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Blood, 15 July 2001, Vol. 98, No. 2, pp. 405-413
NEOPLASIA
Mitochondrial membrane sensitivity to depolarization in acute
myeloblastic leukemia is associated with spontaneous in vitro
apoptosis, wild-type TP53, and vicinal thiol/disulfide
status
Monica Pallis,
Martin Grundy,
Julie Turzanski,
Reinhard Kofler, and
Nigel Russell
From the Division of Haematology, University of
Nottingham and Nottingham City Hospital, United Kingdom; and the
Institute of General and Experimental Pathology and Tyrolean Cancer
Research Institute, Innsbruck, Austria.
Nonresponse to remission-induction chemotherapy, which remains a
major problem in acute myeloblastic leukemia (AML), has been linked to
cellular resistance to apoptosis. Because the apoptosis induced
by chemotherapeutic drugs is mediated by loss of mitochondrial transmembrane potential (MTP), it was postulated that sensitivity to
mitochondrial membrane depolarization might be heterogeneous in AML.
Using the uncoupling agent carbonyl cyanide m-chlorophenylhydrazone (mClCCP), the mitochondrial membrane sensitivity to depolarization (mClCCP concentrations that inhibit 50% of the transmembrane potential [IC50]) in AML blasts was measured and demonstrated
marked interclonal heterogeneity, with the existence of
comparatively sensitive (median mClCCP IC50, 4 µM) and
resistant (median mClCCP IC50, 10 µM) clones. Furthermore, the mClCCP IC50 was inversely associated with
spontaneous in vitro apoptosis (P = .001). It was high in
cases with mutant TP53 and correlated with the total cellular level of
the multidrug resistance-associated protein (P = .019)
but not of bcl-2, bax, or bcl-x. It was also found that the dithiol
oxidant diamide, in contrast to the monovalent thiol oxidant diethyl
maleate, increased the sensitivity of mitochondrial membranes to
mClCCP. To confirm that TP53 directly affects MTP in leukemic cells and
to establish the role of vicinal thiol oxidation in the TP53-dependent
pathway, CEM 4G5 leukemia cells with forced, temperature-dependent
expression of TP53 were studied. Monobromobimane, which inhibits
mitochondrial membrane depolarization by preventing dithiol
cross-linking, inhibited depolarization and apoptosis in 4G5
cells. It was concluded that in leukemia, TP53 and vicinal
thiol/disulfide status are determinants of mitochondrial membrane
sensitivity to depolarization, which is in turn associated with
spontaneous apoptosis.
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