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Cell Rep. 2018 Jan 30;22(5):1211-1224. doi: 10.1016/j.celrep.2018.01.017.

A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis.

Author information

1
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
3
Institute for Quantitative and Computational Biology and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
4
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
5
Institute for Quantitative and Computational Biology and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: arispe@mcdb.ucla.edu.

Abstract

Given its role as the source of definitive hematopoietic cells, we sought to determine whether mutations initiated in the hemogenic endothelium would yield hematopoietic abnormalities or malignancies. Here, we find that endothelium-specific transposon mutagenesis in mice promotes hematopoietic pathologies that are both myeloid and lymphoid in nature. Frequently mutated genes included previously recognized cancer drivers and additional candidates, such as Pi4ka, a lipid kinase whose mutation was found to promote myeloid and erythroid dysfunction. Subsequent validation experiments showed that targeted inactivation of the Pi4ka catalytic domain or reduction in mRNA expression inhibited myeloid and erythroid cell differentiation in vitro and promoted anemia in vivo through a mechanism involving deregulation of AKT, MAPK, SRC, and JAK-STAT signaling. Finally, we provide evidence linking PI4KAP2, previously considered a pseudogene, to human myeloid and erythroid leukemia.

KEYWORDS:

Akt; Erk; PI4KAP2; Pi4ka; erythropoiesis; hematopoiesis; hemogenic endothelium; leukemia; lipid kinase; myelopoiesis

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