C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

Alberich-Jordà, Meritxell; Wouters, Bas J.; Balastik, Martin; Shapiro-Koss, Clara; Zhang, Hong; Ruscio, Annalisa Di; Radomska, Hanna S.; Ebralidze, Alexander K.; Amabile, Giovanni; Ye, Min; Zhang, Junyan; Lowers, Irene; Avellino, Roberto; Melnick, Ari; Figueroa, María E.; Valk, Peter J.M.; Delwel, Ruud; Tenen, Daniel G.

doi:10.1172/jci65102

Cited by 53 publications

(33 citation statements)

References 79 publications

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“…By contrast, both SPI1 and CEBPA were robust hits in our CRISPRa activation screen. These observations are consistent with the inhibitory functions of SPI1 and CEBPA : silencing of CEBPA leads to de-repression of CEBPG (Alberich-Jordà et al, 2012) and the protein encoded by SPI1 (PU.1) is a direct binding partner of GATA-1 and inhibits its transcriptional activity (Zhang et al, 2000). …”

Section: Resultssupporting

confidence: 66%

Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation

Gilbert

Horlbeck

Adamson

et al. 2014

Cell

2,392

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SUMMARY While the catalog of mammalian transcripts and their expression levels in different cell types and disease states is rapidly expanding, our understanding of transcript function lags behind. We present a robust technology enabling systematic investigation of the cellular consequences of repressing or inducing individual transcripts. We identify rules for specific targeting of transcriptional repressors (CRISPRi), typically achieving 90–99% knockdown with minimal off-target effects, and activators (CRISPRa) to endogenous genes via endonuclease-deficient Cas9. Together they enable modulation of gene expression over a ~1000-fold range. Using these rules, we construct genome-scale CRISPRi and CRISPRa libraries, each of which we validate with two pooled screens. Growth-based screens identify essential genes, tumor suppressors and regulators of differentiation. Screens for sensitivity to a cholera-diphtheria toxin provide broad insights into the mechanisms of pathogen entry, retro-translocation and toxicity. Our results establish CRISPRi and CRISPRa as powerful tools that provide rich and complementary information for mapping complex pathways.

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Section: Resultssupporting

confidence: 66%

Genome-Scale CRISPR-Mediated Control of Gene Repression and Activation

Gilbert

Horlbeck

Adamson

et al. 2014

Cell

2,392

2,715

View full text Add to dashboard Cite

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“…Previous studies from our laboratory demonstrated that C/EBPα inhibits Myc and Cebpg transcription through interfering with E2F1 transactivation on these promoters (Alberich-Jorda et al, 2012; Johansen et al, 2001). We therefore first examined whether C/EBPα mediated Sox4 repression through a similar mechanism.…”

Section: Resultsmentioning

confidence: 91%

“…ChIP assays were performed on stem/progenitor cells (Lin − c-kit + ) or myeloid cells (Mac1 + Gr1 + ) as described previously (Alberich-Jorda et al, 2012). Immunoprecipitation was performed with rabbit antibodies against C/EBPα (sc-61X, Santa Cruz) or normal rabbit IgG (12–370, Millipore).…”

Section: Methodsmentioning

confidence: 99%

Sox4 Is a Key Oncogenic Target in C/EBPα Mutant Acute Myeloid Leukemia

et al. 2013

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Summary Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype.

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“…Gene expression profiling of 526 AML cases was carried out on Affymetrix HGU133A Plus2.0 GeneChips as previously described (63). The validation of the scaling/normalization factors of the GeneChips was less than 3-fold.…”

Section: Methodsmentioning

confidence: 99%