The biology of chronic myeloid leukemia.

Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
New England Journal of Medicine (Impact Factor: 54.42). 08/1999; 341(3):164-72. DOI: 10.1056/NEJM199907153410306
Source: PubMed
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The BCR-ABL fusion protein is characteristic of chronic myeloid leukaemia and may be an effective tumour-specific antigen. CD8+ T cell responses to BCR-ABL fusion peptides have been reported in normal subjects and CML patients but CD4+ T cell responses have been less well characterised. Here, the 23-mer e14a2 fusion peptide VHSATGFKQSSKALQRPVASDFE has been used to stimulate T cell responses. Most normal subjects and CML patients showed no proliferative responses to this peptide, with stimulation indices not significantly greater than 1.0. Following a second stimulation with the same peptide, small proliferative responses were obtained in normal subjects but not CML patients. These responses were not improved following a third stimulation with 23-mer peptide, nor by using mature autologous dendritic cells to present the peptide. Intracellular interferon-gamma production by CD4+ T cells was also not induced by the 23-mer e14a2 peptide. Hence, this e14a2 peptide does not stimulate CD4+ T cell proliferation in vitro in most normal subjects or CML patients. The precise sequence of amino acids may be critical in defining immunogenicity for CD4+ T cell responses against BCR-ABL peptides.
    Leukemia Research 01/2008; 31(12):1675-81. DOI:10.1016/j.leukres.2007.01.007 · 2.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The human AF-6, a scaffold protein between cell membrane-associated proteins and the actin cytoskeleton, plays an important role in special cell-cell junctions and signal transduction. It can be phosphorylated by the protein kinase Bcr, which allows efficient binding of the C terminus of Bcr to the PDZ domain of AF-6 and consequently enhances the binding affinity of AF-6 to Ras. Formation of the AF-6, Bcr, and Ras ternary complex results in down-regulation of the Ras-mediated signal transduction pathway. To better understand the molecular basis for the recognition of the AF-6 PDZ domain and Bcr, we solve the solution structure of the AF-6 PDZ domain complexed with the C-terminal peptide of Bcr and explore the interactions between them in detail. Compared with previously reported structures, the complex exhibits a noncanonical binding mode of PDZ/peptide. Owing to the distinct residues involved in the AF-6 PDZ domain and Bcr peptide interaction, the interaction mode does not adapt to the existing classification rules that have been put forward, based on the ligand or the PDZ domain specificity. Furthermore, the PDZ domain of AF-6 can bind to the C terminus of Bcr efficiently after phosphorylation of AF-6 by the Bcr kinase. The phosphorylation may induce a conformational change of AF-6, which makes the binding surface on the PDZ domain accessible to Bcr for efficient binding. This study not only characterizes the structural details of the AF-6 PDZ/Bcr peptide complex, but also provides a potential target for future drug design and disease therapy.
    Protein Science 07/2007; 16(6):1053-62. DOI:10.1110/ps.062440607 · 2.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sphingolipids function as bioactive mediators of different cellular processes, mostly proliferation, survival, differentiation and apoptosis, besides being structural components of cellular membranes. Involvement of sphingolipid metabolism in cancerogenesis was demonstrated in solid tumors as well as in hematological malignancies. Herein, we describe the main biological and clinical aspects of leukemias and summarize data regarding sphingolipids as mediators of apoptosis triggered in response to anti-leukemic agents and synthetic analogs as inducers of cell death as well. We also report the contribution of molecules that modulate sphingolipid metabolism to development of encouraging strategies for leukemia treatment. Finally we address how deregulation of sphingolipid metabolism is associated to occurrence of therapy resistance both in vitro and in vivo. Sphingolipids can be considered promising therapeutic tools alone or in combination with other compounds, as well as valid targets in the attempt to eradicate leukemia and overcome drug resistance.
    Biochimica et Biophysica Acta 01/2007; 1758(12):2121-32. DOI:10.1016/j.bbamem.2006.06.016 · 4.66 Impact Factor


Available from