%0 Journal Article
%T Wnt/£¿-Catenin: A New Therapeutic Approach to Acute Myeloid Leukemia
%A Y. Kim
%A S. Thanendrarajan
%A I. G. H. Schmidt-Wolf
%J Leukemia Research and Treatment
%D 2011
%I Hindawi Publishing Corporation
%R 10.4061/2011/428960
%X Recent studies have shown genetic and epigenetic aberrations resulting in aberrant activation of the Wingless-Int (Wnt) pathway, thus influencing the initiation and progression of acute myeloid leukemia (AML). Of major importance, these findings may lead to novel treatment strategies exploiting targeted modulation of Wnt signaling. This paper comprises the latest status of knowledge concerning the role of Wnt pathway alteration in AML and outlines future lines of research and their clinical perspectives. 1. Acute Leukemia Acute myeloid leukemia (AML), a hematologic malignancy of the myeloid line of white blood cells in the bone marrow, is the most common leukemia of the adult [1, 2]. Despite major progress in the treatment of AML during the last couple of years, the majority of patients still cannot be cured. Different genetic causes result in variable clinical courses of AMLs and different responses to standard chemotherapy including stem cell transplant [1, 3, 4]. Due to high mortality rates and high relapse rates even among transplanted patients, new therapeutic strategies are required [4, 5]. The Wingless-Int (Wnt)/beta-catenin pathway has been shown to play an essential role in the regulation of cell proliferation, differentiation, and apoptosis of haematopoietic stem cells [1, 2, 4, 5]. Recently, it was demonstrated that deregulation of this pathway resulted in different malignancies including AML. Thus, Wnt/beta-catenin signaling molecules are attractive candidates for developing novel targeted therapies for this disease [1¨C4, 6]. 2. Wnt Signaling Pathway Wnt (wingless) proteins constitute a family of cysteine-rich glycosylated proteins that contribute to lymphopoiesis and early stages of both B-cell and T-cell development [7¨C10]. They function as extracellular signaling molecules that may activate the Wnt/beta-catenin signaling pathway by binding to the extracellular domain of Frizzled receptors. In addition to their extracellular Wnt-binding domain, Frizzled receptors have seven transmembrane-spanning sequences and a C-terminal tail [10¨C12]. Wnt proteins regulate cell proliferation, cell morphology, cell motility, and cell fate. To date, 19 Wnt members have been identified in humans and more than eight mammalian Frizzled genes are known [11¨C13]. Wnt signaling results in the activation of intracellular signaling cascades which are associated with several forms of cancer [11, 14]. Binding of Wnt either to Frizzled and the low-density lipoprotein receptor-related proteins (LRPs) 5 and 6 or to Frizzled protein alone results in the stabilization of
%U http://www.hindawi.com/journals/lrt/2011/428960/