A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival
By Julian Jude, Gary J. Spencer, Xu Huang, T. Somerville, David R. Jones, N. Divecha, T. Somervaille. 2014
80 citations recorded by the source corpus.
Given the importance of deregulated phosphoinositide (PI) signaling in leukemic hematopoiesis, genes coding for proteins that regulate PI metabolism may have significant and as yet unappreciated roles in leukemia. We performed a targeted knockdown (KD) screen of PI modulator genes in human acute myeloid leukemia (AML) cells and identified candidates required to sustain proliferation or prevent apoptosis. One of these, the lipid kinase phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A) regulates cellular levels of phosphatidylinositol-5-phosphate (PtsIns5P) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). We found PIP4K2A to be essential for the clonogenic and leukemia-initiating potential of human AML cells, and for the clonogenic potential of murine MLL-AF9 AML cells. Importantly, PIP4K2A is also required for the clonogenic potential of primary human AML cells. Its KD results in accumulation of the cyclin-dependent kinase inhibitors CDKN1A and CDKN1B, G1 cell cycle arrest and apoptosis. Both CDKN1A accumulation and apoptosis were partially dependent on activation of the mTOR pathway. Critically, however, PIP4K2A KD in normal hematopoietic stem and progenitor cells, both murine and human, did not adversely impact either clonogenic or multilineage differentiation potential, indicating a selective dependency that we suggest may be the consequence of the regulation of different transcriptional programs in normal versus malignant cells. Thus, PIP4K2A is a novel candidate therapeutic target in myeloid malignancy.
Subfields: Genetics, Hematology, Molecular Biology
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Genetics
In Molecular Biology
Citations in the corpus
- In B cells, phosphatidylinositol 5-phosphate 4-kinase–α synthesizes PI(4,5)P2 to impact mTORC2 and Akt signaling (2016, background): “For example, stable knockout of Drosophila dPIP4K (orthologous to the highactivity PIP4K2A in higher species) results in a dramatic attenuation of Akt phosphorylation (20), whereas acute depletion of PIP4K2A in human leukocytes by RNAi results in increased Akt phosphorylation (19).”
- The lipid kinase PI5P4Kβ is an intracellular GTP sensor for metabolism and tumorigenesis (2016, unknown): “PI5P4Ks have been shown to promote tumorigenesis in several types of cancers (Emerling et al., 2013; Jude et al., 2015; Keune et al., 2013; Luoh et al., 2004), raising the possibility that the GTP-sensing activity of PI5P4Kb is involved in its tumorigenic activity.”