General AML,   RUNX1,  IDH1/2,  NPM1,  Cohesin,  DNMT3A,  Chromatin Regulation

The effect of HOPX expression in AML: A Taiwan study

Homeodomain-only Protein Homeobox (HOPX) functions as an adapter protein that mediates transcriptional repression. HOPX has been described as a stem cell marker which plays a role in tumorigenesis with clinical consequences. The clinical and biological impact of HOPX in Acute Myeloid Leukemia (AML) is yet to be elucidated hence the rationale for this study.

In an article published ahead of print in Haematologica, Chien-Chin Lin  and colleagues from the National Taiwan University Hospital (NUTH), Taipei, Taiwan, retrospectively studied the impact of HOPX expression in patients with de novo AML.

347 de novo AML patients with cryopreserved Bone Marrow cells in the NUTH were enrolled. Patients were either treated with standard chemotherapy (n = 227) or palliative therapy/ low-dose chemotherapy (n = 120). HOPX gene levels were analzyed and patients were divided into two cohorts based on HOPX expression above (Higher HOPX Expression, n = 174) or below (Lower HOPX expression, n = 173) the median level of HOPX expression.

The key results of the study were:
  • Older age (P = 0.0023), higher platelet count (P = 0.008), lower White Blood Cell (WBC) counts (P = 0.011) and lower Lactate Dehydrogenase (LDH) levels (P < 0.001) at diagnosis were associated with higher HOPX expression
  • High incidence of mutations in RUNX1 (P < 0.001), IDH2 (P = 0.001), ASXL1 (P = 0.017) and DNMT3A (P = 0.040) were associated with higher HOPX expression
  • Complete Remission (CR) in patients (n = 227) with higher HOPX and lower HOPX expression; 58.3% vs 85.5%, P < 0.001
  • Median Overall Survival (OS) in patients (n = 227) with higher HOPX (n = 103) and lower HOPX expression (n = 124); 23.7 vs 116.8 months, P < 0.001
  • Median Disease Free Survival (DFS) in patients with higher HOPX and lower HOPX expression; 5.9 months vs not reached, P < 0.001
  • Higher HOPX expression was a poor prognostic factor for OS; P = 0.005

Higher HOPX expression was associated with the upregulation of Hematopoietic Stem Cell (HSC) and Leukemia Stem Cell (LSC) signatures

Higher expression of HOPX is an independent unfavorable prognostic factor in AML patients. The authors concluded by stating that “HOPX is a distinctive homeobox gene with characteristic clinical and biological implications and its expression is a powerful predictor of prognosis” in AML patients.

The authors highlighted that their study is the first to report on the prognostic significance of HOPX expression in de novo AML. They further suggested that a prospective study should be explored to confirm the findings of their study.

Abstract

Homeodomain-only protein homeobox (HOPX) is the smallest homeodomain protein. It was regarded as a stem cell marker in several non-hematopoietic systems. While the prototypic homeobox genes such as HOX family have been well characterized in acute myeloid leukemia, the clinical and biological implications of HOPX in the disease remain unknown. Thus we analyzed HOPX and global gene expression patterns in 347 newly diagnosed de novo acute myeloid leukemia patients in our institute. We found that higher HOPX expression was closely associated with older age, higher platelet counts, lower white blood cell counts, lower lactate dehydrogenase levels, and mutations in RUNX1, IDH2, ASXL1, and DNMT3A, but negatively associated with acute promyelocytic leukemia, favorable karyotypes, CEBPA double mutations and NPM1 mutation. Patients with higher HOPX expression had a lower complete remission rate and shorter survival. The finding was validated in two independent cohorts. Multivariate analysis revealed that higher HOPX expression was an independent unfavorable prognostic factor irrespective of other known prognostic parameters and gene signatures derived from multiple cohorts. Gene set enrichment analysis showed higher HOPX expression was associated with both hematopoietic and leukemia stem cell signatures. While HOPX and HOX family genes showed concordant expression patterns in normal hematopoietic stem/progenitor cells, their expression patterns and associated clinical and biological features were distinctive in acute myeloid leukemia settings, demonstrating HOPX as a unique homeobox gene. Therefore, HOPX is a distinctive homeobox gene with characteristic clinical and biological implications and its expression is a powerful predictor of prognosis in acute myeloid leukemia patients.

References
  1. Lin C.C. et al. Higher HOPX Expression Is Associated With Distinct Clinical And Biological Features And Predicts Poor Prognosis In De Novo Acute Myeloid Leukemia. Haematologica. 2017 Mar 24. DOI: 3324/haematol.2016.161257.