title: Acute myeloblastic leukemic cells acquire cellular cytotoxicity under genotoxic stress: implication of granzyme B and perforin.
abstract: Granzyme B (GrB) and perforin (PFN) are the major components of cytoplasmic granules contained in immune cellular effectors. The granule secretory pathway is one of the mechanisms by which these cells exert their cellular cytotoxicity. Recently, it has been reported that GrB and PFN are also present in circulating hemopoietic CD34(+) progenitor cells mobilized by chemotherapy and granulocyte-colony stimulating factor, whereas these proteins are undetected in steady-state peripheral CD34(+) cells. In this study, we hypothesized that anticancer agents may increase GrB and PFN expression in immature myeloid leukemic cells and that these treated leukemic cells become cellular effectors through a granule-dependent mechanism. Our results show that KG1a, HEL, and TF-1 CD34(+) acute myeloblastic leukemia cells expressed both GrB and PFN. Moreover, ionizing radiation, aracytine, and etoposide not only increase GrB and PFN expression but also conferred potent cellular cytotoxicity to these cells toward various cellular targets. Cellular cytotoxicity required cell-cell contact, was not influenced by anti-tumor necrosis factor alpha or anti-Fas blocking antibodies, and was abrogated by GrB inhibitors or antisense. These results suggest that, when exposed to genotoxic agents, immature leukemic cells acquire potent GrB- and PFN-dependent cellular cytotoxicity that can be potentially directed against normal residual myeloid progenitors or immune effectors. (Blood. 2000;96:1914-1920)
authors.affiliation: Equipe Propre de l'Institut National de la Santé et de la Recherche Médicale (INSERM) E9910, Institut Claudius Régaud, Toulouse, France.
authors.forename: A P
authors.initials: AP
authors.lastname: Bruno
authors.forename: D
authors.initials: D
authors.lastname: Lautier
authors.forename: A T
authors.initials: AT
authors.lastname: d'Orgeix
authors.forename: G
authors.initials: G
authors.lastname: Laurent
authors.forename: A
authors.initials: A
authors.lastname: Quillet-Mary
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003374:Coumarins / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D003601:Cytotoxicity Tests, Immunologic; D016373:DNA, Antisense / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D053804:Granzymes; D006367:HeLa Cells; D006801:Humans; D049934:Isocoumarins; D019169:Jurkat Cells; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015636:Magnesium Chloride / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D003374:Coumarins; D016373:DNA, Antisense; D049934:Isocoumarins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D015636:Magnesium Chloride; D003561:Cytarabine; D054353:Perforin; C046235:3,4-dichloroisocoumarin; D005047:Etoposide; D004492:Edetic Acid; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D003630:Daunorubicin