PMID- 24681948
OWN - NLM
STAT- MEDLINE
DCOM- 20150610
LR  - 20240210
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 10
DP  - 2015 Mar 5
TI  - A targeted knockdown screen of genes coding for phosphoinositide modulators 
      identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and 
      survival.
PG  - 1253-1262
LID - 10.1038/onc.2014.77 [doi]
AB  - 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)P(2)). 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, G(1) 
      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.
FAU - Jude, Julian G
AU  - Jude JG
AD  - Inositide Laboratory, Cancer Research UK Manchester Institute, The University of 
      Manchester, Manchester, M20 4BX, United Kingdom.
AD  - Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, M20 4BX, United Kingdom.
FAU - Spencer, Gary J
AU  - Spencer GJ
AD  - Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, M20 4BX, United Kingdom.
FAU - Huang, Xu
AU  - Huang X
AD  - Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, M20 4BX, United Kingdom.
FAU - Somerville, Tim D D
AU  - Somerville TDD
AD  - Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, M20 4BX, United Kingdom.
FAU - Jones, David R
AU  - Jones DR
AD  - Inositide Laboratory, Cancer Research UK Manchester Institute, The University of 
      Manchester, Manchester, M20 4BX, United Kingdom.
FAU - Divecha, Nullin
AU  - Divecha N
AD  - Inositide Laboratory, Cancer Research UK Manchester Institute, The University of 
      Manchester, Manchester, M20 4BX, United Kingdom.
FAU - Somervaille, Tim C P
AU  - Somervaille TCP
AD  - Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The 
      University of Manchester, Manchester, M20 4BX, United Kingdom.
LA  - eng
GR  - 19280/CRUK_/Cancer Research UK/United Kingdom
GR  - C5759/A12328/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140331
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Phosphatidylinositol Phosphates)
RN  - 0 (Phosphatidylinositols)
RN  - 0 (phosphatidylinositol 5-phosphate)
RN  - EC 2.7.1.- (PIP4K2A protein, human)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Cell Survival/genetics
MH  - Cluster Analysis
MH  - Enzyme Activation
MH  - Gene Expression Profiling
MH  - *Gene Knockdown Techniques
MH  - Humans
MH  - Intracellular Space/metabolism
MH  - Leukemia, Myeloid, Acute/*genetics/*metabolism/pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neoplastic Stem Cells/metabolism
MH  - Phosphatidylinositol Phosphates/metabolism
MH  - Phosphatidylinositols/*metabolism
MH  - Phosphotransferases (Alcohol Group Acceptor)/*genetics/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Tumor Stem Cell Assay
PMC - PMC4130659
MID - EMS57110
OID - NLM: EMS57110
EDAT- 2014/04/01 06:00
MHDA- 2015/06/11 06:00
PMCR- 2015/09/05
CRDT- 2014/04/01 06:00
PHST- 2013/06/14 00:00 [received]
PHST- 2014/01/28 00:00 [revised]
PHST- 2014/02/20 00:00 [accepted]
PHST- 2014/04/01 06:00 [entrez]
PHST- 2014/04/01 06:00 [pubmed]
PHST- 2015/06/11 06:00 [medline]
PHST- 2015/09/05 00:00 [pmc-release]
AID - 10.1038/onc.2014.77 [doi]
PST - ppublish
SO  - Oncogene. 2015 Mar 5;34(10):1253-1262. doi: 10.1038/onc.2014.77. Epub 2014 Mar 
      31.