scholarly journals ZEB1 serves as an oncogene in acute myeloid leukaemia via regulating the PTEN/PI3K/AKT signalling pathway by combining with P53

2021 ◽  
Author(s):  
Lanlan Li ◽  
Yubin Feng ◽  
Shuang Hu ◽  
Yan Du ◽  
Xiaoling Xu ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Signalling Pathway ◽  
Acute Myeloid

scholarly journals Constitutive activation of the Wnt/β-catenin signalling pathway in acute myeloid leukaemia

Oncogene ◽  
2005 ◽  
Vol 24 (14) ◽  
pp. 2410-2420 ◽  
Author(s):  
Maria Simon ◽  
Victoria L Grandage ◽  
David C Linch ◽  
Asim Khwaja
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Signalling Pathway ◽  
Constitutive Activation ◽  
Acute Myeloid

scholarly journals Chronic loss of STAG2 leads to altered chromatin structure contributing to de-regulated transcription in AML

2019 ◽  
Author(s):  
James S Smith ◽  
Stephanie G Craig ◽  
Fabio G Liberante ◽  
Katrina M Lappin ◽  
Clare M Crean ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Myelodysplastic Syndromes ◽  
Genome Structure ◽  
Response To Therapy ◽  
Signalling Pathway ◽  
Cohesin Complex ◽  
Mapk Signalling Pathway ◽  
Mapk Signalling ◽  
Acute Myeloid

ABSTRACTThe cohesin complex plays a major role in folding the human genome into 3D structural domains. Mutations in members of the cohesin complex are known early drivers of myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), with STAG2 the most frequently mutated complex member. Here we use functional genomics to investigate the impact of chronic STAG2 loss on three-dimensional genome structure and transcriptional programming in a clinically relevant model of chronic STAG2 loss. The chronic loss of STAG2 led to loss of smaller loop domains and the maintenance/formation of large domains which in turn led to altered genome compartmentalisation. These changes in genome structure were linked with altered gene expression, including deregulation of the HOXA locus and the MAPK signalling pathway, which may contribute to disease development and response to therapy.AUTHOR SUMMARYAcute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) are clonal malignant diseases that affect the myeloid blood cell lineage. Around 40 different mutations have been identified as being associated with MDS and AML; several mutations effect genes in the cohesin complex particularly STAG2. STAG2 is an X-linked gene that is pivotal to the cohesin complex and the mutations result in a truncated gene and loss of function. We have introduced a clinically relevant truncating mutation into an isogeneic AML model. This has shown that changes in the sizes of loop and domains formed in the genome resulting in appropriate gene compartmentalisations. The associated changes in gene transcription has resulted in deregulation of HOX genes, essential for development and differentiation, and in the MAPK signalling pathway that could a therapeutic target.

scholarly journals "Function First" Screen of Primary AML Cells Identifies Common and Personalised Therapeutic Targets

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1517-1517
Author(s):  
Jamshid S Khorashad ◽  
Carme Ripoll Fiol ◽  
Eva Yebra-Fernandez ◽  
Elisabet Nadal-Melsio ◽  
Mahroo Karimpoor ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Research Funding ◽  
Therapeutic Targets ◽  
Signalling Pathway ◽  
Signalling Pathways ◽  
Library Screen ◽  
Shrna Library ◽  
Personalised Therapy ◽  
Acute Myeloid

Abstract Background Acute myeloid leukaemia (AML) is a tremendously heterogeneous clonal disorder of haemopoietic progenitor cells and is the most common malignant myeloid disorder in adults. Identified mutations from genomic data cannot provide information about their therapeutic significance without functional data. Hereby, we applied a pooled shRNA library screen to identify the activated signalling pathways essential for the survival of AML cells. Methods Mononuclear cells from seven karyotypically normal AML patients were separated from peripheral blood or bone marrow aspirate at diagnosis and transduced with a pooled shRNA library containing 27500 shRNAs targeting 5000 individual genes (Human Module 1, Decipher, Cellecta). The targeted genes were components of known signalling pathways. At 72h post transduction, 30% of the cells were stored for baseline measurements and the rest were co-cultured with HS-5 stromal cells for the selection period. DNA was then extracted and the shRNA barcodes were sequenced on the Illumina NextSeq platform. The frequency of barcode appearance after the selection period was compared to their prevalence at baseline to calculate the shRNA depletion. The shRNAs were filtered to identify those genes which had multiple shRNA meeting a threshold depletion. Results Our data analysis of the 7 AML samples identified various signalling pathways for each of these patients. These data support the notion of heterogeneity in AML. The top 100 depleted genes (with depletion in at least 3 shRNA per gene) in each patient were selected and compared. Our limited initial data showed there to be several activated signalling pathways for each AML sample indicating that inhibition of more than one gene or pathway might be required for efficiently suppressing these leukaemia cells. Common targets: NOX1 was the most commonly identified therapeutic target among the screened patients being significantly depleted in AML cells from 5/7 patients. This is an important finding as there are available NOX1 inhibitors for treatment of colon cancers and can be investigated as a therapeutic option for acute myeloid leukaemia. The other most common targets were CDK5R1, DISC1, FSCN3, and PSMB7 which were found to be significantly depleted among 3 of the 7 screened patients. The merged data also showed 58 essential genes for AML cell survival were common in at least 2/7 patients. Using Enrichr the activated signalling pathways based on the top selected genes were identified. Various signalling pathways were observed for each patient showcasing the heterogeneity among AML patients (Figure 1). However, some signalling pathways were indeed common among multiple patients - with different genes being responsible for the activation of those pathways among the patients. The most common pathway was the metabolic pathway which was observed among the top 20 essential pathways in 6/7 patients. The JAK-STAT5 signalling pathway, purine metabolism and cAMP signalling pathway were also among the top 20 essential pathways in 3/7 patients while the following pathways: FoxO, PI3K-AKT, HIF-1, P53, Glucagon, and proteasome were observed in 2/7 patients. Identification of several essential survival pathways provides the opportunity to develop personalised therapy through combined targeting of more than one pathway. Conclusion The signalling pathways analysis using candidate genes from a pooled shRNA library screen showed patient-specific signalling pathways and also common pathways among these screened patients. Absence of a common gene among the screened patients further highlights the significance of personalised therapy in AML and the necessity of developing diagnostic tools to identify potential targets at diagnosis. Identification of crucial genes such as NOX1 (a gene known to have a role in the survival of leukemic stem cells) and other genes with known significance in the pathogenesis of AML supports the application of this method for identifying therapeutic targets at diagnosis or relapse. Figure 1. Figure 1. Disclosures Knapper: Jazz: Other: Meeting and travel support; Daiichi Sankyo: Other: Meeting and travel support; Chroma Therapeutics: Research Funding; Celgene: Other: Meeting and travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Apperley:Pfizer: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau.

The acute myeloid leukaemia market

2019 ◽  
Vol 19 (4) ◽  
pp. 233-234
Author(s):  
Jorrit Schaefer ◽  
Sorcha Cassidy ◽  
Rachel M. Webster
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Acute Myeloid
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