Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse

Scott H. Kaufmann, Judith Karp, Phyllis A. Svingen, Stan Krajewski, Philip J. Burke, Steven D. Gore, John C. Reed

Research output: Contribution to journalArticle

Abstract

Bcl-2, Bcl-x(L), 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 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 hone marrow samples harvested from 123 adult AML patients and 36 adult ALL patients before initial antileukemic therapy. Levels of Bcl-2, Mcl-1, Bcl- x(L), 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 greeter then 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 end 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 end 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 contra 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-x(L) (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 e variety of chemotherapeutic agents, raise the possibility that some chemotherapeutic regimens might select for leukemia cells with elevated levels of this particular apoptosis inhibitor.

Original languageEnglish (US)
Pages (from-to)991-1000
Number of pages10
JournalBlood
Volume91
Issue number3
StatePublished - Feb 1 1998
Externally publishedYes

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Recurrence
Peptides
Apoptosis
bcl-2-Associated X Protein
Chemotherapy
Leukemia
Cells
Immunoblotting
Bone Marrow
Drug Therapy
Cell Line
Therapeutics

ASJC Scopus subject areas

  • Hematology

Cite this

Kaufmann, S. H., Karp, J., Svingen, P. A., Krajewski, S., Burke, P. J., Gore, S. D., & Reed, J. C. (1998). Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood, 91(3), 991-1000.

Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. / Kaufmann, Scott H.; Karp, Judith; Svingen, Phyllis A.; Krajewski, Stan; Burke, Philip J.; Gore, Steven D.; Reed, John C.

In: Blood, Vol. 91, No. 3, 01.02.1998, p. 991-1000.

Research output: Contribution to journalArticle

Kaufmann, SH, Karp, J, Svingen, PA, Krajewski, S, Burke, PJ, Gore, SD & Reed, JC 1998, 'Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse', Blood, vol. 91, no. 3, pp. 991-1000.
Kaufmann SH, Karp J, Svingen PA, Krajewski S, Burke PJ, Gore SD et al. Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood. 1998 Feb 1;91(3):991-1000.
Kaufmann, Scott H. ; Karp, Judith ; Svingen, Phyllis A. ; Krajewski, Stan ; Burke, Philip J. ; Gore, Steven D. ; Reed, John C. / Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. In: Blood. 1998 ; Vol. 91, No. 3. pp. 991-1000.
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