guthridge-inositolpolyphosphate-2015.pdf (1.35 MB)
Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML
journal contribution
posted on 2015-01-01, 00:00 authored by Sewa Rijal, Shaun Fleming, Nik Cummings, Natalie K Rynkiewicz, Lisa M Ooms, Nhu-Y N Nguyen, Tse-Chieh Teh, Sharon Avery, Julie F McManus, Anthony T Papenfuss, Catriona McLean, Mark GuthridgeMark Guthridge, Christina A Mitchell, Andrew H WeiPhosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, 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)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 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.
History
Journal
BloodVolume
125Issue
18Pagination
2815 - 2824Publisher
American Society of HematologyLocation
Washington, D. C.Publisher DOI
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ISSN
0006-4971eISSN
1528-0020Language
engPublication classification
C1 Refereed article in a scholarly journalUsage metrics
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