PUBLICATION
A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis
- Authors
- Ziyad, S., Riordan, J.D., Cavanaugh, A.M., Su, T., Hernandez, G.E., Hilfenhaus, G., Morselli, M., Huynh, K., Wang, K., Chen, J.N., Dupuy, A.J., Iruela-Arispe, M.L.
- ID
- ZDB-PUB-190529-11
- Date
- 2018
- Source
- Cell Reports 22: 1211-1224 (Journal)
- Registered Authors
- Chen, Jau-Nian
- Keywords
- Akt, Erk, PI4KAP2, Pi4ka, erythropoiesis, hematopoiesis, hemogenic endothelium, leukemia, lipid kinase, myelopoiesis
- MeSH Terms
-
- Animals
- Cell Differentiation/genetics
- Erythropoiesis/physiology*
- Hemangioblasts/cytology
- Hemangioblasts/metabolism
- Humans
- Leukemia/genetics*
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Minor Histocompatibility Antigens/genetics*
- Minor Histocompatibility Antigens/metabolism
- Mutagenesis
- Myelopoiesis/physiology*
- Phosphotransferases (Alcohol Group Acceptor)/genetics*
- Phosphotransferases (Alcohol Group Acceptor)/metabolism
- Zebrafish
- PubMed
- 29386109 Full text @ Cell Rep.
Citation
Ziyad, S., Riordan, J.D., Cavanaugh, A.M., Su, T., Hernandez, G.E., Hilfenhaus, G., Morselli, M., Huynh, K., Wang, K., Chen, J.N., Dupuy, A.J., Iruela-Arispe, M.L. (2018) A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis. Cell Reports. 22:1211-1224.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping