Role of Myeloid Cell Factor-1 (Mcl-1) in Chronic Lymphocytic Leukemia

Abstract

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.

Pathway-specific apoptotic gene expression profiling in chronic lymphocytic leukemia and follicular lymphoma

“…MCL1 has been extensively studied and is a BCL2 family protein that has antiapoptotic function. 10 It has been implicated in conferring resistance to chemotherapy in chronic lymphocytic leukemia, [24][25][26] and overexpression of MCL1 promotes tumorigenesis in a transgenic mice model. 27 High levels of MCL1 expression has been found in several types of malignant lymphoma, including anaplastic large cell lymphoma 28 and mantle cell lymphoma.…”

MiR-15a and miR-16-1 cluster functions in human leukemia

“…This signature (which includes Ϸ2% of the down-regulated genes in MEG-01 and Ϸ11% of those repressed in patients) contains oncogenes such as MCL1, JUN, SCAP2, TRA1, PDCD6IP, RAD51C, and HSPA1A/1B, which could explain the oncosuppressor effect of miR-15a/16-1 observed in MEG-01 both in vitro (22),and in vivo (present work). MCL1 is an antiapoptotic BCL-2 family member that contributes to B cell survival in CLL and has been associated with resistance to chemotherapy (35,36). Despite the fact that MCL-1 expression is not different in ZAP 70-positive (aggressive) vs.…”

Upregulation of bfl-1 is a potential mechanism of chemoresistance in B-cell chronic lymphocytic leukaemia

“…However, bfl-1 expression correlated with in vivo response to chlorambucil. Previously, Mcl-1 expression was reported to correlate to in vitro chlorambucilinduced apoptosis but not to fludarabine-induced apoptosis (Johnston et al, 2004). Although both drugs induce apoptosis through a mitochondria-dependent pathway, initiation of the pathway may depend on different mechanisms, which might be selectively counteracted by bfl-1 or mcl-1.…”