Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML

Abstract

Phosphoinositide signaling regulates 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. (Blood. 2015;125(18):2815-2824

INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia

“…Therefore, maybe there exists cross interaction between NF-KB and ATM, there still remain more research to indentify the role of p65 nuclear translocation in the process of INPP4B-mediated DNA repair, and other repair signaling may also be participated in this process. INPP4B contains a functional N-terminal C2-lipid binding domain, which is involved in the regulation of AKT activation, besides, it also contains a Nervy homology 2 domain known to mediate oligomerization (i.e., AML1-ETO oligomerization) or protein-protein interaction [39], our data (Supplemental Figure 1) and the previous study [14] both showed a no evident relationship between the AKT activation and INPP4B-mediated resistance to chemotherapy, so does it possible INPP4B directly interacts with ATM? This remains to be explored.…”

“…As an oncogene, INPP4B was also reported to enhance oncogenic activity of the kinase SGK3 in breast cancer and promote resistance by upregulation of hexokinase 2 in laryngeal cancer cells [9,10], and in nasopharyngeal cancer Hep2 cells, induction of INPP4B triggers the development of a tumor-resistance phenotype and targeting INPP4B can resolve the radioresistance of cancer cells [11]. Interestingly, INPP4B has been recently reported to be functioned as a poor prognostic maker, and resist to radiotherapy and chemotherapy in AML, including cytarabine, daunorubicin, etoposide, and irradiation [12][13][14]. At present, there is little reports about the underlying mechanisms mediated INPP4B high leukemic cells to genotoxic treatment, and the downstream targets of INPP4B are unclear, however, an enhanced ability to resist genotoxic exposure might explain this clinical observation in AML, leading us to focus on the DNA damage repair pathway in INPP4B high AML cells.…”

Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: A distinct branch of PI3K signaling

“…It also remains possible that antagonize the migratory capacity of breast cancer cells [22] and melanoma cells [44] by inhibiting Akt, but was also recently reported to enhance oncogenic activity of the kinase SGK3 in breast cancer [52]. Consistent with potential oncogenic functions of INPP4B, two recent reports suggest that INPP4B over-expression correlates with poor prognosis in AML [53,54], with one report suggesting this effect is not related to phosphatase activity of the enzyme [54].…”

INPP4B reverses docetaxel resistance and epithelial-to-mesenchymal transition via the PI3K/Akt signaling pathway in prostate cancer

“…Reduced INPP4B expression was found in breast cancer, melanoma, nasopharyngeal carcinoma, and ovarian and prostate cancer, and was identified as a tumor suppressor [22e26]. Furthermore, recent advances have suggested that INPP4B is associated with chemo-resistance in acute myeloid leukemia [27] and laryngeal cancer cells [28], implicating a potential role of INPP4B as a novel tumor resistance gene.…”