Transcriptomics,Genomics

Dataset Information

297

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates Fasudil as an anti-leukemic drug.


ABSTRACT: 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.

ORGANISM(S): Homo sapiens  

SUBMITTER: Maciej Paszkowski-Rogacz   Sebastian Brenner  Aylin Camgoz  Uwe Platzbecker  Martin Wermke  Gerhard Ehninger  Andreas Dahl  Frank Buchholz  Sebastian Thieme  Mirko Theis  Martin Bornhaeuser 

PROVIDER: E-GEOD-68925 | ArrayExpress | 2015-05-16

SECONDARY ACCESSION(S): GSE68925SRP058383PRJNA284119

REPOSITORIES: GEO, ArrayExpress, ENA

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RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug.

Wermke Martin M   Camgoz Aylin A   Paszkowski-Rogacz Maciej M   Thieme Sebastian S   von Bonin Malte M   Dahl Andreas A   Platzbecker Uwe U   Theis Mirko M   Ehninger Gerhard G   Brenner Sebastian S   Bornhäuser Martin M   Buchholz Frank F  

Blood 20150430 24


Acute myeloid leukemia (AML) is characterized by a marked genetic heterogeneity, which complicates the development of novel therapeutics. The delineation of pathways essential within an individual patient's mutational background might overcome this limitation and facilitate personalized treatment. We report the results of a large-scale lentiviral loss-of-function RNA interference (RNAi) screen in primary leukemic cells. Stringent validation identified 6 genes (BNIPL1, ROCK1, RPS13, STK3, SNX27,  ...[more]

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