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.

[1]  S. Korsmeyer,et al.  Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1 , 2003, Nature.

[2]  E. Henson,et al.  Increased expression of Mcl‐1 is responsible for the blockage of TRAIL‐induced apoptosis mediated by EGF/ErbB1 signaling pathway , 2003, Journal of cellular biochemistry.

[3]  Dylan T. Jones,et al.  Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis. , 2003, Blood.

[4]  C. Fegan,et al.  The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. , 2003, Blood.

[5]  G. Schuurhuis,et al.  Multiparameter flow cytometric quantification of apoptosis-related protein expression , 2003, Leukemia.

[6]  Bin Zhang,et al.  IL-6-independent expression of Mcl-1 in human multiple myeloma , 2003, Oncogene.

[7]  J. Bae,et al.  Tankyrase 1 Interacts with Mcl-1 Proteins and Inhibits Their Regulation of Apoptosis* , 2003, The Journal of Biological Chemistry.

[8]  T. McDonnell,et al.  Expression of Mcl‐1 in mantle cell lymphoma is associated with high‐grade morphology, a high proliferative state, and p53 overexpression , 2003, The Journal of pathology.

[9]  D. Weidner,et al.  Physical and Functional Interaction between Myeloid Cell Leukemia 1 Protein (MCL1) and Fortilin , 2002, The Journal of Biological Chemistry.

[10]  A. Anel,et al.  Role of caspases and apoptosis-inducing factor (AIF) in cladribine-induced apoptosis of B cell chronic lymphocytic leukemia , 2002, Leukemia.

[11]  T. Kipps,et al.  Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1. , 2002, Blood.

[12]  Axel Benner,et al.  Stromal-derived factor 1 inhibits the cycling of very primitive human hematopoietic cells in vitro and in NOD/SCID mice. , 2002, Blood.

[13]  D. Oscier,et al.  Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. , 2002, Blood.

[14]  R. Craig.  MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis , 2002, Leukemia.

[15]  I. Gojo,et al.  Myeloid cell factor-1 is a critical survival factor for multiple myeloma. , 2002, Blood.

[16]  E. Henson,et al.  Epidermal growth factor protects epithelial-derived cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by inhibiting cytochrome c release. , 2002, Cancer research.

[17]  L. Bullinger,et al.  VH mutation status , CD 38 expression level , genomic aberrations , and survival in chronic lymphocytic leukemia , 2002 .

[18]  David Botstein,et al.  Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia , 2001, The Journal of experimental medicine.

[19]  P. Feugier,et al.  Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. , 2001, Blood.

[20]  J. Weinberg,et al.  Use of serum-free media to minimize apoptosis of chronic lymphocytic leukemia cells during in vitro culture , 2001, Leukemia.

[21]  C. Fegan,et al.  Flavopiridol circumvents Bcl‐2 family mediated inhibition of apoptosis and drug resistance in B‐cell chronic lymphocytic leukaemia , 2001, British journal of haematology.

[22]  R. Gascoyne,et al.  MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. , 2001, Blood.

[23]  E. Yeh,et al.  Regulation of Apoptosis and Cell Cycle Progression by MCL1 , 2000, The Journal of Biological Chemistry.

[24]  B. Cheson,et al.  Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. , 2000, The New England journal of medicine.

[25]  J. Binet,et al.  When and how to treat chronic lymphocytic leukemia. , 2000, The New England journal of medicine.

[26]  M. Hengartner.  The biochemistry of apoptosis , 2000, Nature.

[27]  John Calvin Reed,et al.  Protein Kinase Inhibitors Flavopiridol and 7-hydroxy-staurosporine Down-regulate Antiapoptosis Proteins in B-cell Chronic Lymphocytic Leukemia , 2022 .

[28]  D. Rose,et al.  Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. , 2000, Blood.

[29]  D. Spiller,et al.  Apoptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells. , 2000, Blood.

[30]  F. Cotter,et al.  Antisense‐mediated suppression of Bcl‐2 highlights its pivotal role in failed apoptosis in B‐cell chronic lymphocytic leukaemia , 1999, British journal of haematology.

[31]  E. Montserrat,et al.  In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia. , 1999, Blood.

[32]  Min-Liang Kuo,et al.  The Antiapoptotic Gene mcl-1 Is Up-Regulated by the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway through a Transcription Factor Complex Containing CREB , 1999, Molecular and Cellular Biology.

[33]  T J Hamblin,et al.  B-cell chronic lymphocytic leukemia: a bird of a different feather. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  N. Chiorazzi,et al.  Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. , 1999, Blood.

[35]  C. Croce,et al.  Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. , 1998, Blood.

[36]  John Calvin Reed,et al.  Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. , 1998, Blood.

[37]  C. Pepper,et al.  Elevated Bcl-2/Bax are a consistent feature of apoptosis resistance in B-cell chronic lymphocytic leukaemia and are correlated with in vivo chemoresistance. , 1998, Leukemia & lymphoma.

[38]  N. Fotouhi,et al.  Relationship between nitrogen mustard drug resistance in B-cell chronic lymphocytic leukemia (B-CLL) and protein expression of Bcl-2, Bax, Bcl-X and p53. , 1997, Cancer letters.

[39]  G. Kroemer.  The proto-oncogene Bcl-2 and its role in regulating apoptosis , 1997, Nature Medicine.

[40]  A. Fornace,et al.  Induction of BCL2 family member MCL1 as an early response to DNA damage , 1997, Oncogene.

[41]  K. Lee,et al.  P53, MDM-2, BAX and BCL-2 and drug resistance in chronic lymphocytic leukemia. , 1997, Leukemia & lymphoma.

[42]  J. Johnston,et al.  Chlorambucil in chronic lymphocytic leukemia: mechanism of action. , 1996, Leukemia & lymphoma.

[43]  M. Grever,et al.  National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. , 1996, Blood.

[44]  R. Craig,et al.  MCL‐1, a member of the BCL‐2 family, is induced rapidly in response to signals for cell differentiation or death, but not to signals for cell proliferation , 1996, Journal of cellular physiology.

[45]  T. McDonnell,et al.  Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. , 1996, Leukemia.

[46]  K. Lee,et al.  Comparison of antitumor activities of 2-chlorodeoxyadenosine and 9-beta-arabinosyl-2-fluoroadenine in chronic lymphocytic leukemia and marrow cells in vitro. , 1995, Leukemia.

[47]  R. Craig,et al.  The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2 , 1995, The Journal of cell biology.

[48]  R. Gascoyne,et al.  Immunohistochemical analysis of Mcl-1 and Bcl-2 proteins in normal and neoplastic lymph nodes. , 1994, The American journal of pathology.

[49]  R. Craig,et al.  MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[50]  John Calvin Reed,et al.  bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. , 1993, Blood.

[51]  S. Molica,et al.  Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia , 1987, Cancer.

[52]  D C Case,et al.  Clinical staging of chronic lymphocytic leukemia. , 1977, The Journal of the Maine Medical Association.