Highly phosphorylated FOXO3A is an adverse prognostic factor in acute myeloid leukemia.
OBJECTIVE
The Forkhead transcription factors (FOXO) are tumor suppressor genes regulating differentiation, 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.


METHODS
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 diagnosed 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 mutations. 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.
Kornblau
Steven M
SM
Departments of Stem Cell Transplantation and Cellular Therapy and Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4095, USA. skornblau@mdanderson.org
Singh
Neera
N
Qiu
YiHua
Y
Chen
Wenjing
W
Zhang
Nianxiang
N
Coombes
Kevin R
KR
D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D040081:Protein Array Analysis; D012074:Remission Induction; D015996:Survival Rate; D055815:Young Adult
D018952:Antigens, CD34; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins