Julie A.I. Thoms

UNSW Sydney

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Co-Authors

John E. Pimanda

UNSW Sydney

106

Jason W.H. Wong

Naval Information Warfare Center Pacific

Dominik Beck

Ruijin Hospital

Ashwin Unnikrishnan

UNSW Sydney

Kathy Knezevic

Peter MacCallum Cancer Centre

Rebecca C. Poulos

University of Sydney

Yao‐Chung Liu

Taipei Veterans General Hospital

Junsu Kwon

National University Cancer Institute, Singapore

Junyu Yang

Kunming University

Li Chai

Harvard University

Cooperative Institutions

UNSW Sydney

152

University of Sydney

Cancer Institute of New South Wales

Monash University

Harvard University

University of Cambridge

Prince of Wales Hospital

Children's Cancer Institute Australia

Australian Centre for HIV and Hepatitis Virology Research

University of Melbourne

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Data from Constitutive CHK1 Expression Drives a pSTAT3–CIP2A Circuit that Promotes Glioblastoma Cell Survival and Growth

Anchit Khanna Julie A.I. Thoms Brett W. Stringer Sylvia A. Chung Kathleen S. Ensbey

<div>AbstractHigh-constitutive activity of the DNA damage response protein checkpoint kinase 1 (CHK1) has been shown in glioblastoma (GBM) cell lines and in tissue sections. However, whether constitutive activation and overexpression of CHK1 in GBM plays a functional role in tumorigenesis or has prognostic significance is not known. We interrogated multiple glioma patient cohorts for expression levels of CHK1 and the oncogene cancerous inhibitor of protein phosphatase 2A (CIP2A), a known target of high-CHK1 activity, and examined the relationship between these two proteins in GBM. Expression levels of CHK1 and CIP2A were independent predictors for reduced overall survival across multiple glioma patient cohorts. Using siRNA and pharmacologic inhibitors we evaluated the impact of their depletion using both in vitro and in vivo models and sought a mechanistic explanation for high CIP2A in the presence of high-CHK1 levels in GBM and show that; (i) CHK1 and pSTAT3 positively regulate CIP2A gene expression; (ii) pSTAT3 and CIP2A form a recursively wired transcriptional circuit; and (iii) perturbing CIP2A expression induces GBM cell senescence and retards tumor growth in vitro and in vivo. Taken together, we have identified an oncogenic transcriptional circuit in GBM that can be destabilized by targeting CIP2A.Implications:High expression of CIP2A in gliomas is maintained by a CHK1-dependent pSTAT3–CIP2A recursive loop; interrupting CIP2A induces cell senescence and slows GBM growth adding impetus to the development of CIP2A as an anticancer drug target.</div>

Expression (computer science)

10.1158/1541-7786.c.6540991

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Prospective Identification of Acute Myeloid Leukemia Patients Who Benefit from Gene-Expression Based Risk Stratification

Blood (2019)

Diego Chacon Ali Braytee Yizhou Huang Julie A.I. Thoms Shruthi Subramanian

Chemotherapy regimen

10.1182/blood-2019-129519

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Supplement Figure 4 from Targeting an Inducible SALL4-Mediated Cancer Vulnerability with Sequential Therapy

Junyu Yang Chong Gao Miao Liu Yao‐Chung Liu Junsu Kwon

Supplement Figure 4

Vulnerability

Cancer Therapy

10.1158/0008-5472.22430479

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BloodChIP Xtra: an expanded database of comparative genome-wide transcription factor binding and gene-expression profiles in healthy human stem/progenitor subsets and leukemic cells

Nucleic Acids Research (2023)

Julie A.I. Thoms Forrest Koch Alireza Raei Shruthi Subramanian Jason W.H. Wong

Abstract The BloodChIP Xtra database (http://bloodchipXtra.vafaeelab.com/) facilitates genome-wide exploration and visualization of transcription factor (TF) occupancy and chromatin configuration in rare primary human hematopoietic stem (HSC-MPP) and progenitor (CMP, GMP, MEP) cells and acute myeloid leukemia (AML) cell lines (KG-1, ME-1, Kasumi1, TSU-1621-MT), along with chromatin accessibility and gene expression data from these and primary patient AMLs. BloodChIP Xtra features significantly more datasets than our earlier database BloodChIP (two primary cell types and two cell lines). Improved methodologies for determining TF occupancy and chromatin accessibility have led to increased availability of data for rare primary cell types across the spectrum of healthy and AML hematopoiesis. However, there is a continuing need for these data to be integrated in an easily accessible manner for gene-based queries and use in downstream applications. Here, we provide a user-friendly database based around genome-wide binding profiles of key hematopoietic TFs and histone marks in healthy stem/progenitor cell types. These are compared with binding profiles and chromatin accessibility derived from primary and cell line AML and integrated with expression data from corresponding cell types. All queries can be exported to construct TF–gene and protein–protein networks and evaluate the association of genes with specific cellular processes.

Chromatin immunoprecipitation

10.1093/nar/gkad918

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AML-079: The PNT Domain of ERG Regulates Hematopoietic Stemness and is Required for the Maintenance of ERG-Induced Leukemia

Clinical Lymphoma Myeloma & Leukemia (2020)

Eitan Kugler Yehudit Birger Darren Yong Julie A.I. Thoms Avigail Rein

Erg

10.1016/s2152-2650(20)30713-8

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Single cell genotyping of matched bone marrow and peripheral blood cells in treatment naive and AZA-treated MDS and CMML

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Annatina Schnegg‐Kaufmann Julie A.I. Thoms Golam Sarower Bhuyan Henry R. Hampton Lachlin Vaughan

ABSTRACT Progressively acquired somatic mutations in hematopoietic stem cells are central to pathogenesis in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). They can lead to proliferative advantages, impaired differentiation and progressive cytopenias. MDS or CMML patients with high-risk disease are treated with hypomethylating agents including 5-azacytidine (AZA). Clinical improvement does not require eradication of mutated cells and may be related to improved differentiation capacity of mutated hematopoietic stem and progenitor cells (HSPCs). However, the contribution of mutated HSPCs to steadystate hematopoiesis in MDS and CMML is unclear. To address this, we characterised the somatic mutations of individual stem, progenitor (common myeloid progenitor, granulocyte monocyte progenitor, megakaryocyte erythroid progenitor), and matched circulating (monocyte, neutrophil, naïve B cell) haematopoietic cells in treatment naïve and AZA-treated MDS and CMML via high-throughput single cell genotyping. The mutational burden was similar across multiple hematopoietic cell types, and even the most mutated stem and progenitor clones maintained their capacity to differentiate to mature myeloid and, in some cases, lymphoid cell types in vivo. Our data show that even highly mutated HSPCs contribute significantly to circulating blood cells in MDS and CMML, prior to and following AZA treatment. Key points * Highly mutated HSPCs contribute significantly to circulating blood cells in MDS and CMML, prior to and following AZA treatment. * The mutational burden in matched bone marrow and peripheral blood cells in MDS and CMML was similar throughout myelopoiesis.

Myelopoiesis

Chronic myelomonocytic leukemia

10.1101/2022.01.20.476890

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Data from Systematic Screening of Promoter Regions Pinpoints Functional Cis-Regulatory Mutations in a Cutaneous Melanoma Genome

Rebecca C. Poulos Julie A.I. Thoms Anushi Shah Dominik Beck John E. Pimanda

<div>AbstractWith the recent discovery of recurrent mutations in the TERT promoter in melanoma, identification of other somatic causal promoter mutations is of considerable interest. Yet, the impact of sequence variation on the regulatory potential of gene promoters has not been systematically evaluated. This study assesses the impact of promoter mutations on promoter activity in the whole-genome sequenced malignant melanoma cell line COLO-829. Combining somatic mutation calls from COLO-829 with genome-wide chromatin accessibility and histone modification data revealed mutations within promoter elements. Interestingly, a high number of potential promoter mutations (n = 23) were found, a result mirrored in subsequent analysis of TCGA whole-melanoma genomes. The impact of wild-type and mutant promoter sequences were evaluated by subcloning into luciferase reporter vectors and testing their transcriptional activity in COLO-829 cells. Of the 23 promoter regions tested, four mutations significantly altered reporter activity relative to wild-type sequences. These data were then subjected to multiple computational algorithms that score the cis-regulatory altering potential of mutations. These analyses identified one mutation, located within the promoter region of NDUFB9, which encodes the mitochondrial NADH dehydrogenase (ubiquinone) 1 beta subcomplex 9, to be recurrent in 4.4% (19 of 432) of TCGA whole-melanoma exomes. The mutation is predicted to disrupt a highly conserved SP1/KLF transcription factor binding motif and its frequent co-occurrence with mutations in the coding sequence of NF1 supports a pathologic role for this mutation in melanoma. Taken together, these data show the relatively high prevalence of promoter mutations in the COLO-829 melanoma genome, and indicate that a proportion of these significantly alter the regulatory potential of gene promoters.Implications: Genomic-based screening within gene promoter regions suggests that functional cis-regulatory mutations may be common in melanoma genomes, highlighting the need to examine their role in tumorigenesis. Mol Cancer Res; 13(8); 1218–26. ©2015 AACR.</div>

10.1158/1541-7786.c.6540747

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A tropomyosin 1 induced defect in cytokinesis can be rescued by elevated expression of cofilin

Cell Motility and the Cytoskeleton (2008)

Julie A.I. Thoms Heather M. Loch James R. Bamburg Peter W. Gunning Ron P. Weinberger

Abstract Cytokinesis in eukaryotic cells is mediated by the contractile ring, an actomyosin‐based structure which provides the force required to separate daughter cells. Isoforms of the actin‐binding protein tropomyosin are also localised to the contractile ring in both fission yeast and human astrocytes. Although tropomyosin is required for cytokinesis in yeast, its precise role in the contractile ring is unknown. In this study we find that increased expression of a single tropomyosin isoform, tropomyosin 1, in U373MG astrocytoma cells leads to multinucleated cells and mitotic spindle defects. Furthermore, cells expressing increased levels of tropomyosin 1 usually fail to complete cytokinesis and this is accompanied by reduced accumulation of actin depolymerising factor/cofilin in the contractile ring. Adenovirus mediated expression of cofilin is able to relieve the tropomyosin 1 induced effects on cytokinesis. We conclude that tropomyosin 1 and cofilin play antagonistic roles within the contractile ring and that the balance between tropomyosin 1 and cofilin expression is important for cytokinesis. Cell Motil. Cytoskeleton 2008. © 2008 Wiley‐Liss, Inc.

Tropomyosin

Cofilin

Profilin

10.1002/cm.20320

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Citations (16)

Supplemental Methods and Materials from Disruption of a −35 kb Enhancer Impairs CTCF Binding and MLH1 Expression in Colorectal Cells

Qing Liu Julie A.I. Thoms Andrea C. Nunez Yizhou Huang Kathy Knezevic

Supplemental methods and supplemental figures 1-6

CTCF

MLH1

10.1158/1078-0432.22469439