George Giotopoulos
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View article: A Step-wise, Deterministic and Fatal Mouse Model of Myeloid Neoplasm with Spontaneous Acquisition of Patient-relevant RTK–RAS Mutations
A Step-wise, Deterministic and Fatal Mouse Model of Myeloid Neoplasm with Spontaneous Acquisition of Patient-relevant RTK–RAS Mutations Open
Leukaemia arises through the stepwise transformation of healthy haematopoietic cells, yet the asymptomatic premalignant phase and its progression to overt disease remain poorly understood. To model this process, we engineered a patient-der…
View article: Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in <i>NPM1</i>-mutant AML
Posttranscriptional depletion of ribosome biogenesis factors engenders therapeutic vulnerabilities in <i>NPM1</i>-mutant AML Open
NPM1 is a multifunctional phosphoprotein with key roles in ribosome biogenesis among its many functions. NPM1 gene mutations drive 30% of acute myeloid leukemia (AML) cases. The mutations disrupt a nucleolar localization signal and create …
View article: CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition
CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition Open
B-cell acute lymphoblastic leukemia (B-ALL) is a leading cause of death in childhood and outcomes in adults remain dismal. There is therefore an urgent clinical need for therapies that target the highest risk cases. Mutations in the histon…
View article: Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein
Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein Open
Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer…
View article: Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis
Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis Open
Somatic DNMT3A -R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk 1,2 . Preventing expansion of DNMT3A -R882-mutant haematopoietic stem/progen…
View article: A Step-Wise, Deterministic and Fatal Mouse Model of Myeloid Neoplasm with Spontaneous Acquisition of Patient-Relevant RTK–RAS Mutations
A Step-Wise, Deterministic and Fatal Mouse Model of Myeloid Neoplasm with Spontaneous Acquisition of Patient-Relevant RTK–RAS Mutations Open
View article: Preleukemic single-cell landscapes reveal mutation-specific mechanisms and gene programs predictive of AML patient outcomes
Preleukemic single-cell landscapes reveal mutation-specific mechanisms and gene programs predictive of AML patient outcomes Open
View article: Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition
Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition Open
B-cell acute lymphoblastic leukemia (B-ALL) is a leading cause of death in childhood and outcomes in adults remain dismal. There is therefore an urgent clinical need for therapies that target the highest risk cases. Mutations in the histon…
View article: In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis
In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis Open
Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin…
View article: Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death
Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death Open
View article: HOXA9 forms a repressive complex with nuclear matrix–associated protein SAFB to maintain acute myeloid leukemia
HOXA9 forms a repressive complex with nuclear matrix–associated protein SAFB to maintain acute myeloid leukemia Open
HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matri…
View article: HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia
HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia Open
HOXA9 is commonly upregulated in acute myeloid leukemia (AML), where it confers poor prognosis. Characterising the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix att…
View article: Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 co-activation
Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 co-activation Open
Initial clinical trials with drugs targeting epigenetic modulators - such as bromodomain and extraterminal (BET) inhibitors - demonstrate modest results in acute myeloid leukemia (AML). The main reason for this involves an increased transc…
View article: Systematic functional screening of chromatin factors identifies strong lineage and disease dependencies in normal and malignant haematopoiesis
Systematic functional screening of chromatin factors identifies strong lineage and disease dependencies in normal and malignant haematopoiesis Open
Interactions between transcription factors (TF) and chromatin factors (CF) regulate gene expression programmes to determine cellular fate. However, unlike for TF, the exact role of CF in this process is poorly understood. Using haematopoie…
View article: Transcriptional variability accelerates preleukemia by cell diversification and perturbation of protein synthesis
Transcriptional variability accelerates preleukemia by cell diversification and perturbation of protein synthesis Open
Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of premalignancy to cancer. To investigate this,…
View article: Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell death
Mannose metabolism inhibition sensitizes acute myeloid leukemia cells to cytarabine and FLT3 inhibitor therapy by modulating fatty acid metabolism to drive ferroptotic cell death Open
Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosph…
View article: Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma
Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma Open
The accessibility of cell surface proteins makes them tractable for targeting by cancer immunotherapy, but identifying suitable targets remains challenging. Here we describe plasma membrane profiling of primary human myeloma cells to ident…
View article: KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia
KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia Open
Epigenetic histone modifiers are key regulators of cell fate decisions in normal and malignant hematopoiesis. Their enzymatic activities are of particular significance as putative therapeutic targets in leukemia. In contrast, less is known…
View article: Transcriptional variability accelerates pre-leukemia by cell diversification and perturbation of protein synthesis
Transcriptional variability accelerates pre-leukemia by cell diversification and perturbation of protein synthesis Open
Transcriptional variability facilitates stochastic cell diversification and can in turn underpin adaptation to stress or injury. We hypothesize that it may analogously facilitate progression of pre-malignancy to cancer. To investigate this…
View article: Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression
Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression Open
View article: Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis
Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis Open
DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutation…
View article: CML: new tools to answer old questions
CML: new tools to answer old questions Open
View article: Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction
Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction Open
Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3-D) DNA topology is unknown. Here we apply an integrated g…
View article: Dissecting the early steps of MLL induced leukaemogenic transformation using a mouse model of AML
Dissecting the early steps of MLL induced leukaemogenic transformation using a mouse model of AML Open
View article: Dissecting the early steps of MLL induced leukaemogenic transformation using a mouse model of AML.
Dissecting the early steps of MLL induced leukaemogenic transformation using a mouse model of AML. Open
Leukaemogenic mutations commonly disrupt cellular differentiation and/or enhance proliferation, thus perturbing the regulatory programs that control self-renewal and differentiation of stem and progenitor cells. Translocations involving th…
View article: Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells
Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells Open
Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with abnormal progenitor self-renewal and defective white blood cell differentiation. Its pathogenesis comprises subversion of transcriptional regulation, through mutat…
View article: Author response: Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells
Author response: Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells Open
Article Figures and data Abstract eLife digest Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Acute Myeloid Leukemia (AML) …
View article: Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia
Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia Open
Approximately 18% of acute myeloid leukemia (AML) cases express a fusion transcript. However, few fusions are recurrent across AML and the identification of these rare chimeras is of interest to characterize AML patients. Here, we studied …
View article: Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies
Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies Open
Cohesin mutations are common in myeloid malignancy. Sasca et al elucidate the potential role of cohesin loss in myelodysplastic syndrome and acute myeloid leukemia (MDS/AML). They demonstrate that cohesin binding is critical for erythroid-…
View article: Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML
Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML Open
Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function EZH2 mutations are common in myeloid malignancies. We have examined the importance of cellular context for Ezh2 loss during the evolution of acute …