Tumor Suppressor Role for B55 alpha PP2A Isoform in AML

S180 205 Incidence of and risk factors for acute myeloid leukemia involvement of the central nervous system Uri Rozovski, Maro Ohanian, Farhad Ravandi, Guillermo Garcia-Manero, Sherry Pierce, Jorge Cortes, Zeev Estrov Department of Leukemia, The University of Texas MD Anderson Cancer Center The exact incidence of central nervous system (CNS) leukemia in adult patients with acute myeloid leukemia (AML) is unknown. Nevertheless, because CNS involvement is thought to be less common in AML than in acute lymphoblastic leukemia, and because induction chemotherapy typically includes cytarabine which penetrates the bloodebrain-barrier, unlike in ALL, routine lumbar puncture (LP) is rarely performed in adult patients with newly diagnosed AML. Objective: To assess the cumulative incidence, the risk factors, and the outcome of CNS involvement in a large cohort of AML patients treated with cytarabine-based and non-cytarabine-based induction chemotherapy. Design and Setting: This is a retrospective study of newly diagnosed patients with AML who received induction chemotherapy between 2000 and 2012 at the University of Texas MD Anderson Cancer Center. Patients: 1412 newly diagnosed patients of all subtypes except for acute promyelocytic leukemia were included. The majority (1370/1412, 97%) underwent diagnostic LP only if signs or symptoms suggestive of CNS disease were suspected. Forty two patients were treated with an investigational protocol that required diagnostic LP at time of diagnosis. CNS leukemia was defined as the presence of leukemic blasts in cytospun cerebrospinal fluid. Results: In 1370 patients for which LP was performed if clinically indicated, CNS disease was detected in 45 (3.3%) patients. In 42 patients who underwent LP at time of diagnosis leukemia blasts were detected in 8 (19%). Patients treated with high-dose cytarabine-based regimens (n1⁄4 788) and those who were not (n 1⁄4 582) had similar post-induction rates of CNS involvement. In patients who achieved complete remission after induction chemotherapy, disease free survival and overall survival were significantly shorter if CNS disease was detected. In a univariate analysis, high levels of LDH, a high percentage of BM blasts, African American or Hispanic ethnicity, monoblastic FAB subtype (M5), and FLT3-ITD were predictive for CNS involvement. In the multivariate analysis, only high levels of LDH and African-American ethnicity remained predictive for CNS involvement. Conclusion: The CNS may serve as a sanctuary for residual AML cells and become a source of relapse. Whether CNS prophylaxis will aid in attaining longer DFS remains to be determined. Clinical Lymphoma, Myeloma & Leukemia June 2015 206 Tumor Suppressor Role for B55 alpha PP2A Isoform in AML Peter P. Ruvolo, Vivian R. Ruvolo, Rodrigo Jacamo, Jared K. Burks, Zhihong Zeng, Yihua Qiu, Suk Y. Yoo, Rongqing Pan, Numsen Hail, Jr., Marina Konopleva, George Calin, Steven M. Kornblau, Michael Andreeff Division of Molecular Hematology, Department of Leukemia at the University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioinformatics and Computational Biology at the University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Stem Cell Transplantation and Experimental Therapeutics at the University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Stem Cell Transplantation at the University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: Acute myeloid leukemia (AML) remains a highly fatal disease despite best efforts to develop novel therapies. Targeting relevant survival kinases is difficult as AML patients with the poorest outcome have multiple active survival kinase cascades. Signal transduction is a dynamic process and one possible mechanism for kinase activation involves loss of protein phosphatase. AKT, PKC, and ERK have all been shown to be regulated by Protein Phosphatase 2A (PP2A). Study Design: We analyzed B55 alpha expression by Reverse Phase Protein Analysis (RPPA) in AML patients. Peripheral blood and bone marrow specimens were collected from 511 patients with newly diagnosed AML evaluated at The University of Texas MD Anderson Cancer Center (MDACC) between September 1999 and March 2007. Samples were acquired during routine diagnostic assessments in accordance with the regulations and protocols approved by the Investigational Review Board of MDACC. B55 alpha expression was correlated with patient survival and disease characteristics including French-AmericanBritish (FAB) classification, cytogenetics, and mutational status. Expression of B55 alpha was also compared to 230 other proteins by RPPA. For proof of principle, B55 alpha was suppressed in OCIAML3 cells and effects on drug resistance, signal transduction, and miR expression was determined. Results: RPPA revealed that in AML cells the B55 alpha PP2A subunit is under expressed, is negatively correlated with AKT activation status, and is unfavorable for remission duration and relapse in patients. RPPA suggested the PP2A B subunit was negatively correlated with a number of proteins including phosphorylated AKT, phosphorylated PKC alpha, and MYC. Suppression of B55 alpha in OCI-AML3 cells demonstrated that loss of the B subunit induces AKT and PKC alpha phosphorylation. Reduction of the B subunit in the AML cells sensitized cells to FTY-720. This finding is consistent with a previous report that FTY-720 induces B55 alpha expression. Suppression of B55 alpha inhibited MYC expression which is likely due to increased levels of the MYC negative regulator B56 alpha. PP2A control of microRNA expression is not well characterized and presently unknown in leukemia. Suppression of B55 alpha induces expression of miR-191-5p (associated with poor survival in AML) and suppresses miR-142-3p (which is mutated in 2% of AML patients) as