AML1-ETO targets and suppresses cathepsin G, a serine protease, which is able to degrade AML1-ETO in t(8;21) acute myeloid leukemia.
Although the significance of cathepsin G (CTSG) in host defense has been intensively investigated, little is known about its potential roles in granulopoiesis or leukemogenesis. We report here that CTSG is directly targeted and suppressed by AML1-ETO in t(8;21) acute myeloid leukemia (AML). Luciferase assays demonstrate that the CTSG promoter is strongly transactivated by AML1 and the AML1-dependent transactivation is suppressed by AML1-ETO. We also define a novel regulatory mechanism by which AML1-ETO-mediated transrepression requires both AML1-ETO and AML1 binding at adjacent sites, instead of the replacement of AML1 by AML1-ETO, and wild-type AML1 binding is a prerequisite for the repressive effect caused by AML1-ETO. Further evidence shows that CTSG, as a hematopoietic serine protease, can degrade AML1-ETO both in vitro and in vivo. Restoration of CTSG induces partial differentiation, growth inhibition and apoptosis in AML1-ETO-positive cells. In addition to t(8;21) AML, CTSG downregulation is observed in AML patients with other cytogenetic/genetic abnormalities that potentially interrupt normal AML1 function, that is, inv(16) and EVI1 overexpression. Thus, the targeting and suppression of CTSG by AML1-ETO in t(8;21) AML may provide a mechanism for leukemia cells to escape from the intracellular surveillance system by preventing degradation of foreign proteins.
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
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Jin
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Wu
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Li
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Zou
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Zhang
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Zhang
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Wang
D017209:Apoptosis; D056649:Cathepsin G / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D018922:HL-60 Cells; D006367:HeLa Cells; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007157:Immunologic Surveillance; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D000074008:MDS1 and EVI1 Complex Locus Protein; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology*
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; C471254:inv(16) fusion protein, human; D056649:Cathepsin G