Clinical and Prognostic Relevance of Expression of Homeodomain-Only Protein Homeobox (HOPX) in Acute Myeloid Leukemia

Homeodomain-only protein homeobox (HOPX) gene encodes a homeodomain protein without DNA-binding domains and functions as an adaptor protein to mediate transcriptional repression. HOPX is known to regulate cardiac development through interaction with serum responsive factor (SRF), thereby inhibiting SRF-dependent transcription either by interference of its DNA binding or recruitment of histone deacetylase. Recent studies have suggested that HOPX acts as a tumor suppressor gene since loss of its expression has been reported in several solid cancers. However the biological effects of HOPX in hematopoietic malignancies have not been explored. In this study, we aim to see the clinical and biological relevance of HOPX expression in acute myeloid leukemia (AML).

We performed global mRNA arrays for 181 newly diagnosed AML patients in the National Taiwan University Hospital. There are also detailed demographic, clinical and genetic data for these patients. The HOPX gene expression levels extracted from the array data were analyzed for its clinical and biological relevance. We also tried to validate our findings by analyzing the public databases of AML.

The 181patients were divided into two groups based on the median level of HOPX expression on the arrays. Patients with higher expression had higher platelet counts than those with lower expression (median, 59000/μL vs. 35000/μL, P=0.008). Higher HOPX expression was negatively associated with favorable karyotypes including t(8;21) and t(15;17).

To investigate the association of gene mutations with HOPX expression in AML, we also performed a mutational screening for 17 genes. We found that patients with higher HOPX expression had significantly higher incidence of RUNX1 mutation (23.1% vs. 4.4%, P<0.001), IDH2 mutation (19.8% vs. 7.8%, P=0.019) but lower incidence of CEBPA mutation (2.2% vs. 12.2%, P=0.015) and FLT3-TKD (4.4% vs. 14.4%, P=0.020) than those with lower HOPX expression.

With a median follow-up of 33 months, patients with higher HOPX expression had shorter overall survival (OS) compared with patients with lower HOPX expression (median, 17 months vs. not reached, P=0.004). In multivariate analyses, higher expression of HOPX still represented a poor prognostic factor for OS independent of age, white blood cell counts, karyotype, NPM1 mutation, FLT3-ITD, CEBPA^{double mutation} and RUNX1 mutation (P=0.021). Considering the hypothetical role of HOPX as a tumor suppressor in solid tumors, it seems surprising to see the negative impact on OS of high HOPX expression in AML. To be more assuring, we analyzed HOPX expression in another two large independent AML patient cohorts, TCGA and GSE12417_GPL96. We obtained the same results that higher HOPX expression was an unfavorable prognostic factor.

Higher expression of HOPX in AML patients was correlated with higher platelet counts and mutations in RUNX1 and IDH2, but negatively associated with favorable karyotypes such as t(8;21) and t(15;17) and CEBPA mutation or FLT3-TKD. Higher expression of HOPX appeared to be an independent unfavorable prognostic factor in our cohort, and its negative prognostic impact could be validated in another 2 large independent cohorts of AML. Further studies are needed to explore the biological significance of this gene expression in AML.

No relevant conflicts of interest to declare.