title: TGF-beta1-induced PI3K/Akt/NF-kappaB/MMP9 signalling pathway is activated in Philadelphia chromosome-positive chronic myeloid leukaemia hemangioblasts.
abstract: Overwhelming evidence from chronic myeloid leukaemia (CML) research indicates that patients harbour quiescent CML stem cells that are responsible for blast crisis. While the haematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, recently CML-initiating cells beyond HSCs are also being investigated. We have previously isolated fetal liver kinase-1-positive (Flk1(+)) cells carrying the BCR/ABL fusion gene from the bone marrow of Philadelphia chromosome-positive (Ph(+)) patients with hemangioblast property. Here, we show that these cells behave abnormally comparing with the hemangioblasts in healthy donors. These Ph(+) putative CML hemangioblast up-regulated TGF-β1 and result in activating matrix metalloproteinase-9 to enhance s-KitL and s-ICAM-1 secretion. Further studies showed that phosphatidylinositol-3 kinase (PI3K)/Akt/nuclear factor-κB signalling pathway was involved in CML pathogenesis. These findings provide direct evidence for the first time that hemangioblasts beyond HSCs play a critical role in the progression of CML.
authors.affiliation: Institute of Basic Medical Sciences & School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
authors.forename: Xishan
authors.initials: X
authors.lastname: Zhu
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Dou
authors.forename: Robert Chunhua
authors.initials: RC
authors.lastname: Zhao
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D055018:Hemangioblasts / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D058539:Phosphatidylinositol 3-Kinase; D016044:Fusion Proteins, bcr-abl; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9