Histone deacetylase inhibitors trichostatin A and valproic acid circumvent apoptosis in human leukemic cells expressing the RUNX1 chimera.
Disturbance of the normal functions of wild-type RUNX1 resulting from chromosomal translocations or gene mutations is one of the major molecular mechanisms in human leukemogenesis. RUNX1-related chimeras generated by the chromosomal translocations repress transcriptional activity of wild-type RUNX1 by recruiting the co-repressor/histone deacetylase complex. Thus, histone deacetylase inhibitors are expected to restore normal functions of wild-type RUNX1 and thereby affect the growth and differentiation ability of leukemic cells expressing the chimera. We investigated the in vitro effects of histone deacetylase inhibitors, trichostatin A and valproic acid, on human leukemic cell lines such as SKNO-1 and Kasumi-1 expressing RUNX1/ETO, Reh expressing TEL/RUNX1 and SKH-1 co-expressing RUNX1/EVI1 and BCR/ABL. We also employed K562 cells expressing BCR/ABL without such a chimera as a control. Treatment with each inhibitor increased acetylated histone 4 in all of these cell lines. Interestingly, proliferation of SKNO-1, Kasumi-1, SKH-1 and Reh cells was significantly suppressed after 3-day culture with trichostatin A or valproic acid, when compared to that of K562 cells. We observed cell cycle arrest and apoptotic induction in the RUNX1 chimera-expressing cells by the propidium iodide staining. Up- and downregulation of cell cycle regulator genes appeared to be the molecular basis for the former, and activation of both extrinsic and intrinsic apoptotic caspases for the latter. We propose histone deacetylase inhibitors to be an attractive choice in the molecular targeting therapy of RUNX1-related leukemia.
Sasaki
Ko
K
Department of Hematology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan.
Yamagata
Tetsuya
T
Mitani
Kinuko
K
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D050506:Mutant Chimeric Proteins / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050506:Mutant Chimeric Proteins; C493728:RUNX1 protein, human; C012589:trichostatin A; D014635:Valproic Acid; D006655:Histone Deacetylases