Journal article
A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis
Cell reports (Cambridge), Vol.22(5), pp.1211-1224
01/30/2018
DOI: 10.1016/j.celrep.2018.01.017
PMCID: PMC5828030
PMID: 29386109
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.
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•Initiation of mutagenesis in the hemogenic endothelium yields hematopoietic malignancy•Pi4ka is expressed in hematopoietic stem progenitor cells•Pi4ka has a regulatory role in myelo- and erythropoiesis•PI4KAP2 is a protein-coding negative regulator of Pi4ka signaling
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.
Details
- Title: Subtitle
- A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis
- Creators
- Safiyyah Ziyad - Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USAJesse D Riordan - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USAAnn M Cavanaugh - Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USATrent Su - Institute for Quantitative and Computational Biology and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USAGloria E Hernandez - Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USAGeorg Hilfenhaus - Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USAMarco Morselli - Institute for Quantitative and Computational Biology and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USAKristine Huynh - Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USAKevin Wang - Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USAJau-Nian Chen - Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USAAdam J Dupuy - Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USAM. Luisa Iruela-Arispe - Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.22(5), pp.1211-1224
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2018.01.017
- PMID
- 29386109
- PMCID
- PMC5828030
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Grant note
- DOI: 10.13039/100007185, name: UCLA; DOI: 10.13039/100007185, name: UCLA, award: CURE/P30 DK041301; name: UCLA/CFAR, award: 5P30 AI028697; DOI: 10.13039/100000002, name: NIH, award: CA197943, T32 HL69766; name: United Negro College Fund (UNCF)/Merck Graduate Science Research Dissertation, award: 20145117
- Language
- English
- Date published
- 01/30/2018
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984025371002771
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