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Elevated Expression of the Apoptotic Regulator Mcl-1 at the Time
of Leukemic Relapse
Scott H. Kaufmann,
Judith E. Karp,
Phyllis A. Svingen,
Stan Krajewski,
Philip J. Burke,
Steven D. Gore, and
John C. Reed
From the Division of Oncology Research, Mayo Clinic, Rochester, MN;
Greenebaum Cancer Center, University of Maryland Medical Systems,
Baltimore, MD; Burnham Institute, La Jolla, CA; and Adult Leukemia
Program, Johns Hopkins Oncology Center, Baltimore, MD.
Bcl-2, Bcl-xL, and Mcl-1 are three related intracellular
polypeptides that have been implicated as negative regulators of apoptosis. In contrast, the partner protein Bax acts as a positive regulator of apoptosis. Based on the observation that all four of these
polypeptides are expressed in a variety of acute myelogenous leukemia
(AML) and acute lymphocytic leukemia (ALL) cell lines, cellular levels
of these polypeptides were examined by immunoblotting in bone marrow
samples harvested from 123 adult AML patients and 36 adult ALL patients
before initial antileukemic therapy. Levels of Bcl-2, Mcl-1,
Bcl-xL, and Bax each varied over a more than 10-fold range
in different pretreatment leukemia specimens. When the 54 AML and 23 ALL samples that contained greater than 80% malignant cells were
examined in greater detail, it was observed that pretreatment levels of
Bcl-2 and Mcl-1 correlated with each other (R = .44,
P < .001 for AML and R = .79,
P < .0001 for ALL). In addition, a weak negative
correlation between Bax expression and age was observed in AML samples
(R =  0.35, P < .02) but not ALL samples. There was
no relationship between pretreatment levels of these polypeptides and
response to initial therapy. However, examination of 19 paired samples
(the first harvested before chemotherapy and the second harvested 23 to
290 days later at the time of leukemic recurrence) revealed a greater
than or equal to twofold increase in Mcl-1 levels in 10 of 19 pairs (7 of 15 AML and 3 of 4 ALL) at recurrence. In contrast, 2 of 19 pairs
contained twofold less Mcl-1 at the time of recurrence. Approximately
equal numbers of samples showed twofold increases and decreases in
Bcl-2 (5 increases, 3 decreases) and Bcl-xL (1 increase, 4 decreases) at recurrence. Bax levels did not show a twofold decrease in
any patient. These results, coupled with recent observations that cells
overexpressing Mcl-1 are resistant to a variety of chemotherapeutic
agents, raise the possibility that some chemotherapeutic regimens might
select for leukemia cells with elevated levels of this particular
apoptosis inhibitor.
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 991-1000
© 1998 by The American Society of Hematology.
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