Role of myeloid cell factor-1 (Mcl-1) in chronic lymphocytic leukemia.
The primary abnormality in chronic lymphocytic leukemia (CLL) is a defect in apoptosis, probably related to alterations in the expressions of Bcl-2 family members. In transgenic mice over expressing the anti-apoptotic Bcl-2 family member, myeloid cell factor-1 (Mcl-1), B cell lymphomas occur. Moreover, mice conditional for the loss of Mcl-1 display a profound reduction in B and T lymphocytes. This suggests that Mcl-1 is an essential survival factor in lymphocytes. In the present study, we have evaluated the role of Mcl-1 in CLL. Mcl-1 protein expression was measured by Western blot analysis in the CLL cells of 45 patients and correlated with clinical variables and survival. Mcl-1 levels were similar in 29 patients to normal B and T lymphocytes, were decreased in 8 patients and increased in 12 patients. An inverse correlation was found between Mcl-1 expression and Rai stage (P = 0.001). When assessed by flow cytometry, Mcl-1 expressions were normally distributed among CLL cells in individual patients and the mean levels correlated with those obtained by Western blotting. To evaluate the role of Mcl-1 in drug resistance, Mcl-1 levels were sequentially measured in the leukemic cells of 4 CLL patients during therapy with fludarabine (Flu). The Mcl-1 levels were found to increase in 2 patients while the peripheral blood lymphocyte counts dropped, suggesting that the residual drug-resistant cells had the highest Mcl-1 levels. Primary CLL cells were also treated with chlorambucil (CLB) or Flu in vitro and the Mcl-1 levels decreased correlating with the sensitivity of these cells to undergo apoptosis. Drug sensitivities of the CLL cells to CLB and Flu were also measured by MTT assay and the concentrations of drug required to decrease cell viability by 50% (IC50) varied from 1.9 to 9.27 microM for Flu (median, 9.4 microM) and 10 to 32.5 microM (median, 5.5 microM) for CLB. The sensitivities of the leukemic cells to CLB correlated inversely with Mcl-1 levels (P < 0.05). These results suggest that Mcl-1 may contribute to cell survival in CLL.
Johnston
James B
JB
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg R3E 0V9, Canada.
Paul
James T
JT
Neufeld
Nathan J
NJ
Haney
Neil
N
Kropp
Dianne M
DM
Hu
Xiaojie
X
Cheang
Mary
M
Gibson
Spencer B
SB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002699:Chlorambucil / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000502:physiology*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D002699:Chlorambucil; D014740:Vidarabine; C024352:fludarabine