title: Targeting the PI3K/AKT pathway via GLI1 inhibition enhanced the drug sensitivity of acute myeloid leukemia cells.
abstract: Combination targeted therapy is commonly used to treat acute myeloid leukemia (AML) patients, particularly in refractory/relapse (RR) population. However, concerns have been raised regarding the safety and patient tolerance of combination chemotherapy. It is critical to choose the appropriate treatment for precision therapy. We performed genome-wide RNA profiling using RNA-Seq to compare the RR group and the complete remission (CR) group (a total of 42 adult AML patients). The Hedgehog (Hh) and PI3K/AKT pathways were upregulated in the RR population, which was further confirmed by western blot and/or qPCR. Overexpression of GLI1 in AML cells led to increased AKT phosphorylation and decreased drug sensitivity, which was attenuated by GLI1 inhibition. By contrast, neither the expression of GLI1 nor apoptosis in response to Ara-C treatment of AML cells was significantly affected by PI3K inhibition. Furthermore, co-inhibition of GLI1 and PI3K induced apoptosis of hematopoietic stem/progenitor cells (HSPCs), which raised serious concerns about the side effects of this treatment. These results indicated that GLI1 inhibition alone, but not combined inhibition, is sufficient to enhance AML drug sensitivity, which provides a novel therapeutic strategy for AML treatment.
authors.affiliation: Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Qi-Li
authors.initials: QL
authors.lastname: Zheng
authors.affiliation: Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Fang
authors.affiliation: Department of Hematology, Third Xiangya Hospital, Central South University, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Genomic Core, Weill Cornell Medical College, NY, USA.
authors.forename: Tuo
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Endocrinology, Xiangya Hospital, Central South University, China.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Surgery Genomic Core, Weill Cornell Medical College, NY, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Robinson
authors.affiliation: Department of Surgery Genomic Core, Weill Cornell Medical College, NY, USA.
authors.forename: Shui-Bing
authors.initials: SB
authors.lastname: Chen
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, China.|Institute of Clinical Pharmacology, Central South University, China.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Chen
authors.affiliation: Department of Hematology, Third Xiangya Hospital, Central South University, China.
authors.forename: Fang-Ping
authors.initials: FP
authors.lastname: Chen
authors.affiliation: Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zeng
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult; D000071676:Zinc Finger Protein GLI1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C400551:GLI1 protein, human; D047428:Protein Kinase Inhibitors; D000071676:Zinc Finger Protein GLI1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt