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Article ; Online: Gene regulation in t(6;9) DEK::NUP214 Acute Myeloid Leukemia resembles that of FLT3-ITD/NPM1 Acute Myeloid Leukemia but with an altered HOX/MEIS axis.

Potluri, Sandeep / Kellaway, Sophie G / Coleman, Daniel J L / Keane, Peter / Imperato, Maria Rosaria / Assi, Salam A / Cockerill, Peter N / Bonifer, Constanze

Leukemia

2024 Volume 38, Issue 2, Page(s) 403–407

MeSH term(s)	Humans ; Leukemia, Myeloid, Acute/genetics ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; fms-Like Tyrosine Kinase 3/genetics ; Mutation ; Prognosis ; Nuclear Pore Complex Proteins/genetics
Chemical Substances	Nuclear Proteins ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; FLT3 protein, human (EC 2.7.10.1) ; NUP214 protein, human ; Nuclear Pore Complex Proteins
Language	English
Publishing date	2024-01-04
Publishing country	England
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-023-02118-1
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Zs.A 2295: Show issues

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Article ; Online: RUNX1-EVI1 disrupts lineage determination and the cell cycle by interfering with RUNX1 and EVI1 driven gene regulatory networks.

Kellaway, Sophie G / Keane, Peter / Kennett, Ella / Bonifer, Constanze

Haematologica

2021 Volume 106, Issue 6, Page(s) 1569–1580

Abstract: Hematological malignancies are characterised by a block in differentiation, which in many cases is caused by recurrent mutations affecting the activity of hematopoietic transcription factors. RUNX1-EVI1 is a fusion protein formed by the t(3;21) ... ...

Abstract	Hematological malignancies are characterised by a block in differentiation, which in many cases is caused by recurrent mutations affecting the activity of hematopoietic transcription factors. RUNX1-EVI1 is a fusion protein formed by the t(3;21) translocation linking two transcription factors required for normal hematopoiesis. RUNX1-EVI1 expression is found in myelodysplastic syndrome, secondary acute myeloid leukemia, and blast crisis of chronic myeloid leukemia; with clinical outcomes being worse than in patients with RUNX1-ETO, RUNX1 or EVI1 mutations alone. RUNX1-EVI1 is usually found as a secondary mutation, therefore the molecular mechanisms underlying how RUNX1-EVI1 alone contributes to poor prognosis are unknown. To address this question, we induced expression of RUNX1-EVI1 in hematopoietic cells derived from an embryonic stem cell differentiation model. Induction resulted in disruption of the RUNX1-dependent endothelial-hematopoietic transition, blocked the cell cycle and undermined cell fate decisions in multipotent hematopoietic progenitor cells. Integrative analyses of gene expression with chromatin and transcription factor binding data demonstrated that RUNX1-EVI1 binding caused the re-distribution of endogenous RUNX1 within the genome and interfered with both RUNX1 and EVI1 regulated gene expression programs. In summary, RUNX1-EVI1 expression alone leads to extensive epigenetic reprogramming which is incompatible with healthy blood production.
MeSH term(s)	Cell Cycle/genetics ; Core Binding Factor Alpha 2 Subunit/genetics ; Gene Regulatory Networks ; Humans ; Leukemia, Myeloid, Acute/genetics ; MDS1 and EVI1 Complex Locus Protein/genetics ; Translocation, Genetic
Chemical Substances	Core Binding Factor Alpha 2 Subunit ; MDS1 and EVI1 Complex Locus Protein ; RUNX1 protein, human
Language	English
Publishing date	2021-06-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2019.241885
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Uh III Zs.76: Show issues

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Article ; Online: Analysis of Falls within Paediatric Hospital and Community Healthcare Settings.

Parker, Caitlin / Kellaway, Jasmine / Stockton, Kellie

Journal of pediatric nursing

2019 Volume 50, Page(s) 31–36

Abstract: ... setting (39.84%, p < .001) and the emergency department (72.13%, p < .001). Falls from furniture/equipment ...

Abstract	Purpose: To identify characteristics of paediatric falls within a healthcare setting. Design and methods: A retrospective analysis of falls occurring within inpatient, outpatient, emergency and community healthcare settings of children aged 0-<18 years was conducted using data from the Children's Health Queensland Hospital and Health Service (CHQ-HHS) Clinical Incident Database and Electronic Medical Record between January 1st 2015 and December 31st 2017. One-sample and two-sample Chi-squared tests with post-hoc tests were performed to assess relationships between categorical variables. Results: The final dataset contained 385 fall events. Children 0-2 years fell most frequently (46.75%) and falls were higher in males (55.58%). Falls from bed were the most common mechanism (30.65%). The incidence rate of inpatient falls was 0.53 falls per 1000 bed days in the tertiary hospital setting and 1.2% of presentations to inpatient community health facilities. Falls from bed were most common in the tertiary hospital inpatient setting (39.84%, p < .001) and the emergency department (72.13%, p < .001). Falls from furniture/equipment constituted 26.04% of outpatient falls. Most falls occurred in the presence of parents/caregivers (79.48%) and 4.66% of fallers sustained multiple falls. Conclusions: This study provides a comprehensive review of the characteristics of fall events in CHQ-HHS over a three-year period and summarises the existing literature in paediatric fall prevention. Practice implications: Risk assessment and management plans should focus on education, particularly surrounding bed safety. Our findings have informed the development of an integrated evidence-based paediatric-specific fall risk assessment tool and management plan to prevent falls in hospital and community healthcare settings.
MeSH term(s)	Accidental Falls/prevention & control ; Accidental Falls/statistics & numerical data ; Adolescent ; Age Factors ; Child ; Child, Hospitalized ; Child, Preschool ; Community Health Services/statistics & numerical data ; Female ; Hospitals, Pediatric/statistics & numerical data ; Humans ; Infant ; Infant, Newborn ; Male ; Retrospective Studies ; Risk Assessment ; Sex Factors
Language	English
Publishing date	2019-11-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	632731-x
ISSN	1532-8449 ; 0882-5963
ISSN (online)	1532-8449
ISSN	0882-5963
DOI	10.1016/j.pedn.2019.09.026
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Zs.B 2871: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 375: Show issues

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Article ; Online: Different mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories.

Kellaway, Sophie G / Keane, Peter / Edginton-White, Benjamin / Regha, Kakkad / Kennett, Ella / Bonifer, Constanze

Life science alliance

2021 Volume 4, Issue 2

Abstract: Mutations of the haematopoietic master regulator RUNX1 are associated with acute myeloid leukaemia, familial platelet disorder and other haematological malignancies whose phenotypes and prognoses depend upon the class of the RUNX1 mutation. The ... ...

Abstract	Mutations of the haematopoietic master regulator RUNX1 are associated with acute myeloid leukaemia, familial platelet disorder and other haematological malignancies whose phenotypes and prognoses depend upon the class of the RUNX1 mutation. The biochemical behaviour of these oncoproteins and their ability to cause unique diseases has been well studied, but the genomic basis of their differential action is unknown. To address this question we compared integrated phenotypic, transcriptomic, and genomic data from cells expressing four types of RUNX1 oncoproteins in an inducible fashion during blood development from embryonic stem cells. We show that each class of mutant RUNX1 deregulates endogenous RUNX1 function by a different mechanism, leading to specific alterations in developmentally controlled transcription factor binding and chromatin programming. The result is distinct perturbations in the trajectories of gene regulatory network changes underlying blood cell development which are consistent with the nature of the final disease phenotype. The development of novel treatments for RUNX1-driven diseases will therefore require individual consideration.
MeSH term(s)	CCAAT-Binding Factor/metabolism ; Cell Differentiation/genetics ; Core Binding Factor Alpha 2 Subunit/genetics ; Core Binding Factor Alpha 2 Subunit/metabolism ; Hematopoiesis/genetics ; Humans ; Models, Biological ; Mutation ; Oncogene Proteins/genetics ; Oncogene Proteins/metabolism ; Protein Binding
Chemical Substances	CCAAT-Binding Factor ; Core Binding Factor Alpha 2 Subunit ; Oncogene Proteins ; RUNX1 protein, human
Language	English
Publishing date	2021-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202000864
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Article ; Online: A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification.

Edginton-White, B / Maytum, A / Kellaway, S G / Goode, D K / Keane, P / Pagnuco, I / Assi, S A / Ames, L / Clarke, M / Cockerill, P N / Göttgens, B / Cazier, J B / Bonifer, C

Nature communications

2023 Volume 14, Issue 1, Page(s) 267

Abstract: Developmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. To date no global experiments have been conducted that identify their cell type ... ...

Abstract	Developmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. To date no global experiments have been conducted that identify their cell type and cell stage-specific activity within one developmental pathway and in a chromatin context. Here, we describe a high-throughput method that identifies thousands of differentially active cis-elements able to stimulate a minimal promoter at five stages of hematopoietic progenitor development from embryonic stem (ES) cells, which can be adapted to any ES cell derived cell type. We show that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of cis-elements which respond to cytokine signals terminating at signalling responsive transcription factors. Our work provides an important resource for studies of hematopoietic specification and highlights the mechanisms of how and where extrinsic signals program a cell type-specific chromatin landscape driving hematopoietic differentiation.
MeSH term(s)	Regulatory Sequences, Nucleic Acid ; Chromatin/genetics ; Cell Differentiation/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Promoter Regions, Genetic/genetics ; Enhancer Elements, Genetic/genetics
Chemical Substances	Chromatin ; Transcription Factors
Language	English
Publishing date	2023-01-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-35910-9
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Article ; Online: Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth.

Kellaway, Sophie G / Potluri, Sandeep / Keane, Peter / Blair, Helen J / Ames, Luke / Worker, Alice / Chin, Paulynn S / Ptasinska, Anetta / Derevyanko, Polina K / Adamo, Assunta / Coleman, Daniel J L / Khan, Naeem / Assi, Salam A / Krippner-Heidenreich, Anja / Raghavan, Manoj / Cockerill, Peter N / Heidenreich, Olaf / Bonifer, Constanze

Nature communications

2024 Volume 15, Issue 1, Page(s) 1359

Abstract: Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell ... ...

Abstract	Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.
MeSH term(s)	Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mutation ; Stem Cells/metabolism ; Neoplastic Stem Cells/metabolism
Language	English
Publishing date	2024-02-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45691-4
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Article ; Online: Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1.

Coleman, Daniel J L / Keane, Peter / Chin, Paulynn S / Ames, Luke / Kellaway, Sophie / Blair, Helen / Khan, Naeem / Griffin, James / Holmes, Elizabeth / Maytum, Alexander / Potluri, Sandeep / Strate, Lara / Koscielniak, Kinga / Raghavan, Manoj / Bushweller, John / Heidenreich, Olaf / Rabbitts, Terry / Cockerill, Peter N / Bonifer, Constanze

iScience

2024 Volume 27, Issue 4, Page(s) 109576

Abstract: AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and ... ...

Abstract	AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier.
Language	English
Publishing date	2024-03-26
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109576
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Article: The use of sedative-induced sleep as an aid to electroencephalographic diagnosis in children.

KELLAWAY, P

The Journal of pediatrics

2003 Volume 37, Issue 6, Page(s) 862–877

MeSH term(s)	Barbital/analogs & derivatives ; Electroencephalography ; Hypnotics and Sedatives ; Seizures ; Sleep
Chemical Substances	Hypnotics and Sedatives ; Barbital (5WZ53ENE2P)
Language	English
Publishing date	2003-12-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	3102-1
ISSN	1097-6833 ; 0022-3476
ISSN (online)	1097-6833
ISSN	0022-3476
DOI	10.1016/s0022-3476(50)80048-3
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Um IV Zs.116: Show issues

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Article: The electroencephalographic features of benign centrotemporal (rolandic) epilepsy of childhood.

Kellaway, P

Epilepsia

2000 Volume 41, Issue 8, Page(s) 1053–1056

MeSH term(s)	Brain Mapping ; Cerebral Cortex/physiopathology ; Child ; Electroencephalography/statistics & numerical data ; Epilepsy, Rolandic/diagnosis ; Epilepsy, Rolandic/physiopathology ; Frontal Lobe/physiopathology ; Functional Laterality/physiology ; Humans ; Neural Pathways/physiopathology ; Sleep, REM/physiology ; Temporal Lobe/physiopathology ; Thalamus/physiopathology
Language	English
Publishing date	2000-08
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/j.1528-1157.2000.tb00296.x
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Zs.A 517: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 475: Show issues

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Article ; Online: Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth.

Coleman, Daniel J L / Keane, Peter / Luque-Martin, Rosario / Chin, Paulynn S / Blair, Helen / Ames, Luke / Kellaway, Sophie G / Griffin, James / Holmes, Elizabeth / Potluri, Sandeep / Assi, Salam A / Bushweller, John / Heidenreich, Olaf / Cockerill, Peter N / Bonifer, Constanze

Cell reports

2023 Volume 42, Issue 12, Page(s) 113568

Abstract: Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene ... ...

Abstract	Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.
MeSH term(s)	Humans ; Gene Regulatory Networks ; Regulon ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mutation/genetics ; RNA, Small Interfering ; fms-Like Tyrosine Kinase 3/genetics
Chemical Substances	RNA, Small Interfering ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; FLT3 protein, human (EC 2.7.10.1)
Language	English
Publishing date	2023-12-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.113568
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