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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1914-1920
NEOPLASIA
Acute myeloblastic leukemic cells acquire cellular cytotoxicity
under genotoxic stress: implication of granzyme B and
perforin
Alain Pierre Bruno,
Dominique Lautier,
Aurélie de Thonel d'Orgeix,
Guy Laurent, and
Anne Quillet-Mary
From Equipe Propre de l'Institut National de la
Santé et de la Recherche Médicale (INSERM) E9910, Institut
Claudius Régaud, Toulouse, France.
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  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.
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