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Title: RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates Fasudil as an anti-leukemic drug      
dateReleased:
05-16-2015
description:
Acute myeloid leukemia (AML) is characterized by a marked genetic heterogeneity, which complicates the development of novel therapeutics. The delineation of pathways essential within the patient-individual mutational background might overcome this limitation and facilitate personalized treatment. We report the results of a large-scale lentiviral loss-offunction RNA-interference-(RNAi)-screen in primary leukemic cells. Stringent validation identified six genes (BNIPL1, ROCK1, RPS13, STK3, SNX27, WDHD1) whose knockdown impaired growth and viability of the cells. Dependence on these genes was not caused by mutation or overexpression and while some of the candidates seemed to be rather patientspecific, others were essential in cells isolated from other AML patients. In addition to the phenotype observed after ROCK1 knockdown, treatment with the approved ROCK-inhibitor fasudil resulted in increased apoptosis and decreased viability of primary AML cells. In contrast to observations in some other malignancies, ROCK1-inhibition did not foster growth of immature malignant progenitors; but was also toxic to this cell fraction in feeder-co-culture and xenotransplantion experiments, indicating a distinct effect of ROCK1 inhibition on leukemic progenitors. We conclude that large scale RNAi screens in primary patient-derived cells are feasible and can complement other methods for personalized cancer therapies, such as expression and mutation profiling. Large-scale lentiviral loss-of-function shRNA screen in primary leukemic cells with two time points, exome sequencing of primary leukemic cells, and a gene expression profiling of primary cells from four leukemic and three healthy samples.
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-68925
refinement:
raw
alternateIdentifiers:
68925
keywords:
functional genomics
dateModified:
08-19-2015
availability:
available
types:
gene expression
name:
Homo sapiens
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-68925/E-GEOD-68925.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-68925/E-GEOD-68925.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE68925
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress

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