Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML.
Phosphoinositide 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.
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia;
Sewa
S
Rijal
Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia;
Shaun
S
Fleming
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia;
Nik
N
Cummings
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia;
Natalie K
NK
Rynkiewicz
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia;
Lisa M
LM
Ooms
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia;
Nhu-Y N
NY
Nguyen
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia;
Tse-Chieh
TC
Teh
Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia;
Sharon
S
Avery
Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia;
Julie F
JF
McManus
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; and.
Anthony T
AT
Papenfuss
Department of Anatomical Pathology, The Alfred Hospital, Melbourne, VIC, Australia.
Catriona
C
McLean
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia;
Mark A
MA
Guthridge
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia;
Christina A
CA
Mitchell
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia; Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia;
Andrew H
AH
Wei
D000293:Adolescent; D000328:Adult; D000368:Aged; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D056726:Genetic Association Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D059467:Transcriptome; D016896:Treatment Outcome; D055815:Young Adult
D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase