INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia.
In this study, we investigated the role of inositol polyphosphate-4-phosphatase, type-II (INPP4B) in acute myeloid leukemia (AML). We observed that AML patients with high levels of INPP4B (INPP4B(high)) had poor response to induction therapy, shorter event-free survival and shorter overall survival. Multivariate analyses demonstrated that INPP4B(high) was an independent predictor of poor prognosis, significantly improving current predictive models, where it outperformed conventional biomarkers including FLT3-ITD and NPM1. Furthermore, INPP4B(high) effectively segregated relative risk in AML patients with normal cytogenetics. The role of INPP4B on the biology of leukemic cells was assessed in vitro. Overexpression of INPP4B in AML cell lines enhanced colony formation potential, recapitulated the chemotherapy resistance observed in AML patients and promoted proliferation in a phosphatase-dependent, and Akt-independent manner. These findings reveal that INPP4B(high) has an unexpected role consistent with oncogenesis in AML, in contrast to its previously reported tumor-suppressive role in epithelial cancers. Overall, we propose that INPP4B is a novel prognostic biomarker in AML that has potential to be translated into clinical practice both as a disease marker and therapeutic target.
1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
I
I
Dzneladze
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
R
R
He
1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
J F
JF
Woolley
1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
M H
MH
Son
1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
M H
MH
Sharobim
1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
S A
SA
Greenberg
1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
M
M
Gabra
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
C
C
Langlois
1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
A
A
Rashid
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
A
A
Hakem
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
N
N
Ibrahimova
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
A
A
Arruda
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
B
B
Löwenberg
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
P J M
PJ
Valk
1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada [3] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
M D
MD
Minden
1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada [3] Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
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000000034023658X
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Salmena
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D000090243:Nucleophosmin; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D020080:Tandem Repeat Sequences / Q000235:genetics; D014407:Tumor Cells, Cultured; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
C000716967:NPM1 protein, human; D012333:RNA, Messenger; D003561:Cytarabine; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; D003630:Daunorubicin