Clinical and prognostic implications of Roundabout 4 (robo4) in adult patients with acute myeloid leukemia

PLoS One. 2015 Mar 20;10(3):e0119831. doi: 10.1371/journal.pone.0119831. eCollection 2015.

Abstract

Background: Robo4 is involved in hematopoietic stem/progenitor cell homeostasis and essential for tumor angiogenesis. Expression of Robo4 was recently found in solid tumors and leukemia stem cells. However, the clinical implications of Robo4 expression in patients with acute myeloid leukemia (AML) remain unclear.

Methods: We investigated the clinical and prognostic relevance of mRNA expression of Robo4 in bone marrow (BM) mononuclear cells from 218 adult patients with de novo AML. We also performed immunohistochemical staining to assess the Robo4 protein expression in the BM biopsy specimens from 30 selected AML patients in the cohort.

Results: Higher Robo4 expression was closely associated with lower white blood cell counts, expression of HLA-DR, CD13, CD34 and CD56 on leukemia cells, t(8;21) and ASXL1 mutation, but negatively correlated with t(15;17) and CEBPA mutation. Compared to patients with lower Robo4 expression, those with higher expression had significantly shorter disease-free survival (DFS) and overall survival (OS). This result was confirmed in an independent validation cohort. Furthermore, multivariate analyses showed that higher Robo4 expression was an independent poor prognostic factor for DFS and OS in total cohort and patients with intermediate-risk cytogenetics, irrespective of age, WBC count, karyotype, and mutation status of NPM1/FLT3-ITD, and CEBPA.

Conclusions: BM Robo4 expression can serve as a new biomarker to predict clinical outcomes in AML patients and Robo4 may serve as a potential therapeutic target in patients with higher Robo4 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Chromosome Aberrations
  • Female
  • Gene Expression
  • Humans
  • Kaplan-Meier Estimate
  • Karyotype
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • Mutation
  • Nucleophosmin
  • Prognosis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Remission Induction
  • Treatment Outcome
  • Young Adult

Substances

  • NPM1 protein, human
  • RNA, Messenger
  • ROBO4 protein, human
  • Receptors, Cell Surface
  • Nucleophosmin

Grants and funding

This work was partially sponsored by grants NSC 100-2314-B002-057-MY3, NSC 100-2314-B-002 -112 -MY3 and NSC 100-2628 -B-002-003-MY3 from the National Science Council (Taiwan), MOHW103-TD-B-111-04 from the Ministry of Health and Welfare (Taiwan) and NTUH 102P06 and UN 102-015 from the Department of Medical Research, National Taiwan University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.