29 results on '"Heatley, Susan L"'
Search Results
2. Exploring the oncogenic and therapeutic target potential of the MYB-TYK2 fusion gene in B-cell acute lymphoblastic leukemia
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Shirazi, Paniz Tavakoli, Eadie, Laura N., Heatley, Susan L., Page, Elyse C., François, Maxime, Hughes, Timothy P., Yeung, David, and White, Deborah L.
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- 2022
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3. HMGN1 plays a significant role in CRLF2 driven Down Syndrome leukemia and provides a potential therapeutic target in this high-risk cohort
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Page, Elyse C., Heatley, Susan L., Eadie, Laura N., McClure, Barbara J., de Bock, Charles E., Omari, Sofia, Yeung, David T., Hughes, Timothy P., Thomas, Paul Q., and White, Deborah L.
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- 2022
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4. Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions
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Sadras, Teresa, Heatley, Susan L., Kok, Chung H., Dang, Phuong, Galbraith, Kate M., McClure, Barbara J., Muskovic, Walter, Venn, Nicola C., Moore, Sarah, Osborn, Michael, Revesz, Tamas, Moore, Andrew S., Hughes, Timothy P., Yeung, David, Sutton, Rosemary, and White, Deborah L.
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- 2017
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5. Pre-B acute lymphoblastic leukaemia recurrent fusion, EP300-ZNF384, is associated with a distinct gene expression
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McClure, Barbara J., Heatley, Susan L., Kok, Chung H, Sadras, Teresa, An, Jiyuan, Hughes, Timothy P., Lock, Richard B., Yeung, David, Sutton, Rosemary, and White, Deborah L
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- 2018
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6. 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.
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Eadie, Laura N., Rehn, Jacqueline A., Schutz, Caitlin E., Heatley, Susan L., Kutyna, Monika M., Hiwase, Devendra K., White, Deborah L., and Yeung, David T.
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LYMPHOBLASTIC leukemia ,ACUTE leukemia ,MYELODYSPLASTIC syndromes ,MYELOPROLIFERATIVE neoplasms ,ACUTE myeloid leukemia ,MYELOFIBROSIS - Abstract
Summary: 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. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Reproducible Bioinformatics Analysis Workflows for Detecting IGH Gene Fusions in B-Cell Acute Lymphoblastic Leukaemia Patients.
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Thomson, Ashlee J., Rehn, Jacqueline A., Heatley, Susan L., Eadie, Laura N., Page, Elyse C., Schutz, Caitlin, McClure, Barbara J., Sutton, Rosemary, Dalla-Pozza, Luciano, Moore, Andrew S., Greenwood, Matthew, Kotecha, Rishi S., Fong, Chun Y., Yong, Agnes S. M., Yeung, David T., Breen, James, and White, Deborah L.
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IMMUNOGLOBULINS ,LYMPHOBLASTIC leukemia ,B cell lymphoma ,BIOINFORMATICS ,WORKFLOW ,GENES ,RESEARCH funding ,SENSITIVITY & specificity (Statistics) ,ALGORITHMS - Abstract
Simple Summary: B-cell acute lymphoblastic leukaemia (B-ALL) is a haematological malignancy driven by diverse genomic alterations, the most common being gene fusions, which can be detected via transcriptomic analysis. However, detecting gene fusions involving the Immunoglobulin Heavy Chain (IGH) region can be challenging due to its hyper variability. Our aim was to develop a workflow containing the algorithms FusionCatcher, Arriba, and STAR-Fusion, to achieve best-case sensitivity for IGH gene fusion detection. We analysed 35 patient samples harbouring IGH gene fusions and assessed the detection rates for each caller, before optimising the parameters to enhance sensitivity for IGH fusions. FusionCatcher and Arriba outperformed STAR-Fusion; however, by adjusting specific filtering parameters, we were able to improve STAR-Fusion's performance. This analysis highlights the importance of filtering optimization for IGH gene fusion events, offering alternative workflows for difficult-to-detect high-risk B-ALL alterations. B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by diverse genomic alterations, the most frequent being gene fusions detected via transcriptomic analysis (mRNA-seq). Due to its hypervariable nature, gene fusions involving the Immunoglobulin Heavy Chain (IGH) locus can be difficult to detect with standard gene fusion calling algorithms and significant computational resources and analysis times are required. We aimed to optimize a gene fusion calling workflow to achieve best-case sensitivity for IGH gene fusion detection. Using Nextflow, we developed a simplified workflow containing the algorithms FusionCatcher, Arriba, and STAR-Fusion. We analysed samples from 35 patients harbouring IGH fusions (IGH::CRLF2 n = 17, IGH::DUX4 n = 15, IGH::EPOR n = 3) and assessed the detection rates for each caller, before optimizing the parameters to enhance sensitivity for IGH fusions. Initial results showed that FusionCatcher and Arriba outperformed STAR-Fusion (85–89% vs. 29% of IGH fusions reported). We found that extensive filtering in STAR-Fusion hindered IGH reporting. By adjusting specific filtering steps (e.g., read support, fusion fragments per million total reads), we achieved a 94% reporting rate for IGH fusions with STAR-Fusion. This analysis highlights the importance of filtering optimization for IGH gene fusion events, offering alternative workflows for difficult-to-detect high-risk B-ALL subtypes. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Gain of chromosome 21 increases the propensity for P2RY8::CRLF2 acute lymphoblastic leukemia via increased HMGN1 expression.
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Page, Elyse C., Heatley, Susan L., Rehn, Jacqueline, Thomas, Paul Q., Yeung, David T., and White, Deborah L.
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GENE expression ,LYMPHOBLASTIC leukemia ,ACUTE leukemia ,CHROMOSOMES ,THYMIC stromal lymphopoietin ,CHIMERIC proteins - Abstract
Acute lymphoblastic leukemia (ALL) patients with a gain of chromosome 21, intrachromosomal amplification of chromosome 21 (iAMP21), or Down syndrome (DS), have increased expression of genes in the DS critical region (DSCR) of chromosome 21, including the high-mobility group nucleosomebinding protein 1, HMGN1. Children with DS are predisposed to develop hematologic malignancies, providing insight into the role of chromosome 21 in the development of leukemias. A 320-kb deletion in the pseudoautosomal region of the X/Y chromosome in leukemic cells, resulting in a gene fusion between the purinergic receptor and cytokine receptor-like factor-2 (P2Y Receptor Family Member 8 (P2RY8)::CRLF2), is a common feature in ~60% of DS-ALL and ~40% of iAMP21 patients, suggesting a link between chromosome 21 and P2RY8::CRLF2. In an Australian cohort of pediatric B-ALL patients with P2RY8::CRLF2 (n = 38), eight patients harbored gain of chromosome 21 (+21), and two patients had iAMP21, resulting in a significantly increased HMGN1 expression. An inducible CRISPR/Cas9 system was used to model P2RY8::CRLF2 and investigate its cooperation with HMGN1. This model was then used to validate HMGN1 as an influencing factor for P2RY8::CRLF2 development. Using Cas9 to cleave the DNA at the pseudoautosomal region without directed repair, cells expressing HMGN1 favored repair, resulting in P2RY8::CRLF2 generation, compared with cells without HMGN1. CRISPR/Cas9 P2RY8::CRLF2 cells expressing HMGN1 exhibit increased proliferation, thymic stromal lymphopoietin receptor (TSLPR) expression, and JAK/ STAT signaling, consistent with cells from patients with P2RY8::CRLF2. Our patient expression data and unique CRISPR/Cas9 modeling,when taken together, suggest that HMGN1 increases the propensity for P2RY8::CRLF2 development. This has important implications for patients with DS, +21, or iAMP21. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Case Report: Rare IKZF1 Gene Fusions Identified in Neonate with Congenital KMT2A -Rearranged Acute Lymphoblastic Leukemia.
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Eadie, Laura N., Rehn, Jacqueline A., Breen, James, Osborn, Michael P., Jessop, Sophie, Downes, Charlotte E. J., Heatley, Susan L., McClure, Barbara J., Yeung, David T., Revesz, Tamas, Saxon, Benjamin, and White, Deborah L.
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GENE fusion ,LYMPHOBLASTIC leukemia ,ACUTE leukemia ,NEWBORN infants ,CHROMOSOMAL rearrangement ,INFANTS ,PREMATURE infants - Abstract
Chromosomal rearrangements involving the KMT2A gene occur frequently in acute lymphoblastic leukaemia (ALL). KMT2A-rearranged ALL (KMT2Ar ALL) has poor long-term survival rates and is the most common ALL subtype in infants less than 1 year of age. KMT2Ar ALL frequently occurs with additional chromosomal abnormalities including disruption of the IKZF1 gene, usually by exon deletion. Typically, KMT2Ar ALL in infants is accompanied by a limited number of cooperative le-sions. Here we report a case of aggressive infant KMT2Ar ALL harbouring additional rare IKZF1 gene fusions. Comprehensive genomic and transcriptomic analyses were performed on sequential samples. This report highlights the genomic complexity of this particular disease and describes the novel gene fusions IKZF1::TUT1 and KDM2A::IKZF1. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Rascall: Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL).
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Rehn, Jacqueline, Mayoh, Chelsea, Heatley, Susan L, McClure, Barbara J, Eadie, Laura N, Schutz, Caitlin, Yeung, David T, Cowley, Mark J, Breen, James, and White, Deborah L
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LYMPHOBLASTIC leukemia ,ACUTE leukemia ,PHARMACOGENOMICS ,RNA sequencing ,SINGLE nucleotide polymorphisms ,MEDICAL screening - Abstract
RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, integrating RNA-seq in a clinical setting requires rapid detection and accurate reporting of clinically relevant alterations. Here we present RaScALL, an implementation of the k-mer based variant detection tool km, capable of identifying more than 100 prognostically significant lesions observed in ALL, including gene fusions, single nucleotide variants and focal gene deletions. We compared genomic alterations detected by RaScALL and those reported by alignment-based de novo variant detection tools in a study cohort of 180 Australian patient samples. Results were validated using 100 patient samples from a published North American cohort. RaScALL demonstrated a high degree of accuracy for reporting subtype defining genomic alterations. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% of reported cases in the study cohort (n = 164) and 95% of samples (n = 63) in the validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n = 12) and IKZF1 p.N159Y (n = 4). Intragenic IKZF1 deletions resulting in aberrant transcript isoforms were also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches. The application of RaScALL enables rapid identification and reporting of previously identified genomic alterations of known clinical relevance. Author summary: Acute lymphoblastic leukaemia is a life-threatening malignancy characterised by various genomic alterations. RNA-sequencing (RNA-seq) is an effective method for identifying genomic lesions that drive patient disease, providing critical information about patient prognosis and treatment. However, analysis of RNA-seq data to identify clinically relevant genomic alterations is often time and resource intensive. Here, we present RaScALL, an integrated platform for rapid (Ra) screening (Sc) of RNA-seq data to identify genomic alterations of clinical significance in acute lymphoblastic leukaemia (ALL). RaScALL can detect more than 100 lesions of clinical importance from raw RNA-seq data, including gene fusions and sequence variants. A comparison of alterations detected by RaScALL and those reported by de novo variant detection tools confirmed that RaScALL is highly accurate and computationally efficient, with an average runtime of fewer than 30 minutes. Where RNA-seq data is available RaScALL provides rapid detection and reporting of prognostically significant lesions, which may ultimately assist with patient risk-stratification and therapeutic triage. [ABSTRACT FROM AUTHOR]
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- 2022
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11. Mannose-binding lectin status is associated with risk of major infection following myeloablative sibling allogeneic hematopoietic stem cell transplantation
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Mullighan, Charles G., Heatley, Susan L., Danner, Silke, Dean, Melinda M., Doherty, Kathleen, Hahn, Uwe, Bradstock, Kenneth F., Minchinton, Robyn, Schwarer, Anthony P., Szer, Jeff, and Bardy, Peter G.
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- 2008
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12. Donor Mannose-binding lectin deficiency increases the likelihood of clinically significant infection after liver transplantation
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Worthley, Daniel L., Johnson, Douglas F., Eisen, Damon P., Dean, Melinda M., Heatley, Susan L., Tung, John-Paul, Scott, Justin, Padbury, Robert T.A., Harley, Hugh A., Bardy, Peter G., Angus, Peter W., and Mullighan, Charles G.
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Lectins -- Research ,Lectins -- Physiological aspects ,Genetic polymorphisms -- Research ,Infection -- Risk factors ,Immune system -- Research ,Immune system -- Physiological aspects ,Liver -- Transplantation ,Liver -- Complications and side effects ,Health ,Health care industry - Published
- 2009
13. Case Report: Precision Medicine Target Revealed by In Vitro Modeling of Relapsed, Refractory Acute Lymphoblastic Leukemia From a Child With Neurofibromatosis.
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Heatley, Susan L., Page, Elyse C., Eadie, Laura N., McClure, Barbara J., Rehn, Jacqueline, Yeung, David T., Osborn, Michael, Revesz, Tamas, Kirby, Maria, and White, Deborah L.
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LYMPHOBLASTIC leukemia ,ACUTE leukemia ,INDIVIDUALIZED medicine ,NEUROFIBROMATOSIS ,ACUTE myeloid leukemia - 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. [ABSTRACT FROM AUTHOR]
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- 2022
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14. Two novel cases of NUTM1‐rearranged B‐cell acute lymphoblastic leukaemia presenting with high‐risk features.
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McClure, Barbara J., Pal, Manika, Heatley, Susan L., Rehn, Jacqueline, Schutz, Caitlin, Breen, James, Venn, Nicola C., Sutton, Rosemary, Khaw, Seong Lin, Yeung, David T., and White, Deborah L.
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LYMPHOBLASTIC leukemia ,ACUTE leukemia ,CHRONIC leukemia ,HYDROPS fetalis ,TUMOR lysis syndrome ,HEMATOPOIETIC stem cells - Abstract
(D) Analysis of deletions in key B-ALL genes in Case 1 were identified by multiplex ligand-dependent probe amplification (MLPA) on BM TWC using probes sets P202-erg and (E) P335 respectively. Congenital B-ALL, adult B-ALL, NUTM1-rearranged, CRLF2-rearranged, B-cell acute lymphoblastic leukaemia (B-ALL) (D) Analysis of deletions in key B-ALL genes in Case 2 were identified by multiplex ligand-dependent probe amplification (MLPA) on BM MNC using probes sets P202-erg and (E) P335 respectively. Keywords: B-cell acute lymphoblastic leukaemia (B-ALL); congenital B-ALL; adult B-ALL; NUTM1-rearranged; CRLF2-rearranged EN B-cell acute lymphoblastic leukaemia (B-ALL) congenital B-ALL adult B-ALL NUTM1-rearranged CRLF2-rearranged 1407 1411 5 03/22/22 20220315 NES 220315 Rare recurrent chromosomal rearrangements involving 15q13-15 have been reported in paediatric B-cell acute lymphoblastic leukaemia (B-ALL), occurring with higher frequency in infant than non-infant B-ALL.1 High-throughput sequencing identified these as NUT midline carcinoma family member 1 ( I NUTM1 i ) (15q14) rearrangements ( I NUTM1 i -r).2-7 I NUTM1 i -r were originally identified as the driving lesion of NUT midline carcinomas (NMC), an aggressive malignancy with poor prognosis.8 I NUTM1-r i infant B-ALL however is associated with favourable prognosis,3,9 in contrast to infants with I KMT2A i rearrangements.10 Multiple 5' partners have been identified in I NUTM1 i -r B-ALL including I BRD9 i , I IKZF1 i , I CUX1 i , I AFF1 i , I ZNF618 i , I SLC12A6 i , and the cytogenetically cryptic I ACIN1 i .6 I NUTM1 i -r increases I NUTM1 i expression,3-6 upregulates I HOX1 i family genes5 and downregulates I NOTCH i and Hedgehog pathways.5 Rare cases of infant B-ALL that co-harbour I KMT2A- i r and I NUTM1 i -r have been reported2,6 and no cases of adult I NUTM1 i -r B-ALL have been identified. [Extracted from the article]
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- 2022
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15. Identification of a novel GOLGA4–JAK2 fusion gene in B‐cell acute lymphoblastic leukaemia.
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Downes, Charlotte E. J., Rehn, Jacqueline, Heatley, Susan L., Yeung, David, McClure, Barbara J., and White, Deborah L.
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LYMPHOBLASTIC leukemia ,GENE fusion ,ACUTE leukemia - Abstract
Summary: Rearrangements of Janus kinase 2 (JAK2r) 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 diverse 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. [ABSTRACT FROM AUTHOR]
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- 2022
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16. 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
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Annells, Margaret F., Hart, Prue H., Mullighan, Charles G., Heatley, Susan L., Robinson, Jeffrey S., Bardy, Peter, and McDonald, Helen M.
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- 2004
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17. In-vitro modeling of TKI resistance in the high-risk B-cell acute lymphoblastic leukemia fusion gene RANBP2-ABL1 - implications for targeted therapy.
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Heatley, Susan L., Asari, Kartini, Schutz, Caitlin E., Leclercq, Tamara M., McClure, Barbara J., Eadie, Laura N., Hughes, Timothy P., Yeung, David T., and White, Deborah L.
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LYMPHOBLASTIC leukemia , *GENE fusion , *ACUTE leukemia , *CHILD mortality , *PROTEIN-tyrosine kinases , *CD19 antigen , *GASTROINTESTINAL stromal tumors - Abstract
Acute lymphoblastic leukemia remains a leading cause of cancer-related death in children. Furthermore, subtypes such as Ph-like ALL remain at high-risk of relapse, and treatment resistance remains a significant clinical issue. The patient-derived Ph-like ALL RANBP2-ABL1 fusion gene was transduced into Ba/F3 cells and allowed to become resistant to the tyrosine kinase inhibitors (TKIs) imatinib or dasatinib, followed by secondary resistance to ponatinib. RANBP2-ABL1 Ba/F3 cells developed the clinically relevant ABL1 p.T315I mutation and upon secondary resistance to ponatinib, developed compound mutations, including a novel ABL1 p.L302H mutation. Significantly, compound mutations were targetable with a combination of asciminib and ponatinib. In-vitro modeling of Ph-like ALL RANBP2-ABL1 has identified kinase domain mutations in response to TKI treatment, that may have important clinical ramifications. Early detection of mutations is paramount to guide treatment strategies and improve survival in this high-risk group of patients. [ABSTRACT FROM AUTHOR]
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- 2021
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18. Outcomes for Australian children with relapsed/refractory acute lymphoblastic leukaemia treated with blinatumomab.
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Sutton, Rosemary, Pozza, Luciano Dalla, Khaw, Seong Lin, Fraser, Chris, Revesz, Tom, Chamberlain, Janis, Mitchell, Richard, Trahair, Toby N., Bateman, Caroline M., Venn, Nicola C., Law, Tamara, Ong, Erika, Heatley, Susan L., McClure, Barbara J., Meyer, Claus, Marschalek, Rolf, Henderson, Michelle J., Cross, Siobhan, White, Deborah L., and Kotecha, Rishi S.
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- 2021
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19. Polymorphisms in immunoregulatory genes and the risk of histologic chorioamnionitis in Caucasoid women: a case control study
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Heatley Susan L, Mullighan Charles G, Hart Prue H, Annells Margaret F, Robinson Jeffrey S, and McDonald Helen M
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Gynecology and obstetrics ,RG1-991 - Abstract
Abstract Background Chorioamnionitis is a common underlying cause of preterm birth (PTB). It is hypothesised that polymorphisms in immunoregulatory genes influence the host response to infection and subsequent preterm birth. The relationship between histologic chorioamnionitis and 22 single nucleotide polymorphisms in 11 immunoregulatory genes was examined in a case-control study. Methods Placentas of 181 Caucasoid women with spontaneous PTB prior to 35 weeks were examined for histologic chorioamnionitis. Polymorphisms in genes IL1A, IL1B, IL1RN, IL1R1, tumour necrosis factor (TNF), IL4, IL6, IL10, transforming growth factor beta-1 (TGFB1), Fas (TNFRSF6), and mannose-binding lectin (MBL2) were genotyped by polymerase chain reaction and sequence specific primers. Multivariable logistic regression including demographic and genetic variables and Kaplan-Meier survival analyses of genotype frequencies and pregnancy outcome were performed. Results Sixty-nine (34%) women had histologic evidence of acute chorioamnionitis. Carriage of the IL10-1082A/-819T/592A (ATA) haplotype [Multivariable Odds ratio (MOR) 1.9, P = 0.05] and MBL2 codon 54Asp allele (MOR 2.0, P = 0.04), were positively associated with chorioamnionitis, while the TNFRSF6-1377A/-670G (AG) haplotype (MOR 0.4, P = 0.03) and homozygosity for TGFB1-800G/509T (GT) haplotype (MOR 0.2, P = 0.04) were negatively associated. Conclusion These findings demonstrate that polymorphisms in immunoregulatory genes IL10, MBL2, TNFRSF6 and TGFB1 may influence susceptibility to chorioamnionitis.
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- 2005
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20. High‐risk B‐cell acute lymphoblastic leukaemia presenting with hypereosinophilia and acquiring a novel PAX5 fusion on relapse.
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McClure, Barbara J., Heatley, Susan L., Rehn, Jacqueline, Breen, James, Sutton, Rosemary, Hughes, Timothy P., Suppiah, Ram, Revesz, Tamas, Osborn, Michael, White, Daniel, Yeung, David T., and White, Deborah L.
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LYMPHOBLASTIC leukemia , *ACUTE leukemia , *MEDICAL research , *SYMPTOMS , *TEENAGERS - Published
- 2020
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21. The effect of co-occurring lesions on leukaemogenesis and drug response in T-ALL and ETP-ALL.
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Tavakoli Shirazi, Paniz, Eadie, Laura N., Heatley, Susan L., Hughes, Timothy P., Yeung, David T., and White, Deborah L.
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CARCINOGENESIS ,LYMPHOBLASTIC leukemia ,DRUG resistance in cancer cells - 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 individual'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. [ABSTRACT FROM AUTHOR]
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- 2020
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22. Precision medicine approaches may be the future for CRLF2 rearranged Down Syndrome Acute Lymphoblastic Leukaemia patients.
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Page, Elyse C., Heatley, Susan L., Yeung, David T., Thomas, Paul Q., and White, Deborah L.
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LYMPHOBLASTIC leukemia treatment , *INDIVIDUALIZED medicine , *DOWN syndrome , *CYTOKINE receptors , *GENE regulatory networks , *THERAPEUTICS - 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 individual 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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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23. Activating killer‐cell immunoglobulin‐like receptor haplotype influences clinical outcome following HLA‐matched sibling haematopoietic stem cell transplantation.
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Heatley, Susan L., Mullighan, Charles G., Doherty, Kathleen, Danner, Silke, O'Connor, Geraldine M., Hahn, Uwe, Szer, Jeff, Schwarer, Anthony, Bradstock, Kenneth, Sullivan, Lucy C., Bardy, Peter G., and Brooks, Andrew G.
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KILLER cells , *STEM cell transplantation , *GRAFT versus host disease , *IMMUNOGLOBULIN receptors , *HAPLOTYPES - Abstract
Natural killer cells are thought to influence the outcome of haematopoietic stem cell transplant (HSCT), impacting on relapse, overall survival, graft vs host disease (GvHD) and the control of infection, in part through the complex interplay between the large and genetically diverse killer‐cell 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 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 leukaemia undergoing sibling HSCT and receiving myeloablative conditioning. Donor Cen‐B haplotype was also associated with reduced acute GvHD grades II to IV whereas donor telomeric‐B haplotype was associated with decreased incidence of CMV reactivation. In contrast, we were not able to show 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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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24. A novel somatic JAK2 kinase-domain mutation in pediatric acute lymphoblastic leukemia with rapid on-treatment development of LOH.
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Sadras, Teresa, Heatley, Susan L., Kok, Chung H., McClure, Barbara J., Yeung, David, Hughes, Timothy P., Sutton, Rosemary, Ziegler, David S., and White, Deborah L.
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JANUS kinases , *LYMPHOBLASTIC leukemia , *SOMATIC mutation , *KINASE inhibitors , *LYMPHOBLASTIC leukemia treatment , *GENETICS - 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. [ABSTRACT FROM AUTHOR]
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- 2017
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25. Polymorphism in Human Cytomegalovirus UL40 Impacts on Recognition of Human Leukocyte Antigen-E (HLA-E) by Natural Killer Cells.
- Author
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Heatley, Susan L., Pietra, Gabriella, Jie Lin, Jacqueline M. L. Widjaja, Harpur, Christopher M., Lester, Sue, Rossjohn, Jamie, Szer, Jeff, Schwarer, Anthony, Bradstock, Kenneth, Bardy, Peter G., Mingari, Maria Cristina, Moretta, Lorenzo, Sullivan, Lucy C., and Brooks, Andrew G.
- Subjects
- *
KILLER cells , *LEUCOCYTES , *CYTOMEGALOVIRUS diseases , *GENETIC polymorphisms , *CELL receptors - Abstract
Natural killer (NK) cell recognition of the nonclassical human leukocyte antigen (HLA) molecule HLA-E is dependent on the presentation of a nonamer peptide derived from the leader sequence of other HLA molecules to CD94-NKG2 receptors. However, human cytomegalovirus can manipulate this central innate interaction through the provision of a "mimic" of the HLA-encoded peptide derived from the immunomodulatory glycoprotein UL40. Here, we analyzed UL40 sequences isolated from 32 hematopoietic stem cell transplantation recipients experiencing cytomegalovirus reactivation. The UL40 protein showed a "polymorphic hot spot" within the region that encodes the HLA leader sequence mimic. Although all sequences that were identical to those encoded within HLA-I genes permitted the interaction between HLA-E and CD94-NKG2 receptors, other UL40 polymorphisms reduced the affinity of the interaction between HLA-E and CD94-NKG2 receptors. Furthermore, functional studies using NK cell clones expressing either the inhibitory receptor CD94-NKG2A or the activating receptor CD94-NKG2C identified UL40-encoded peptides that were capable of inhibiting target cell lysis via interaction with CD94- NKG2A, yet had little capacity to activate NK cells through CD94-NKG2C. The data suggest that UL40 polymorphisms may aid evasion of NK cell immunosurveillance by modulating the affinity of the interaction with CD94-NKG2 receptors. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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26. The genomic landscape of hypodiploid acute lymphoblastic leukemia.
- Author
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Holmfeldt, Linda, Wei, Lei, Diaz-Flores, Ernesto, Walsh, Michael, Zhang, Jinghui, Ding, Li, Payne-Turner, Debbie, Churchman, Michelle, Andersson, Anna, Chen, Shann-Ching, McCastlain, Kelly, Becksfort, Jared, Ma, Jing, Wu, Gang, Patel, Samir N, Heatley, Susan L, Phillips, Letha A, Song, Guangchun, Easton, John, and Parker, Matthew
- Subjects
LYMPHOBLASTIC leukemia ,ANEUPLOIDY ,PLOIDY ,CHROMOSOME abnormalities ,PROTEIN-tyrosine kinases ,GENETICS - Abstract
The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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27. High Levels of Mannose-Binding Lectin Are Associated With Poor Outcomes After Lung Transplantation.
- Author
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Carroll, Katherine E., Dean, Melinda M., Heatley, Susan L., Meehan, Aislin C., Mifsud, Nicole A., Kotsimbos, Tom C., Snell, Greg I., and Westall, Glen P.
- Published
- 2011
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28. Polymorphisms in immunoregulatory genes and the risk of histologic chorioamnionitis in Caucasoid women: a case control study.
- Author
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Annells, Margaret F., Hart, Prue H., Mullighan, Charles G., Heatley, Susan L., Robinson, Jeffrey S., and McDonald, Helen M.
- Subjects
GENETIC polymorphisms ,POPULATION genetics ,CHROMOSOME polymorphism ,DNA polymerases ,GENETIC research ,CAUCASIAN race - Abstract
Background: Chorioamnionitis is a common underlying cause of preterm birth (PTB). It is hypothesised that polymorphisms in immunoregulatory genes influence the host response to infection and subsequent preterm birth. The relationship between histologic chorioamnionitis and 22 single nucleotide polymorphisms in 11 immunoregulatory genes was examined in a case-control study. Methods: Placentas of 181 Caucasoid women with spontaneous PTB prior to 35 weeks were examined for histologic chorioamnionitis. Polymorphisms in genes IL1A, IL1B, IL1RN, IL1R1, tumour necrosis factor (TNF), IL4, IL6, IL10, transforming growth factor beta-1 (TGFB1), Fas (TNFRSF6), and mannose-binding lectin (MBL2) were genotyped by polymerase chain reaction and sequence specific primers. Multivariable logistic regression including demographic and genetic variables and Kaplan-Meier survival analyses of genotype frequencies and pregnancy outcome were performed. Results: Sixty-nine (34%) women had histologic evidence of acute chorioamnionitis. Carriage of the IL10-1082A/-819T/592A (ATA) haplotype [Multivariable Odds ratio (MOR) 1.9, P = 0.05] and MBL2 codon 54Asp allele (MOR 2.0, P = 0.04), were positively associated with chorioamnionitis, while the TNFRSF6-1377A/-670G (AG) haplotype (MOR 0.4, P = 0.03) and homozygosity for TGFB1-800G/509T (GT) haplotype (MOR 0.2, P = 0.04) were negatively associated. Conclusion: These findings demonstrate that polymorphisms in immunoregulatory genes IL10, MBL2, TNFRSF6 and TGFB1 may influence susceptibility to chorioamnionitis. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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29. Constitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia.
- Author
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Tavakoli Shirazi, Paniz, Eadie, Laura N., Page, Elyse C., Heatley, Susan L., Bruning, John B., and White, Deborah L.
- Subjects
- *
LYMPHOBLASTIC leukemia , *ACUTE leukemia , *HISTONE deacetylase inhibitors , *CHIMERIC proteins , *HISTONE deacetylase , *B cells , *PROTEIN metabolism , *PROTEINS , *RESEARCH , *HETEROCYCLIC compounds , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *CELLULAR signal transduction , *COMPARATIVE studies , *TRANSFERASES , *GENES , *SULFONES , *CARRIER proteins , *DRUG resistance in cancer cells - Abstract
Activating TYK2-rearrangements have recently been identified and implicated in the leukemogenesis of high-risk acute lymphoblastic leukemia (HR-ALL) cases. Pre-clinical studies indicated the JAK/TYK2 inhibitor (JAKi), cerdulatinib, as a promising therapeutic against TYK2-rearranged ALL, attenuating the constitutive JAK/STAT signaling resulting from the TYK2 fusion protein. However, following a period of clinical efficacy, JAKi resistance often occurs resulting in relapse. In this study, we modeled potential mechanisms of JAKi resistance in TYK2-rearranged ALL cells in vitro in order to recapitulate possible clinical scenarios and provide a rationale for alternative therapies. Cerdulatinib resistant B-cells, driven by the MYB-TYK2 fusion oncogene, were generated by long-term exposure to the drug. Sustained treatment of MYB-TYK2-rearranged ALL cells with cerdulatinib led to enhanced and persistent JAK/STAT signaling, co-occurring with JAK1 overexpression. Hyperactivation of JAK/STAT signaling and JAK1 overexpression was reversible as cerdulatinib withdrawal resulted in re-sensitization to the drug. Importantly, histone deacetylase inhibitor (HDACi) therapies were efficacious against cerdulatinib-resistant cells demonstrating a potential alternative therapy for use in TYK2-rearranged B-ALL patients who have lost response to JAKi treatment regimens. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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