Abstract 5283: Elucidating a novel role for inositol polyphosphate 4-phosphatase type II (INPP4B) in mediating chemoresistance in acute myeloid leukemia

Abstract

Abstract Acute myeloid leukaemia (AML) is an aggressive blood cancer that is usually fatal within weeks without effective therapy. Treatment currently involves standard chemotherapy agents such as cytarabine (Ara-C) and anthracyclines but these drugs fail to elicit complete clinical responses in 20-30% of cases. An understanding of the mechanisms in AML mediating resistance to chemotherapy may uncover new oncoproteins amenable to medicinal targeting. Activation of the phosphoinositide 3-kinase (PI3-K)/AKT pathway is prevalent in AML and linked to chemotherapy failure and poor outcomes. Homeostatic regulation of PI3K activity is orchestrated by a triad of lipid phosphatases, categorized functionally as 3-, 4-, or 5-phosphoinositide phosphatases (PIPs). We screened for pathological expression of 3-, 4-, or 5-PIPs in AML using a quantitative multiplexed MassArray platform (Sequenom®) and found marked overexpression of inositol polyphosphate 4-phosphatase II (INPP4B) in a subset of primary AMLs compared to normal bone marrow. Immunohistochemical staining of 120 primary AML bone marrow samples showed INPP4B was overexpressed (>20% blasts positive) in 16% of cases. INPP4B overexpression was associated with an inferior complete response rate to intensive chemotherapy (33%), compared to AMLs low (5-20%; CR 66%) or negative (<5%; CR 93%) for INPP4B. Ectopic overexpression of INPP4B in MV4;11 and HEL AML cells conferred resistance to in vitro cell death (flow-based viability and colony forming capacity) when exposed to standard agents used to treat AML, including cytarabine, daunorubicin and etoposide. High levels of INPP4B in AML also limited the cytotoxic efficacy of drugs such as cytarabine in vivo using human xenograft models of AML. Although INPP4B phosphatase function was proven to be catalytically active in primary AML, expression of a phosphatase inactive mutant (INPP4B C842A) did not abrogate chemoresistance. Conversely, siRNA-mediated knockdown of endogenous INPP4B expression in KG1 and OCI-AML3 AML increased leukemic sensitivity to cytarabine. These findings infer 1) the presence of a novel phosphatase-independent function for this protein and 2) a previously unsuspected role for INPP4B overexpression in mediating chemoresistance and poor clinical outcome in a subset of patients with AML. Citation Format: Sewa Rijal, Nhu-Y Nugyen, Tse-Chieh Teh, Natalie K. Rynkiewicz, Nik Cummings, Lisa Ooms, Sharon Avery, Julie Mcmanus, Mark A. Guthridge, Catriona Mclean, Christina A. Mitchell*, Andrew Wei*. Elucidating a novel role for inositol polyphosphate 4-phosphatase type II (INPP4B) in mediating chemoresistance in acute myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5283. doi:10.1158/1538-7445.AM2014-5283