: 10.1111/ELE.12962
Abstract: Stomatal response to environmental conditions forms the backbone of all ecosystem and carbon cycle models, but is largely based on empirical relationships. Evolutionary theories of stomatal behaviour are critical for guarding against prediction errors of empirical models under future climates. Longstanding theory holds that stomata maximise fitness by acting to maintain constant marginal water use efficiency over a given time horizon, but a recent evolutionary theory proposes that stomata instead maximise carbon gain minus carbon costs/risk of hydraulic damage. Using data from 34 species that span global forest biomes, we find that the recent carbon-maximisation optimisation theory is widely supported, revealing that the evolution of stomatal regulation has not been primarily driven by attainment of constant marginal water use efficiency. Optimal control of stomata to manage hydraulic risk is likely to have significant consequences for ecosystem fluxes during drought, which is critical given projected intensification of the global hydrological cycle.
Clinical relevance of the minor histocompatibility antigen HA-1 in allogeneic bone marrow transplantation between HLA identical siblings
Publisher: Elsevier BV
Date: 02-2001
A Method for Next-Generation Sequencing of Paired Diagnostic and Remission Samples to Detect Mitochondrial DNA Mutations Associated with Leukemia
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.JMOLDX.2017.05.009
Abstract: Somatic mitochondrial DNA (mtDNA) mutations have been identified in many human cancers, including leukemia. To identify somatic mutations, it is necessary to have a control tissue from the same in idual for comparison. When patients with leukemia achieve remission, the remission peripheral blood may be a suitable and easily accessible control tissue, but this approach has not previously been applied to the study of mtDNA mutations. We have developed and validated a next-generation sequencing approach for the identification of leukemia-associated mtDNA mutations in 26 chronic myeloid leukemia patients at diagnosis using either nonhematopoietic or remission blood s les as the control. The entire mt genome was lified by long-range PCR and sequenced using Illumina technology. Variant caller software was used to detect mtDNA somatic mutations, and an empirically determined threshold of 2% was applied to minimize false-positive results because of sequencing errors. Mutations were called against both nonhematopoietic and remission controls: the overall concordance between the two approaches was 81% (73/90 mutations). Some discordant results were because of the presence of somatic mutations in remission s les, because of either minimal residual disease or nonleukemic hematopoietic clones. This method could be applied to study somatic mtDNA mutations in leukemia patients who achieve minimal residual disease, and in patients with nonhematopoietic cancers who have a matched uninvolved tissue available.
Mannose binding lectin acute phase activity in patients with severe infection
Publisher: Springer Science and Business Media LLC
Date: 07-2005
DOI: 10.1007/S10875-005-4702-1
Abstract: Mannose Binding Lectin (MBL) is a liver derived, circulating plasma protein that plays a pivotal role in innate immunity. MBL functions as a pathogen recognition molecule, opsonising organisms and initiating the complement cascade. MBL deficiency arising from mutations and promoter polymorphisms in the MBL2 gene is common and has been associated with risk, severity, and frequency of infection in a number of clinical settings. With MBL therapy on the horizon, the usefulness of replacement MBL therapy has been challenged by the notion, that as an acute phase protein, MBL levels may rise under stress to sufficient levels, in in iduals who are usually deficient. This report demonstrates that in patients with sepsis and septic shock, the majority of patients do not display an MBL acute phase response: 41.4% of in iduals maintained consistent MBL levels throughout hospital stay, 31.3% of in iduals demonstrated a positive acute phase response, and a negative acute phase response was observed in 27.3% of in iduals studied. Importantly, a positive acute phase response was generally observed in in iduals with wild-type MBL2 genes. When a positive acute phase response was observed in in iduals with coding mutation, these in iduals demonstrated a normal MBL level on admission to hospital. Furthermore, no in idual, regardless of genotype who was MBL deficient at admission was able to demonstrate a positive acute phase response into the normal MBL range. These findings indicate MBL demonstrates a variable acute phase response in the clinical setting of sepsis and septic shock.
TYK2 Activating Alterations in Acute Lymphoblastic Leukemia: Novel Driver Oncogenes with Potential Avenues for Precision Medicine?
Publisher: Fortune Journals
Date: 2021
Case report: Rare case of donor cell‐derived T‐cell acute lymphoblastic leukaemia in a female patient after receiving an allo‐transplant from her male sibling
Publisher: Wiley
Date: 31-07-2023
DOI: 10.1111/BJH.19008
Abstract: Donor‐derived haematological neoplasms, in which recipients present with haematological malignancies that have evolved from transplant donor stem cells, have previously been described for myelodysplastic syndrome, myeloproliferative neoplasms, acute myeloid leukaemia and less often, leukaemias of lymphoid origin. Here we describe a rare and complex case of donor‐derived T‐cell acute lymphoblastic leukaemia with a relatively short disease latency of less than 4 years. Through genomic and in vitro analyses, we identified novel mutations in NOTCH1 as well as a novel activating mutation in STAT5B the latter targetable with the clinically available drugs, venetoclax and ruxolitinib.
Fas gene promoter polymorphisms in primary Sjogren's syndrome
Publisher: BMJ
Date: 2004
Abstract: Fas mediated apoptosis may be important in the pathogenesis of primary Sjögren's syndrome (pSS). To examine genetic variation in the promoter region of the Fas gene in pSS. Two single nucleotide polymorphisms at positions -1377(G/A) and -670(G/A) in the Fas gene promoter were genotyped by PCR-SSP in 101 patients with pSS and 108 Caucasoid controls. No significant differences in allele or genotype frequencies were detected between the patients with pSS and controls. However, significant associations were observed with Ro/La autoantibody negative patients, who display milder and later onset disease. The -670A allele was more frequent in Ro/La autoantibody negative patients than in Ro/La autoantibody positive patients (p = 0.04). This study does not confirm an earlier report of an association between pSS and the Fas promoter -670G allele. However, the results suggest that genetically determined variability in Fas expression may modulate Ro/La autoantibody responses in patients with pSS.
High‐risk B‐cell acute lymphoblastic leukaemia presenting with hypereosinophilia and acquiring a novel PAX5 fusion on relapse
Publisher: Wiley
Date: 30-07-2020
DOI: 10.1111/BJH.17002
CREST maps somatic structural variation in cancer genomes with base-pair resolution
Publisher: Springer Science and Business Media LLC
Date: 12-06-2011
DOI: 10.1038/NMETH.1628
Low mannose-binding lectin function is associated with sepsis in adult patients
Publisher: Oxford University Press (OUP)
Date: 11-2006
Seedling growth and biomass allocation in relation to leaf habit and shade tolerance among 10 temperate tree species
Publisher: Oxford University Press (OUP)
Date: 26-06-2015
Abstract: Initial growth of germinated seeds is an important life history stage, critical for establishment and succession in forests. Important questions remain regarding the differences among species in early growth potential arising from shade tolerance. In addition, the role of leaf habit in shaping relationships underlying shade tolerance-related differences in seedling growth remains unresolved. In this study we examined variation in morphological and physiological traits among seedlings of 10 forest tree species of the European temperate zone varying in shade tolerance and leaf habit (broadleaved winter-deciduous species vs needle-leaved conifers) during a 10-week period. Seeds were germinated and grown in a controlled environment simulating an intermediate forest understory light environment to resolve species differences in initial growth and biomass allocation. In the high-resource experimental conditions during the study, seedlings increased biomass allocation to roots at the cost of leaf biomass independent of shade tolerance and leaf habit. Strong correlations between relative growth rate (RGR), net assimilation rate (NAR), leaf area ratio (LAR), specific leaf area (SLA) and leaf mass fraction (LMF) indicate that physiology and biomass allocation were equally important determinants of RGR as plant structure and leaf morphology among these species. Our findings highlight the importance of seed mass- and seed size-related root morphology (specific root length-SRL) for shade tolerance during early ontogeny. Leaf and plant morphology (SLA, LAR) were more successful in explaining variation among species due to leaf habit than shade tolerance. In both broadleaves and conifers, shade-tolerant species had lower SRL and greater allocation of biomass to stems (stem mass fraction). Light-seeded shade-intolerant species with greater SRL had greater RGR in both leaf habit groups. However, the greatest plant mass was accumulated in the group of heavy-seeded shade-tolerant broadleaves. The results of our study suggest that the combinations of plant attributes enhancing growth under high light vary with shade tolerance, but differ between leaf habit groups.
Precision medicine approaches may be the future for CRLF2 rearranged Down Syndrome Acute Lymphoblastic Leukaemia patients
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.CANLET.2018.05.045
Abstract: Breakthrough studies over the past decade have uncovered unique gene fusions implicated in acute lymphoblastic leukaemia (ALL). The critical gene, cytokine receptor-like factor 2 (CRLF2), is rearranged in 5-16% of B-ALL, comprising 50% of Philadelphia-like ALL and cooperates with genomic lesions in the Jak, Mapk and Ras signalling pathways. Children with Down Syndrome (DS) have a predisposition to developing CRLF2 rearranged-ALL which is observed in 60% of DS-ALL patients. These patients experience a poor survival outcome. Mutations of genes involved in epigenetic regulation are more prevalent in DS-ALL patients than non-DS ALL patients, highlighting the potential for alternative treatment strategies. DS-ALL patients also suffer greater treatment-related toxicity from current ALL treatment regimens compared to non-DS-ALL patients. An increased gene dosage of critical genes on chromosome 21 which have roles in purine synthesis and folate transport may contribute. As the genomic landscape of DS-ALL patients is different to non-DS-ALL patients, targeted therapies for in idual lesions may improve outcomes. Therapeutically targeting each rearrangement with targeted or combination therapy that will perturb the transforming signalling pathways will likely improve the poor survival rates of this subset of patients.
Interleukin-3-mediated regulation of β-catenin in myeloid transformation and acute myeloid leukemia
Publisher: Oxford University Press (OUP)
Date: 05-03-2014
Abstract: Aberrant activation of β-catenin is a common event in AML and is an independent predictor of poor prognosis. Although increased β-catenin signaling in AML has been associated with oncogenic translocation products and activating mutations in the FLT3R, the mechanisms that activate β-catenin in AML more broadly are still unclear. Here, we describe a novel link between IL-3 signaling and the regulation of β-catenin in myeloid transformation and AML. In a murine model of HoxB8 and IL-3 cooperation, we show that β-catenin protein levels are modulated by IL-3 and that Cre-induced deletion of β-catenin abolishes IL-3-dependent growth and colony formation. In IL-3-dependent leukemic TF-1.8 cells, we observed increased β-catenin protein levels and nuclear localization in response to IL-3, and this correlated with transcriptional induction of β-catenin target genes. Furthermore, IL-3 promoted β-catenin accumulation in a subset of AML patient s les, and gene-expression profiling of these cells revealed induction of WNT/β-catenin and TCF4 gene signatures in an IL-3-dependent manner. This study is the first to link β-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of β-catenin activity in some patients with AML.
Identification of a novel GOLGA4–JAK2 fusion gene in B‐cell acute lymphoblastic leukaemia
Publisher: Wiley
Date: 25-10-2021
DOI: 10.1111/BJH.17910
Abstract: Rearrangements of Janus kinase 2 ( JAK2 r) form a subtype of acute lymphoblastic leukaemia (ALL) associated with poor patient outcomes. We present a high‐risk case of B‐cell ALL (B‐ALL) where retrospective mRNA sequencing identified a novel GOLGA4–JAK2 fusion gene. Expression of GOLGA4–JAK2 in murine pro‐B cells promoted factor‐independent growth, implicating GOLGA4–JAK2 as an oncogenic driver. Cells expressing GOLGA4–JAK2 demonstrated constitutive activation of JAK/STAT signalling and were sensitive to JAK inhibitors. This study contributes to the erse collection of JAK2 fusion genes identified in B‐ALL and supports the incorporation of JAK inhibitors into treatment strategies to improve outcomes for this subtype.
Variation in immune response genes and chronic Q fever. Concepts: preliminary test with post-Q fever fatigue syndrome
Publisher: Springer Science and Business Media LLC
Date: 2003
Two novel cases of NUTM1‐rearranged B‐cell acute lymphoblastic leukaemia presenting with high‐risk features
Publisher: Wiley
Date: 12-12-2021
DOI: 10.1111/BJH.17995
Mannose-binding lectin gene polymorphisms are associated with major infection following allogeneic hemopoietic stem cell transplantation
Publisher: American Society of Hematology
Date: 15-05-2002
DOI: 10.1182/BLOOD.V99.10.3524
Abstract: Life-threatening complications such as graft versus host disease and infection remain major barriers to the success of allogeneic hemopoietic stem cell transplantation (SCT). While pretransplantation conditioning and posttransplantation immunosuppression are important risk factors for infection, the reasons that similarly immunosuppressed transplant recipients show marked variation in frequency of infection after allogeneic SCT are unclear. Mannose-binding lectin (MBL) deficiency is a risk factor for infection in other situations where immunity is compromised. We investigated associations betweenMBL2 gene polymorphisms and risk of major infection following allogeneic SCT. Ninety-seven related allogeneic donor-recipient pairs were studied. Clinical data including survival, days of fever, graft versus host disease incidence and severity, and infection were collected by case note review. Five single-nucleotide polymorphisms in the MBL2 gene were genotyped using the polymerase chain reaction and sequence-specific primers.MBL2 coding mutations were associated with an increased risk of major infection following transplantation. This association was seen for donor (P = .002, odds ratio [OR] 4.1) and recipient (P = .04, OR 2.6) MBL2 genotype.MBL2 promoter variants were also associated with major infection. The high-producing haplotype HYA was associated with a markedly reduced risk of infection (recipient HYA P = .0001, OR 0.16 donor HYA P = .001, OR 0.23). Donor MBL2 coding mutations and recipientHYA haplotype were independently associated with infection in multivariate analysis. These results suggest that MBL2genotype influences the risk of infection following allogeneic SCT and that both donor and recipient MBL2 genotype are important. These findings raise the possibility that MBL replacement therapy may be useful following transplantation.
HMGN1 plays a significant role in CRLF2 driven Down Syndrome leukemia and provides a potential therapeutic target in this high-risk cohort
Publisher: Springer Science and Business Media LLC
Date: 02-12-2022
DOI: 10.1038/S41388-021-02126-4
Abstract: The genetic basis of the predisposition for Down Syndrome (DS) patients to develop cytokine receptor-like factor 2 rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) is currently unknown. Genes located on chromosome 21 and expressed in hematopoietic cells are likely candidates for investigation of CRLF2r DS-ALL pathogenesis. We explored the high-mobility group nucleosome-binding protein 1 (HMGN1), located in the DS critical region, in an inducible CRISPR/Cas9 knockout (KO) xenograft model to assess the effect of HMGN1 loss of function on the leukemic burden. We demonstrated HMGN1 KO-mitigated leukemic phenotypes including hepatosplenomegaly, thrombocytopenia, and anemia, commonly observed in leukemia patients, and significantly increased survival in vivo. HMGN1 overexpression in murine stem cells and Ba/F3 cells in vitro, in combination with P2RY8-CRLF2, resulted in cytokine-independent transformation and upregulation of cell signaling pathways associated with leukemic development. Finally, in vitro screening demonstrated successful targeting of P2RY8-CRLF2 and HMGN1 co-expressing cell lines and patient s les with fedratinib (JAK2 inhibitor), and GSK-J4 (demethylase inhibitor) in combination. Together, these data provide critical insight into the development and persistence of CRLF2r DS-ALL and identify HMGN1 as a potential therapeutic target to improve outcomes and reduce toxicity in this high-risk cohort of young patients.
Mannose-binding lectin deficiency does not increase the prevalence of Helicobacter pylori seropositivity
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2007
Outcomes for Australian children with relapsed/refractory acute lymphoblastic leukaemia treated with blinatumomab
Publisher: Wiley
Date: 26-02-2021
DOI: 10.1002/PBC.28922
Abstract: We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B‐cell acute lymphoblastic leukaemia (B‐ALL) and high‐risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2‐year progression‐free survival (PFS) of 39% and 2‐year overall survival of 63%. In total, 83% ( n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab ( n = 12) or following additional salvage therapy ( n = 8). Four patients successfully received CD19‐directed chimeric antigen receptor T‐cell therapy despite prior blinatumomab exposure. Inferior 2‐year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A ‐rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B‐ALL respond to blinatumomab and factors such as blast genotype may affect prognosis.
The effect of co-occurring lesions on leukaemogenesis and drug response in T-ALL and ETP-ALL
Publisher: Springer Science and Business Media LLC
Date: 03-12-2020
DOI: 10.1038/S41416-019-0647-7
Abstract: Despite advances in the management of acute lymphoblastic leukaemia (ALL), current regimens fail to significantly transform outcomes for patients with high-risk subtypes. Advances in genomic analyses have identified novel lesions including mutations in genes that encode chromatin modifiers and those that influence cytokine and kinase signalling, rendering many of these alterations potentially targetable by tyrosine kinase and epigenetic inhibitors currently in clinical use. Although specific genomic lesions, gene expression patterns, and immunophenotypic profiles have been associated with specific clinical outcomes in some cancers, the application of precision medicine approaches based on these data has been slow. This approach is complicated by the reality that patients often harbour multiple mutations, and in many cases, the precise functional significance and interaction of these mutations in driving leukaemia and drug responsiveness/resistance remains unknown. Given that signalling pathways driving leukaemic pathogenesis could plausibly result from the co-existence of specific lesions and the resultant perturbation of protein interactions, the use of combined therapeutics that target multiple aberrant pathways, according to an in idual’s mutational profile, might improve outcomes and lower a patient’s risk of relapse. Here we outline the genomic alterations that occur in T cell ALL (T-ALL) and early T cell precursor (ETP)-ALL and review studies highlighting the possible effects of co-occurring lesions on leukaemogenesis and drug response.
The genetic basis of early T-cell precursor acute lymphoblastic leukaemia
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1038/NATURE10725
Mannose-binding lectin status is associated with risk of major infection following myeloablative sibling allogeneic hematopoietic stem cell transplantation
Publisher: American Society of Hematology
Date: 09-2008
DOI: 10.1182/BLOOD-2007-07-100222
Abstract: Mannose-binding lectin (MBL) is a mediator of innate immunity that influences the risk of infection in a range of clinical settings. We previously reported associations between MBL2 genotype and infection in a retrospective study of myeloablative allogeneic hematopoietic stem cell transplantation (allo-HCT). However, other studies have been inconclusive, and the role of MBL in reduced-intensity conditioning (RIC) transplantation is unknown. Here we report a prospective study examining MBL2 genotype, MBL levels, and risk of major infection following HLA-matched sibling myeloablative (n = 83) and RIC (n = 59) HCT. Baseline MBL levels were higher in recipients than donors (P .001), and recipient MBL levels increased during the peritransplantation period (P = .001), most notably in MBL2 wild-type in iduals receiving myeloablative total body irradiation (mTBI). MBL2 coding mutations were associated with major infection in recipients receiving mTBI. The cumulative incidence of major infection in recipient harboring an MBL2 mutation receiving mTBI was 70.6%, compared with 31.1% of those without mutations not receiving mTBI (P = .01). MBL status was not associated with infection in RIC transplants. These results confirm the association of MBL status with risk of infection in myeloablative, TBI-conditioned transplantation. Studies examining the role of MBL replacement therapy to prevent infection in this setting should be considered.
Characterization of leukemias with ETV6-ABL1 fusion
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 26-05-2016
Relapse of BCR-ABL1-like ALL mediated by the ABL1 kinase domain mutation T315I following initial response to dasatinib treatment
Publisher: Springer Science and Business Media LLC
Date: 02-09-2015
DOI: 10.1038/LEU.2014.256
In-vitro modeling of TKI resistance in the high-risk B-cell acute lymphoblastic leukemia fusion gene RANBP2-ABL1 - implications for targeted therapy
Publisher: Informa UK Limited
Date: 02-01-2021
Exploring the oncogenic and therapeutic target potential of the MYB-TYK2 fusion gene in B-cell acute lymphoblastic leukemia
Publisher: Springer Science and Business Media LLC
Date: 12-01-2022
DOI: 10.1038/S41417-021-00421-6
Abstract: TYK2-rearrangements have recently been identified in high-risk acute lymphoblastic leukemia (HR-ALL) cases and are associated with poor outcome. Current understanding of the leukemogenic potential and therapeutic targetability of activating TYK2 alterations in the ALL setting is unclear, thus further investigations are warranted. Consequently, we developed in vitro, and for the first time, in vivo models of B-cell ALL from a patient harboring the MYB-TYK2 fusion gene. These models revealed JAK/STAT signaling activation and the oncogenic potential of the MYB-TYK2 fusion gene in isolation. High throughput screening identified the HDAC inhibitor, vorinostat and the HSP90 inhibitor, tanespimycin plus the JAK inhibitor, cerdulatinib as the most effective agents against cells expressing the MYB-TYK2 alteration. Evaluation of vorinostat and cerdulatinib in pre-clinical models of MYB-TYK2-rearranged ALL demonstrated that both drugs exhibited anti-leukemic effects and reduced the disease burden in treated mice. Importantly, these findings indicate that activating TYK2 alterations can function as driver oncogenes rather than passenger or secondary events in disease development. In addition, our data provide evidence for use of vorinostat and cerdulatinib in the treatment regimens of patients with this rare yet aggressive type of high-risk ALL that warrants further investigation in the clinical setting.
Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
DOI: 10.1097/01.TP.0000111769.45088.A2
Abstract: Existing data indicate that non-human leukocyte antigen (HLA) immunogenetic polymorphisms influence the risk of complications after allogeneic hemopoietic stem-cell transplantation. However, prior studies have been limited by small s le size and limited genotyping. We examined 22 polymorphisms in 11 immunoregulatory genes including cytokines, mediators of apoptosis, and host-defense molecules by polymerase chain reaction using sequence-specific primers in 160 related myeloablative transplants. Associations were confirmed in two independent cohorts. An intronic polymorphism in the tumor necrosis factor gene (TNF 488A) was associated with the risk of acute graft-versus-host disease (GVHD) (odds ratio [OR] 16.9), grades II to IV acute GVHD (OR 3.3), chronic GVHD (OR 12.5), and early death posttransplant (OR 3.4). Recipient Fas -670G and donor interleukin (IL)-6 -174G were independent risk factors for acute GVHD. Recipient IL-10 ATA and Fas -670 genotype were independent risk factors for chronic GVHD. Recipient IL-1beta +3953T was associated with hepatic acute GVHD, and Fas -670G was associated with major infection. These results highlight the potential importance of cytokine and apoptosis gene polymorphisms in stem-cell transplantation, and indicate that non-HLA genotyping may be useful to identify in iduals at the highest risk of complications and new targets for therapeutic intervention.
Mannose-binding lectin deficiency does not appear to predispose to cryptococcosis in non-immunocompromised patients
Publisher: Oxford University Press (OUP)
Date: 2008
DOI: 10.1080/13693780701874515
Abstract: While most patients with cryptococcosis have obvious cellular immune deficiency, a minority have no apparent predisposing factors. However, in the latter there may be subtle innate immune system deficiencies which go unrecognized. Mannose-binding lectin (MBL) deficiency is associated with increased susceptibility to infectious diseases and may predispose to cryptococcosis, particularly when it disseminates to the central nervous system (CNS) in apparently immunocompetent patients. MBL function and levels, as well as MBL2 genotype were determined in 36 HIV-negative cryptococcosis patients (25 with CNS involvement) using C4 deposition and mannan-binding ELISA. MBL deficiency was defined using C4 deposition level < 0.2 U/microl or mannan-binding level < 0.5 microg/ml. MBL results were compared between patients with cryptococcosis and healthy controls and among the cryptococcosis patients according to the site of their disease. There was no difference in MBL function, mannan-binding level or increase in the frequency of MBL deficiency or low producing MBL2 genotypes in any of these comparisons. Patients with CNS cryptococcosis were no more likely to be MBL deficient than those with non-CNS disease. It appears that MBL deficiency is not associated with cryptococcosis in non-immunocompromised hosts. Beta errors consequent on the small number of patients studied may account for the lack of association.
Acute sensitivity of Ph-like acute lymphoblastic leukemia to the SMAC-mimetic birinapant
Publisher: American Association for Cancer Research (AACR)
Date: 31-07-2016
DOI: 10.1158/0008-5472.CAN-16-0523
Abstract: Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a erse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. Cancer Res 76(15) 4579–91. ©2016 AACR.
Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions
Publisher: Springer Science and Business Media LLC
Date: 06-2022
DOI: 10.1038/S41416-022-01806-6
Abstract: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL -positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1 -deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1 . Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow s les previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 s les, r2 = 0.9786, P 0.0001) and Ig/TCR and IKZF1 -deletion results (9 patients, n = 143 s les, r2 = 0.9661, P 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 s les, r2 = 0.4703, P 0.0001) and IKZF1 -deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P 0.0001). MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1 -deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.
Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells
Publisher: Elsevier BV
Date: 03-2013
High prevalence of relapse in children with Philadelphia-like acute lymphoblastic leukemia despite risk-adapted treatment.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 21-09-2017
Activating killer-cell immunoglobulin-like receptor haplotype influences clinical outcome following HLA-matched sibling haematopoietic stem cell transplantation
Publisher: Wiley
Date: 08-2018
DOI: 10.1111/TAN.13327
Abstract: Natural killer cells are thought to influence the outcome of hematopoietic stem cell transplant (HSCT), impacting on relapse, overall survival, graft versus host disease and the control of infection, in part through the complex interplay between the large and genetically erse killer immunoglobulin-like receptor (KIR) family and their ligands. This study examined the relationship between KIR gene content and clinical outcomes including the control of opportunistic infections such as cytomegalovirus in the setting of human leucocyte antigen (HLA)-matched sibling HSCT in an Australian cohort. The presence of the KIR B haplotype which contain more activating receptors in the donor, in particular centromeric B haplotype genes (Cen-B), was associated with improved overall survival of patients with acute myeloid leukemia (AML) undergoing sibling HSCT and receiving myeloablative conditioning. Donor Cen-B haplotype was also associated with reduced acute graft versus host disease grades II-IV whereas donor telomeric-B haplotype was associated with decreased incidence of CMV reactivation. In contrast, we were not able to demonstrate a reduced rate of relapse when the donor had KIR Cen-B, however relapse with a donor Cen-A haplotype was a competing risk factor to poor overall survival. Here we show that the presence of donor activating KIR led to improved outcome for the patient, potentially through reduced relapse rates and decreased incidence of acute GvHD translating to improved overall survival. This article is protected by copyright. All rights reserved.
A novel somatic JAK2 kinase-domain mutation in pediatric acute lymphoblastic leukemia with rapid on-treatment development of LOH
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.CANCERGEN.2017.07.008
Abstract: We report a novel somatic mutation in the kinase domain of JAK2 (R938Q) in a high-risk pediatric case of B-cell acute lymphoblastic leukemia (ALL). The patient developed on-therapy relapse at 12 months, and interestingly, the JAK2 locus acquired loss of heterozygosity during treatment resulting in 100% mutation load. Furthermore, we show that primary ALL mononuclear cells harboring the JAK2 R938Q mutation display reduced sensitivity to the JAK1/2 ATP-competitive inhibitor ruxolitinib in vitro, compared to ALL cells that carry a more common JAK2 pseudokinase domain mutation. Our findings are in line with previous reports that demonstrate that mutations within the kinase domain of JAK2 are associated with resistance to type I JAK inhibitors. Importantly, given the recent inclusion of ruxolitinib in trial protocols for children with JAK pathway alterations, we predict that inter-patient genetic variability may result in suboptimal responses to JAK inhibitor therapy in a subset of cases. The need for alternate targeted and/or combination therapies for patients who display inherent or developed resistance to JAK inhibitor therapy will be warranted, and we propose that kinase-mutants less sensitive to type I JAK inhibitors may present a currently unexplored platform for investigation of improved therapies.
Plant water potential improves prediction of empirical stomatal models
Publisher: Public Library of Science (PLoS)
Date: 12-10-2017
Xenograft-directed personalized therapy for a patient with post-transplant relapse of ALL
Publisher: Springer Science and Business Media LLC
Date: 16-05-2016
DOI: 10.1038/BMT.2016.122
COBL is a novel hotspot for IKZF1 deletions in childhood acute lymphoblastic leukemia
Publisher: Impact Journals, LLC
Date: 13-07-2016
Case Report: Precision Medicine Target Revealed by In Vitro Modeling of Relapsed, Refractory Acute Lymphoblastic Leukemia From a Child With Neurofibromatosis
Publisher: Frontiers Media SA
Date: 20-04-2022
Abstract: Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukemia and acute myeloid leukemia, but rarely develop B-cell acute lymphoblastic leukemia (B-ALL). Through in-vitro modeling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signaling, indicative of leukemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.
The genomic landscape of hypodiploid acute lymphoblastic leukemia
Publisher: Springer Science and Business Media LLC
Date: 20-01-2013
DOI: 10.1038/NG.2532
Plasticity in seedling morphology, biomass allocation and physiology among ten temperate tree species in response to shade is related to shade tolerance and not leaf habit
Publisher: Wiley
Date: 05-01-2017
DOI: 10.1111/PLB.12531
Abstract: Mechanisms of shade tolerance in tree seedlings, and thus growth in shade, may differ by leaf habit and vary with ontogeny following seed germination. To examine early responses of seedlings to shade in relation to morphological, physiological and biomass allocation traits, we compared seedlings of 10 temperate species, varying in their leaf habit (broadleaved versus needle-leaved) and observed tolerance to shade, when growing in two contrasting light treatments - open (about 20% of full sunlight) and shade (about 5% of full sunlight). We analyzed biomass allocation and its response to shade using allometric relationships. We also measured leaf gas exchange rates and leaf N in the two light treatments. Compared to the open treatment, shading significantly increased traits typically associated with high relative growth rate (RGR) - leaf area ratio (LAR), specific leaf area (SLA), and allocation of biomass into leaves, and reduced seedling mass and allocation to roots, and net assimilation rate (NAR). Interestingly, RGR was not affected by light treatment, likely because of morphological and physiological adjustments in shaded plants that offset reductions of in situ net assimilation of carbon in shade. Leaf area-based rates of light-saturated leaf gas exchange differed among species groups, but not between light treatments, as leaf N concentration increased in concert with increased SLA in shade. We found little evidence to support the hypothesis of a increased plasticity of broadleaved species compared to needle-leaved conifers in response to shade. However, an expectation of higher plasticity in shade-intolerant species than in shade-tolerant ones, and in leaf and plant morphology than in biomass allocation was supported across species of contrasting leaf habit.
Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions.
Publisher: Elsevier BV
Date: 11-2017
Environmental and genetic effects on crown shape in young loblolly pine plantations
Publisher: Canadian Science Publishing
Date: 03-2009
DOI: 10.1139/X08-200
Abstract: Tree crown shape is an important trait affecting the light environment in forest canopies. We examined genetic and environmental effects on outer crown shape of young single-family stands of loblolly pine ( Pinus taeda L.). Crown diameter profiles were measured after canopy closure at four experimental sites in the southeastern US. The two examined families of contrasting aboveground productivity differed in crown length but not in their outer crown shapes or crown shape ratios, defined as the ratio of crown diameter to crown length. Within each site, intensive silvicultural treatment, consisting of fertilization and control of competing vegetation, had little effect upon crown shape. A strongly significant effect of site on crown shape parameters was found in the family grown at all four experimental sites however, density differences among the experimental series likely accounted for a part of the across-sites variation in crown shape. In contrast to other studies on crown shape in trees, and to findings at age 2 years in the same stands, we conclude that family effects on the outer crown shape were small compared with the environmental effects in these 5-year-old pine plantations, following canopy closure.
Related Organisations
South Australian Health And Medical Research Institute
Location: Australia
St. Jude Children's Research Hospital
Location: United States of America
Australian Red Cross Blood Service South Australia
Location: Australia
Related Funding Activities
Developing A Robust Screening Tool To Identify Children With Ph-like ALL
Start Date: 2015
End Date: 2015
Funder: Channel 7 Children's Research Foundation
View Funded Activity