A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis
Safiyyah Ziyad,
Jesse D. Riordan,
Ann M. Cavanaugh,
Trent Su,
Gloria E. Hernandez,
Georg Hilfenhaus,
Marco Morselli,
Kristine Huynh,
Kevin Wang,
Jau-Nian Chen,
Adam J. Dupuy,
M. Luisa Iruela-Arispe
Affiliations
Safiyyah Ziyad
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Jesse D. Riordan
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
Ann M. Cavanaugh
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Trent Su
Institute for Quantitative and Computational Biology and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
Gloria E. Hernandez
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
Georg Hilfenhaus
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Marco Morselli
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
Kristine Huynh
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Kevin Wang
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Jau-Nian Chen
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Adam J. Dupuy
Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA
M. Luisa Iruela-Arispe
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; Corresponding author
Summary: 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. : Using transposon mutagenesis that targets the endothelium, Ziyad et al. identify Pi4ka as an important regulator of hematopoiesis. Loss of Pi4ka inhibits myeloid and erythroid cell differentiation. Previously considered a pseudogene in humans, PI4KAP2 is shown to be protein-coding and a negative regulator of PI4KA signaling. Keywords: erythropoiesis, myelopoiesis, hematopoiesis, leukemia, hemogenic endothelium, lipid kinase, Pi4ka, PI4KAP2, Akt, Erk
