title: Targeting GLI1 Suppresses Cell Growth and Enhances Chemosensitivity in CD34+ Enriched Acute Myeloid Leukemia Progenitor Cells.
abstract: OBJECTIVE
  Resistance of leukemia stem cells (LSCs) to chemotherapy in patients with acute myeloid leukemia (AML) causes relapse of disease. Hedgehog (Hh) signaling plays a critical role in the maintenance and differentiation of cancer stem cells. Yet its role in AML remains controversial. The purpose of the present study is to investigate the role of GLI1, the transcriptional activator of Hh signaling, in AML progenitor cells and to explore the anti-AML effects of GLI small-molecule inhibitor GANT61.
  
  
  METHODS
  The expression of GLI1 mRNA and protein were examined in AML progenitor cells and normal cells. The proliferation, colony formation, apoptosis and differentiation of AML progenitor cells were also analyzed in the presence of GANT61.
  
  
  RESULTS
  Kasumi-1 and KG1a cells, containing more CD34+ cells, expressed higher level of GLI1 compared to U937 and NB4 cells with fewer CD34+ cells. Consistently, a positive correlation between the protein levels of GLI1 and CD34 was validated in the bone marrow mononuclear cells (BMMC) of AML patients tested. GANT61 inhibited the proliferation and colony formation in AML cell lines. Importantly, GANT61 induced apoptosis in CD34+ enriched Kasumi-1 and KG1a cells, whereas it induced differentiation in U937 and NB4 cells. Furthermore, GANT61 enhanced the cytotoxicity of cytarabine (Ara-c) in primary CD34+ AML cells, indicating that inhibition of GLI1 could be a promising strategy to enhance chemosensitivity.
  
  
  CONCLUSIONS
  The present findings suggested that Hh signaling was activated in AML progenitor cells. GLI1 acted as a potential target for AML therapy.
authors.forename: Bing
authors.initials: B
authors.lastname: Long
authors.forename: Le-Xun
authors.initials: LX
authors.lastname: Wang
authors.forename: Fei-Meng
authors.initials: FM
authors.lastname: Zheng
authors.forename: Shu-Ping
authors.initials: SP
authors.lastname: Lai
authors.forename: Duo-Rong
authors.initials: DR
authors.lastname: Xu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Lin
authors.forename: Xiang-Zhong
authors.initials: XZ
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Dong
authors.forename: Zi-Jie
authors.initials: ZJ
authors.lastname: Long
authors.forename: Xiu-Zhen
authors.initials: XZ
authors.lastname: Tong
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D055815:Young Adult; D000071676:Zinc Finger Protein GLI1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; C551027:GANT 61; C400551:GLI1 protein, human; D011725:Pyridines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000071676:Zinc Finger Protein GLI1