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

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An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia
Nature Cancer ( IF 23.5 ) Pub Date : 2020-04-20 , DOI: 10.1038/s43018-020-0054-2
Jeevisha Bajaj _{1,

2,

3,

4,

5} , Michael Hamilton _{1,

2,

3,

4} , Yutaka Shima _{1,

2,

3,

4} , Kendall Chambers _{1,

2,

3,

4} , Kyle Spinler _{1,

2,

3,

4} , Eric L Van Nostrand _{2,

3,

6,

7} , Brian A Yee _{2,

3,

6,

7} , Steven M Blue _{2,

3,

6,

7} , Michael Chen _{1,

2,

3,

4} , David Rizzeri ₈ , Charles Chuah ₉ , Vivian G Oehler ₁₀ , H Elizabeth Broome _{3,

11} , Roman Sasik ₁₂ , James Scott-Browne _{13,

14} , Anjana Rao _{1,

2,

3,

13} , Gene W Yeo _{2,

3,

6,

7} , Tannishtha Reya _{1,

2,

3,

4}

Affiliation

Department of Pharmacology, University of California San Diego, School of Medicine, La Jolla, CA, USA.
Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
Moores Cancer Center, University of California San Diego, School of Medicine, La Jolla, CA, USA.
Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA.
Department of Biomedical Genetics and Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
Division of Hematologic Malignancies and Cellular Therapy, Duke Cancer Institute, Durham, NC, USA.
Department of Haematology, Singapore General Hospital, Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Pathology, University of California San Diego, School of Medicine, La Jolla, CA, USA.
Center for Computational Biology and Bioinformatics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA.
Department of Biomedical Research, National Jewish Health, Denver, CO, USA.

Aggressive myeloid leukemias such as blast crisis chronic myeloid leukemia and acute myeloid leukemia remain highly lethal. Here we report a genome-wide in vivo CRISPR screen to identify new dependencies in this disease. Among these, RNA-binding proteins (RBPs) in general, and the double-stranded RBP Staufen2 (Stau2) in particular, emerged as critical regulators of myeloid leukemia. In a newly developed knockout mouse, loss of Stau2 led to a profound decrease in leukemia growth and improved survival in mouse models of the disease. Further, Stau2 was required for growth of primary human blast crisis chronic myeloid leukemia and acute myeloid leukemia. Finally, integrated analysis of CRISPR, eCLIP and RNA-sequencing identified Stau2 as a regulator of chromatin-binding factors, driving global alterations in histone methylation. Collectively, these data show that in vivo CRISPR screening is an effective tool for defining new regulators of myeloid leukemia progression and identify the double-stranded RBP Stau2 as a critical dependency of myeloid malignancies.

中文翻译：

体内全基因组 CRISPR 筛选将 RNA 结合蛋白 Staufen2 鉴定为髓性白血病的关键调节因子

侵袭性粒细胞白血病，例如急变期慢性粒细胞白血病和急性粒细胞白血病，仍然具有高度致死性。在这里，我们报告了一种全基因组的体内 CRISPR 筛选，以识别这种疾病的新依赖性。其中，一般而言，RNA 结合蛋白 (RBP)，特别是双链 RBP Staufen2 (Stau2)，成为髓性白血病的关键调节因子。在一只新开发的基因敲除小鼠中，Stau2 的缺失导致白血病生长显着下降，并提高了该疾病小鼠模型的存活率。此外，Stau2 是原发性人类急变期慢性粒细胞白血病和急性粒细胞白血病的生长所必需的。最后，对 CRISPR、eCLIP 和 RNA 测序的综合分析确定 Stau2 是染色质结合因子的调节因子，驱动组蛋白甲基化的全局变化。集体，

更新日期：2020-04-24

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