A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival.
A targeted knockdown screen of genes coding for phosphoinositide modulators identifies PIP4K2A as required for acute myeloid leukemia cell proliferation and survival.
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鉴于白血病造血中磷酸肌醇（PI）信号转导失调的重要性，编码调节PI代谢的蛋白质的基因可能在白血病中具有重要且尚未被认识到的作用。我们在人AML细胞中进行PI调节剂基因的靶向敲低筛选，并鉴定维持增殖或防止凋亡所需的候选物。其中之一，脂质激酶磷脂酰肌醇-5-磷酸4-激酶，II型，α（PIP 4K 2A）调节磷脂酰肌醇-5-磷酸（PtsIns 5 P）和磷脂酰肌醇4，5-二磷酸（PtdIns（4，5）P2）的细胞水平。我们发现PIP 4K 2A对于人AML细胞的克隆形成和白血病引发潜力以及鼠MLL-AF 9 AML细胞的克隆形成潜力是必需的。重要的是，PIP 4K 2A也是原代人AML细胞的克隆形成潜力所必需的。它的敲低导致细胞周期蛋白依赖性激酶抑制剂CDKN 1A和CDKN 1B的积累，G1期细胞阻滞和凋亡。CDKN 1A的积累和细胞凋亡都部分依赖于mTOR通路的激活。然而，至关重要的是，在正常的造血干细胞和祖细胞，小鼠和人类，PIP 4K 2A敲低，没有产生不利影响克隆或多系分化的潜力，表明选择性的依赖性，我们建议可能是在正常与恶性细胞不同的转录程序的调节的结果。因此，PIP 4K 2A是骨髓恶性肿瘤的新的候选治疗靶点。
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 screen of PI modulator genes in human 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 knockdown 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 upon activation of the mTOR pathway. Critically, however, PIP4K2A knockdown 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 which we suggest may be the consequence of the regulation of different transcriptional programmes in normal versus malignant cells. Thus, PIP4K2A is a novel candidate therapeutic target in myeloid malignancy.
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影响因子：
3.7
作者：
Myhre S;Mohammed H;Tramm T;Alsner J;Finak G;Park M;Overgaard J;Børresen-Dale AL;Frigessi A;Sørlie T
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Sørlie T
影响因子：
3.7
作者：
Ndamukong I;Jones DR;Lapko H;Divecha N;Avramova Z
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Avramova Z
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
9.2
作者：
Halstead, JR;Roefs, M;Divecha, N
通讯作者：
Divecha, N
影响因子：
11.2
作者：
Keune WJ;Sims AH;Jones DR;Bultsma Y;Lynch JT;Jirström K;Landberg G;Divecha N
通讯作者：
Divecha N