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Highly Phosphorylated FOXO3A Is an Adverse Prognostic Factor in Acute Myeloid Leukemia

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Highly Phosphorylated FOXO3A Is an Adverse Prognostic Factor in Acute Myeloid Leukemia Published OnlineFirst March 14, 2010; DOI: 10.1158/1078-0432.CCR-09-2551 Clinical Imaging, Diagnosis, Prognosis Cancer Research Highly Phosphorylated FOXO3A Is an Adverse Prognostic Factor in Acute Myeloid Leukemia Steven M. Kornblau1, Neera Singh1, YiHua Qiu1, Wenjing Chen1, Nianxiang Zhang2, and Kevin R. Coombes2 Abstract Purpose: The Forkhead transcription factors (FOXO) are tumor suppressor genes regulating differentia- tion, metabolism, and apoptosis that functionally interact with signal transduction pathways shown to be deregulated and prognostic in acute myelogenous leukemia (AML). This study evaluated the level of expression and the prognostic relevance of total and phosphorylated FOXO3A protein in AML. Experimental Design: We used reverse-phase protein array methods to measure the level of total and phosphoprotein expression of FOXO3A, in leukemia-enriched protein samples from 511 newly diag- nosed AML patients. Results: The expression range was similar to normal CD34+ cells and similar in blood and marrow. Levels of total FOXO3A were higher at relapse compared with diagnosis. Levels of pFOXO3A or the ratio of phospho to total (PT) were not associated with karyotpe but were higher in patients with FLT3 muta- tions. Higher levels of pFOXO3A or PT-FOXO3A were associated with increased proliferation evidenced by strong correlation with higher WBC, percent marrow, and blood blasts and by correlation with higher levels of Cyclins B1, D1 and D3, pGSK3, pMTOR, and pStat5. Patients with High levels of pFOXO3A or PT-FOXO3A had higher rates of primary resistance and shorter remission durations, which combine to cause an inferior survival experience (P = 0.0002). This effect was independent of cytogenetics. PT-FOXO3A was a statistically significant independent predictor in multivariate analysis. Conclusions: High levels of phosphorylation of FOXO3A is a therapeutically targetable, independent adverse prognostic factor in AML. Clin Cancer Res; 16(6); 1865–74. ©2010 AACR. Forkhead transcription factors are a superfamily of evo- tumors and leukemias. The FOXO1 gene was identified lutionary conserved proteins that function in diverse phys- in the studies of t(2, 13)(q35;q14) and t(1, 13)(p36;q14) iologic processes including cellular differentiation, tumor chromosomal translocations found in rhabdomyosar- suppression, metabolism, cell cycle arrest, resistance, and comas, whereas the FOXO3 gene was identified at t(6;11) apoptosis (1, 2). The forkhead genes are grouped into 19 (q21;q23) chromosomal translocation from an acute mye- subclasses of FOX genes (FOXA to FOXS) based on a con- loid leukemia patient and FOXO4 at t(x;11)(q13;q23) in served 100-residue DNA binding “forkhead box” domain acute lymphoblastic leukemia (9). FOXO3A overexpression (1, 3–5). The Forkhead O transcription factor subfamily inhibits tumor growth in vitro and tumor size in vivo in (FOXO), which consists of four members FOXO1, breast cancer cells and cytoplasmic location of FOXO3A FOXO3, FOXO4, and FOXO6, is deregulated in several tu- correlated with poorer survival in patients with breast can- mor types (3). The role of FOXO proteins in tumorigenesis cer (10, 11). Genetic deletion of five FOXO alleles showed were initially identified by their involvement at sites of modest neoplastic phenotypes, whereas deletion of all of chromosomal rearrangements in humans tumors (6–8). the FOXO alleles generated thymic lymphomas and he- For example, FOXO1, FOXO3A,andFOXO4 genes were mangiomas (12). These data define FOXO proteins as bona found at chromosomal breakpoints in human soft-tissue fide tumor suppressor genes (12). Studies by Fei et al. (13) have suggested that low expres- Authors' Affiliations: Departments of 1Stem Cell Transplantation and sion of FOXO3A expression is associated with the develop- Cellular Therapy and 2Bioinformatics and Computational Biology, The ment of ovarian tumors. More recently, studies have shown University of Texas M.D. Anderson Cancer Center, Houston, Texas the importance of FOXOs in preserving the self-renewal ca- Note: Supplementary data for this article are available at Clinical Cancer pacity of hematopoietic stem cells through undefined me- Research Online (http://clincancerres.aacrjournals.org/). chanisms (14). Studies have shown that FOXO3A Corresponding Author: Steven M. Kornblau, Section of Molecular transcriptional activity may be required to prevent B-chronic Hematology and Therapy, Unit 448, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX lymphocytic leukemia and chronic myelogenous leukemia 77030-4095. Phone: 713-794-1568; Fax: 713-794-1938; E-mail: (14, 15). [email protected]. The FOXO transcription factors are functionally inte- doi: 10.1158/1078-0432.CCR-09-2551 grated (see Fig. 1 for a summary) with several signal trans- ©2010 American Association for Cancer Research. duction pathways including many kinase pathways, e.g., www.aacrjournals.org 1865 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst March 14, 2010; DOI: 10.1158/1078-0432.CCR-09-2551 Kornblau et al. expression and activation status has not been reported. Translational Relevance We have previously shown that numerous signal transduc- tion pathways that regulate FOXO and which are also reg- In this article, we show that the phosphorylation of ulated by FOXO are abnormally activated in AML with FOXO3A, a protein that interacts with numerous signal adverse prognostic consequences (36). This led us to study transduction pathways, is an adverse prognostic factor the role of FOXO3A expression and inactivation through in AML that is associated with increased proliferation, phosphorylation, in a cohort of 511 cases of AML and resistance to therapy, and shorter survival. There is ac- 21 cases of APL using reverse-phase protein array (RPPA). tive investigation into developing therapies aimed at In this study, we report a correlation between phopsho- restoring FOXO3A function by altering localization FOXO3A expression and clinical characteristics, and or inhibiting phosphorylation. Strategies designed to French-American-British classification (FAB) and overall inhibit AKT activity might counteract this effect in pa- survival in leukemia patients. tients with high phospho to total ratios. In contrast, strategies designed to drive resting cells into prolifer- Materials and Methods ation might counteract the inhibitory effect of high levels of unphosphorylated FOXO3A but would be Patient population. Peripheral blood and bone marrow unlikely to have additional effects on those that are specimens were collected from 511 patients with newly di- already highly proliferative due to high PT-FOXO3A agnosed AML and 21 with newly diagnosed acute promye- ratios. FOXO3A therefore makes an attractive target for locytic leukemia (APL) evaluated at The University of Texas therapy in AML but correct application of FOXO3A-di- M.D. Anderson Cancer Center (MDACC) between Septem- rected therapies requires defining the mechanism by ber 1999 and March 2007. Samples were acquired during which FOXO3A is inactivated to optimize efficacy. This routine diagnostic assessments in accordance with the regu- research therefore defines FOXO3A as a target and lations and protocols (Lab 01-473) approved by the Inves- guides the application of FOXO3a directed therapies. tigational Review Board of MDACC. Informed consent was obtained in accordance with the Declaration of Helinski. Samples were analyzed under and Institutional Review Board–approved laboratory protocol (Lab 05-0654). Sam- c-Jun-NH2-kinase (16), MST1 (17) AMPK (18), IkB (11), SGK (19), CDK2 (20), extracellular signal-regulated ki- ples were enriched for leukemic cells by performing ficoll nase (ERK)1/2 (10), DYRK1A (21), Caspase (22), phos- separation to yield a mononuclear fraction followed by phoinositide 3-kinase -AKT (23), and Wnt (24), which CD3/CD19 depletion to remove contaminating T and B can regulate a broad array of cellular process that include cells, if they were calculated to be >5% based on the differ- stem cell proliferation (14, 25), aging (26), and malig- ential. The samples were normalized to a concentration of 1 4 nancy (2). FOXO proteins can act not only as transcrip- ×10 cells/μL and a whole-cell lysate was prepared as previ- tional activators but also as transcriptional repressors ously described (36). A total of 387 marrow and 283 blood (12, 15, 27, 28). Their functions are tightly regulated at samples were studied from the newly diagnosed cases with multiple levels by phosphorylation, ubiquitylation, acetyla- 140 having both available. Among the 142 AML and 4 APL tion, and protein-protein interactions (29–31). Phosphory- cases that relapsed, a paired relapse sample was available for lation on threonine 24, serine 256, or serine 318 by AKT 49 of the AML and 1 of the APL cases. All but one relapse inhibits FOXO3A activity by increasing nuclear export and samples were from the marrow. Outcomes analysis for this this in turn increases proliferation (32). Similar to the reti- report is restricted to the newly diagnosed patients. The as- noblastoma tumor suppressor gene, FOXO function could sociated demographics are described in Table 1. Although therefore be lost by either diminished expression or the in- this population is typical for the MDACC referral pattern, activation by phosphorylation. FOXO transcription factors the median age of these patients (65.7 y) is older than the
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