An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia

Bajaj, Jeevisha; Hamilton, Michael; Shima, Yutaka; Chambers, Kendall R.; Spinler, Kyle R.; Nostrand, Eric L. Van; Yee, Brian A.; Blue, Steven M.; Chen, Michael; Rizzeri, David; Chuah, Charles; Oehler, Vivian G.; Broome, H. Elizabeth; Šášik, Roman; Scott‐Browne, James; Rao, Anjana; Yeo, G; Reya, Tannishtha

doi:10.1038/s43018-020-0054-2

Cited by 45 publications

(50 citation statements)

References 68 publications

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“…Interestingly, Itgα2, Itgα9, Itgβ5, and Itgβ7 have been shown to control both growth and migration and may link the observed migration and growth defects. We then crossed the Sdc1 −/− bcCML downregulated genes with a recent bcCML CRISPR screen performed in our laboratory 37 . The resulting 111 common genes were then used for Cytoscape enrichment analysis and visualization.…”

Section: Resultsmentioning

confidence: 99%

A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia

et al. 2020

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Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus, identifying the cells responsible for residual disease and leukemia re-growth is critical to better understanding how they are regulated. Here, we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of leukemia stem cells in aggressive myeloid malignancies, and provides a strategy for defining their core dependencies. Specifically, we carry out a high throughput screen using Msi2-reporter blast crisis chronic myeloid leukemia (bcCML) and identify several adhesion molecules that are preferentially expressed in therapy resistant bcCML cells and play a key role in bcCML. In particular, we focus on syndecan-1, whose deletion triggers defects in bcCML growth and propagation and markedly improves survival of transplanted mice. Further, live imaging reveals that the spatiotemporal dynamics of leukemia cells are critically dependent on syndecan signaling, as loss of this signal impairs their localization, migration and dissemination to distant sites. Finally, at a molecular level, syndecan loss directly impairs integrin β7 function, suggesting that syndecan exerts its influence, at least in part, by coordinating integrin activity in bcCML. These data present a platform for delineating the biological underpinnings of leukemia stem cell function, and highlight the Sdc1-Itgβ7 signaling axis as a key regulatory control point for bcCML growth and dissemination.

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Section: Resultsmentioning

confidence: 99%

A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia

et al. 2020

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“…In vivo CRISPR screens offer a strategy for identifying novel therapeutic targets for leukemia within the context of the physiologic microenvironment. Previous studies have adapted this approach in a mouse MLL-AF9-driven AML model and a mouse BCR-ABL/NUP98-HOXA9-driven chronic myeloid leukemia model to identify genes essential for tumor growth (8,9). Here, we developed an in vivo CRISPR screening pipeline in orthotopic xenograft models of human AML, providing a complementary approach for AML dependency identification.…”

Section: Discussionmentioning

confidence: 99%

“…Human AML orthotopic disease modeling is highly physiologically relevant, as AML cells will engraft in the bone marrow microenvironment in the mouse. In vivo CRISPR screening has been performed to identify tumor suppressors, oncogenes and fitness genes in various cancer contexts (6,7), including several genetically engineered mouse models of hematologic malignancies (8)(9)(10). However, such an application in human AML orthotopic xenograft models has not been performed.…”

Section: Introductionmentioning

confidence: 99%

An in vivo CRISPR screening platform for prioritizing therapeutic targets in AML

Lin

Larrue

Seong

et al. 2020

Preprint

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CRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancers, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro, evaluating the physiological relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to prioritize AML-enriched dependencies in vivo, complemented by the validation in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, including SLC5A3 as a metabolic vulnerability for AML addicted to exogenous myo-inositol and MARCH5 as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, highlighting the clinical potential of targeting MARCH5 in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets.Statement of significanceThere is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identified SLC5A3 as a metabolic vulnerability and MARCH5 as a critical apoptosis regulator in AML, representing novel therapeutic opportunities.

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“…Finally, a genome-wide in vivo CRISPR/Cas9 screen in BCR-ABL/NUP98-HOXA9 -driven CML mouse model showed a significant enrichment with RBPs (~680 genes), suggesting a “disproportionate dependency” on RBPs in myeloid leukemias. In this study, Bajaj et al identified dsRNA-binding protein Staufen2 ( Stau2) as an essential regulator of chromatin modifiers 52 . The gene expression analysis identified KDM family of H3K4 demethylases being downstream targets of Stau2 , Table 6.…”

Section: Rna Modification Enzymesmentioning

confidence: 94%

Targeting RNA-binding proteins in acute and chronic leukemia

Elcheva

Spiegelman

2020

Leukemia

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RNA-binding proteins (RBPs) play a crucial role in cellular physiology by regulating RNA processing, translation, and turnover. In neoplasms, RBP support of cancer-relevant expression of alternatively spliced, modified, and stabilized mRNA transcripts is essential to self-renewal, proliferation, and adaptation to stress. In this review, we assess the impact of key families of RBPs in leukemogenesis, review progress in targeting those proteins with small molecules, and discuss how multilevel composition of posttranscriptional regulation of gene expression could be used for potential therapies in acute and chronic leukemia.

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An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia

Cited by 45 publications

References 68 publications

A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia

A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia

An in vivo CRISPR screening platform for prioritizing therapeutic targets in AML

Targeting RNA-binding proteins in acute and chronic leukemia

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