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. Using a forward 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1211-1224 |
| Number of pages | 14 |
| Journal | Cell Reports |
| Volume | 22 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jan 30 2018 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis. / Ziyad, Safiyyah; Riordan, Jesse D.; Cavanaugh, Ann; Su, Trent; Hernandez, Gloria E.; Hilfenhaus, Georg; Morselli, Marco; Huynh, Kristine; Wang, Kevin; Chen, Jau Nian; Dupuy, Adam J.; Iruela-Arispe, M. Luisa.
In: Cell Reports, Vol. 22, No. 5, 30.01.2018, p. 1211-1224.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A Forward Genetic Screen Targeting the Endothelium Reveals a Regulatory Role for the Lipid Kinase Pi4ka in Myelo- and Erythropoiesis
AU - Ziyad, Safiyyah
AU - Riordan, Jesse D.
AU - Cavanaugh, Ann
AU - Su, Trent
AU - Hernandez, Gloria E.
AU - Hilfenhaus, Georg
AU - Morselli, Marco
AU - Huynh, Kristine
AU - Wang, Kevin
AU - Chen, Jau Nian
AU - Dupuy, Adam J.
AU - Iruela-Arispe, M. Luisa
PY - 2018/1/30
Y1 - 2018/1/30
N2 - 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 a forward 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.
AB - 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 a forward 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85045578209&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2018.01.017
DO - 10.1016/j.celrep.2018.01.017
M3 - Article
VL - 22
SP - 1211
EP - 1224
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 5
ER -