FOXC1 Expression in Acute Myeloid Leukemia: Potential Predictor of Disease Relapse and/or Refractory Disease

Background:

The mesenchymal transcription factor Forkhead Box C1 (FOXC1), derepressed in hematopoietic stem progenitor cells (HSPCs) in the setting of acute myeloid leukemia (AML), but not in normal HSPCs, was recently demonstrated to play an important role in AML disease onset and progression by blocking myeloid lineage differentiation and enhancing clonogenic potential. Herein we sought to further examine the prognostic value of FOXC1 in AML and whether FOXC1 expression is a potential predictor of disease relapse and/or lack of response to induction chemotherapy in AML.

Methods:

Expression of FOXC1 mRNA in mixed karyotype AML bone marrow samples was examined using publicly available microarray datasets (n=521, n=244). The clinical significance of FOXC1 gene expression as a prognostic biomarker was evaluated using censored overall survival (OS) and event-free survival (EFS) data. Degree of statistical significance in the univariate and multivariate analyses performed was assessed using log-rank test and Cox regression model, respectively.

Results:

FOXC1 mRNA expression was a significant predictor of OS on univariate (hazard ratio [HR] 1.592 95% confidence interval [CI] 1.263-2.007, P = 0.0001) and multivariate (HR 1.755 95% CI 1.355-2.273, P < 0.0001) analyses. This effect on OS could be attributed to disease relapse and/or lack of response to induction chemotherapy as FOXC1 mRNA expression also proved to be a significant predictor of EFS on univariate analysis (hazard ratio [HR] 1.539 95% confidence interval [CI] 1.208-1.961, P = 0.0002) and multivariate analysis (HR 1.678 95% CI 1.280-2.201, P = 0.0001), independent of age, FLT3 ITD status, NPM1 status or cytogenetic risk status. Compared to patients who experienced disease remission, FOXC1 expression was significantly elevated in patients experiencing disease relapse following induction chemotherapy (P<0.02), and in patients who were non-responders to induction chemotherapy (P<0.002)

Conclusions:

FOXC1 expression in AML is an independent prognostic predictor of decreased OS and EFS and is significantly associated with disease relapse and/or refractoriness to induction chemotherapy. A risk of relapse/non-response score that incorporates FOXC1 expression status may prove to be of value in identifying patients at the time of initial diagnosis who are likely to fail induction chemotherapy. Further studies are warranted to explore the prognostic and predictive utility of FOXC1 expression in the clinical management of AML.

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