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

Abstract

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. Figure Figure. Disclosures Ray: Onconostic Technologies, Inc.: Employment. Shah:Onconostic Technologies, Inc.: Employment. Ray:Onconostic Technologies, Inc.: Consultancy, Equity Ownership; 3N Diagnostics Ltd.: Consultancy, Equity Ownership.

FOXC1 in cancer development and therapy: deciphering its emerging and divergent roles

“…Cox's multivariate proportional hazards model revealed that increased FOXC1 expression is related with a worse disease-specific survival for HCC patients and is an independent unfavorable prognostic factor after curative resection. In addition, the negative correlation between upregulated FOXC1 with reduced disease-free survival and OS duration have been analogously observed in GC, 25 pancreatic ductal adenocarcinoma (PDA), 21 NSCLC, 18 ESCC, 26 AML, 72 melanoma, 36 and cervical carcinoma. 23 Conversely, there is another evidence indicating that overexpression of FOXC1 exists as an advantageous prognosis factor in serous ovarian tumor.…”

“…High levels of FOXC1 in AML (FAB-M2) exhibit essential relevance with morphological classifications associated with granulocyte differentiation compared with other AML subtypes. 33 Notably, elevated FOXC1 expression is also considered to be a potential marker of disease relapse and failure during induction chemotherapy in AML, 72 suggesting the diagnostic and predictive utility of FOXC1 expression in the clinical management of AML. In addition, in most cancer types, high FOXC1 expression may predict clinical features such as malignant clinical manifestations, increased pathological grade, and poor outcomes of patients.…”

The Diverse Consequences of FOXC1 Deregulation in Cancer

“…In AML, high expression of FOXC1 is associated with adverse prognosis by comparison with FOXC1 lo cases [40,67]. More recently, high FOXC1 expression was significantly correlated with refractoriness to induction chemotherapy and an increased risk of relapse in a combined study of 765 cases [41]. Thus, FOXC1 expression may represent a predictor of response to treatment that may improve risk-stratification of AML patients.…”

The Role of Forkhead Box Proteins in Acute Myeloid Leukemia

“…Thus, further studies are needed to better clarify the effect of the altered mRNA expression of FOXOs genes and their subcellular localization in FLT3-ITD positive AML. In addition to its role in APL setting, it has been shown that upregulation of FOXC1 has a poor prognostic role in FLT3-ITD AML [41,75]. In a series of 765 FLT3-ITD patients the high expression of FOXC1 was significantly related to chemoresistance and high cumulative incidence of relapse.…”