Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML
Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML
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DOI：
10.1182/blood-2014-09-603555
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发表时间：
2015-04-30
期刊：
影响因子：
20.3
通讯作者：
Wei, Andrew H.
中科院分区：
文献类型：
--
作者：
Rijal, Sewa;Fleming, Shaun;Wei, Andrew H.
磷脂酰肌醇信号调节多种细胞功能。磷酸肌醇-3激酶（PI 3 K）产生PtdIns（3，4，5）P-3和PtdIns（3，4）P-2，导致增殖和抗凋亡信号通路的激活。磷酸肌醇信号传导的终止需要通过PtdIns（3，4，5）P-3 3-磷酸酶（PTEN）、PtdIns（3，4，5）P-3 5-磷酸酶（如SHIP）和PtdIns（3，4）P-2 4-磷酸酶（如INPP 4 B）的作用水解肌醇环磷酸基团。大多数这些磷酸肌醇磷酸酶在急性髓性白血病（AML）中的生物学相关性仍然知之甚少。基于质谱的3-，4-和5-磷酸酶在人AML中的基因表达谱显示INPP 4 B的显著过表达。对诊断时的205例AML病例的扩展组分析显示，INPP 4 B过表达与化疗反应降低、早期复发和总生存率差相关，与其他风险因素无关。INPP 4 B的异位过表达赋予白血病对阿糖胞苷（ara-C）、柔红霉素和依托泊苷的耐药性。磷酸酶惰性变体（INPP 4 B C842 A）的表达未能消除AML细胞对体外或体内化疗的耐药性。相反，通过RNA干扰靶向抑制内源性过表达的INPP 4 B使AML细胞系和原发性AML对化疗敏感。这些发现证明了INPP 4 B功能获得作为AML中化疗耐药性和不良生存结局的介导者的先前未被怀疑和临床相关作用，与其磷酸肌醇磷酸酶功能无关。
Phosphoinositide signalingregulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5) P-3 and PtdIns(3,4) P-2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5) P-3 3-phosphatase (PTEN), PtdIns(3,4,5) P-3 5-phosphatases (eg, SHIP), and PtdIns(3,4) P-2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4-and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function.