title: Clinical and prognostic implications of Roundabout 4 (robo4) in adult patients with acute myeloid leukemia.
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.
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin branch, Yun-Lin, Taiwan.
authors: Yin-Kai
authors: YK
authors: Chen
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Hsin-An
authors: HA
authors: Hou
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Jih-Luh
authors: JL
authors: Tang
authors: Department of Pathology, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors: Jie-Yang
authors: JY
authors: Jhuang
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Yan-Jun
authors: YJ
authors: Lai
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Ming-Cheng
authors: MC
authors: Lee
authors: Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Yuan-Yeh
authors: YY
authors: Kuo
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Wen-Chien
authors: WC
authors: Chou
authors: Biostatistics Consulting Laboratory, Department of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.
authors: Chieh-Yu
authors: CY
authors: Liu
authors: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors: Chung-Wu
authors: CW
authors: Lin
authors: Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.
authors: Shih-Sung
authors: SS
authors: Chuang
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Chien-Yuan
authors: CY
authors: Chen
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Mei-Hsuan
authors: MH
authors: Tseng
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Chi-Fei
authors: CF
authors: Huang
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Ying-Chieh
authors: YC
authors: Chiang
authors: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors: Fen-Yu
authors: FY
authors: Lee
authors: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors: Ming-Chih
authors: MC
authors: Liu
authors: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors: Chia-Wen
authors: CW
authors: Liu
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Ming
authors: M
authors: Yao
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Shang-Yi
authors: SY
authors: Huang
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Bor-Sheng
authors: BS
authors: Ko
authors: Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Szu-Chun
authors: SC
authors: Hsu
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Shang-Ju
authors: SJ
authors: Wu
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Woei
authors: W
authors: Tsay
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Yao-Chang
authors: YC
authors: Chen
authors: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors: Hwei-Fang
authors: HF
authors: Tien
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002869:Chromosome Aberrations; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000090243:Nucleophosmin; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult; D000097905:Roundabout Proteins
chemical_list: D000090243:Nucleophosmin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C000716967:NPM1 protein, human; C462951:ROBO4 protein, human; D000097905:Roundabout Proteins