title: Restoration of INK4a/ARF gene inhibits cell growth and cooperates with imatinib mesylate in Philadelphia chromosome-positive leukemias.
abstract: VSV-G-pseudotyped lentiviral vectors expressing p16(INK4a) or p14(ARF) were used to infect at high-efficiency Philadelphia chromosome (Ph)-positive leukemia cell lines lacking endogenous transcripts. Restoration of p16(INK4a) accumulated cells in the G0/G1 phase of cell cycle and restoration of p14(ARF) induced their apoptosis, followed by significant growth inhibition. Transduction of primary blast cells from chronic myeloid leukemia in blast crisis (CML-BC) and Ph-positive acute lymphoblastic leukemia (ALL) with p16(INK4a) or p14(ARF) virus also resulted in cell growth inhibition and/or apoptosis with a patient-to-patient variation, whereas clonal growth and differentiation of cord blood progenitor cells were not affected by enforced expression of INK4a/ARF. Furthermore, upon viral transduction at low multiplicity of infection, INK4a/ARF potentiated the effect of imatinib mesylate on Ph-positive leukemia cell lines in an additive but not synergistic manner. These results suggest that INK4a/ARF protein-mimetic agents may be promising options for Ph-positive leukemias in combination with imatinib mesylate.
authors: Department of Hematology/Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China.
authors: Yuansong
authors: Y
authors: Bai
authors: Zhenxia
authors: Z
authors: Lu
authors: Yumei
authors: Y
authors: Lin
authors: Butong
authors: B
authors: Sun
authors: Shibao
authors: S
authors: Wang
authors: Guanjun
authors: G
authors: Wang
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019942:Genes, p16; D006801:Humans; D000068877:Imatinib Mesylate; D016086:Lentivirus / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014161:Transduction, Genetic; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D025803:Tumor Suppressor Protein p14ARF; D000068877:Imatinib Mesylate