Abstract
BackgroundRobo4 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.MethodsWe 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.ResultsHigher 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.ConclusionsBM 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.
Highlights
Higher Roundabout 4 (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
bone marrow (BM) Robo4 expression can serve as a new biomarker to predict clinical outcomes in acute myeloid leukemia (AML) patients and Robo4 may serve as a potential therapeutic target in patients with higher Robo4 expression
[3] It is distinct from the other family members in that it is expressed in endothelial cells [4,5] and hematopoietic stem/progenitor cells (HSPCs). [6,7] Robo4 acts as a receptor for Slit 2 and modulates vascular endothelial growth factor A (VEGF)–VEGF receptor signaling. [8,9] The Slit-Robo signaling is essential for angiogenesis, [6,10] especially tumor angiogenesis. [11] obo4 expression was found to be significantly up-regulated in tumor endothelia compared to their normal counterparts
Summary
The Roundabout (Robo) family proteins are highly conserved transmembrane cell adhesion molecules that are expressed predominantly in neuronal tissues and play a role in the development of the nervous system. [1, 2] Roundabout 4 (Robo4), the fourth member of Robo family, was first identified by Huminiecki et al in 2002. [3] It is distinct from the other family members in that it is expressed in endothelial cells [4,5] and hematopoietic stem/progenitor cells (HSPCs). [6,7] Robo acts as a receptor for Slit 2 and modulates vascular endothelial growth factor A (VEGF)–VEGF receptor signaling. [8,9] The Slit-Robo signaling is essential for angiogenesis, [6,10] especially tumor angiogenesis. [11] obo expression was found to be significantly up-regulated in tumor endothelia compared to their normal counterparts. [12] In addition to angiogenesis, Slit2-Robo signaling pathway plays an essential role in BM homing and mobilization of HSPCs. [7,13] Smith-Berdan et al demonstrated that Robo, in cooperation with CXCR4, acted as an HSPC-specific adhesion receptor to localize HSPC to BM niches. [7]Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy regarding the pathogenesis, clinical features and treatment outcomes. The Roundabout (Robo) family proteins are highly conserved transmembrane cell adhesion molecules that are expressed predominantly in neuronal tissues and play a role in the development of the nervous system. [3] It is distinct from the other family members in that it is expressed in endothelial cells [4,5] and hematopoietic stem/progenitor cells (HSPCs). [12] In addition to angiogenesis, Slit2-Robo signaling pathway plays an essential role in BM homing and mobilization of HSPCs. Robo is involved in hematopoietic stem/progenitor cell homeostasis and essential for tumor angiogenesis. Expression of Robo was recently found in solid tumors and leukemia stem cells. The clinical implications of Robo expression in patients with acute myeloid leukemia (AML) remain unclear
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