Efectos De Los Medios De Comunicaión

Pathogenetic, Clinical, and Prognostic Features of Adult t(4;11)(q21;q23)/MLL-AF4 Positive B-Cell Acute Lymphoblastic Leukemia
1. Introduction
The chromosomal translocation occurring between the band 21 of the long arm of chromosome 4 and band 23 of the long arm of chromosome 11 [t(4;11)(q21;q23)] and leading to the generation of the fusion gene MLL-AF4 is one of the most recurrent chromosomalaberrations observed in acute lymphoblastic leukemia (ALL). However, a diagnosis of t(4;11)(q21;q23)/MLL-AF4 positive ALL in adult patients is a rare event, considering the relative low incidence of ALL in adult population. In spite of its rarity, this form of leukemia is of clinical interest because it is universally recognized as a unique and separate biological entity with characteristicimmunophenotypic and clinical features. Here, we briefly describe pathogenetic, clinical, and prognostic characteristics of adult t(4;11)(q21;q23)/MLL-AF4 positive ALL and review the therapeutic approaches proposed for its treatment by most of the important cooperative groups worldwide.
2. Pathogenetic Aspects of MLL Rearrangements
Mixed-Lineage-Leukemia (MLL) gene is one of the most frequentlyinvolved genes in hematologic malignancies, in particular in some forms of acute leukemia, both lymphoblastic and myeloid; the Atlas of Genetics Oncology (http://atlasgeneticsoncology.org/Anomalies/11q23ID1030.html) reports 73 recurrent translocations and 54 chromosome loci as partner site of reciprocal translocations involving the band 23 of the long arm of chromosome 11 (11q23), inparticular MLL gene. The MLL gene, located on 11q23, is the mammalian counterpart of Drosophila trithorax that plays an essential role in positive regulation of gene expression in early embryonic development and hematopoiesis (i.e., Polycomb andHox genes) [1]. MLL encodes a 500kD protein that contains multiple conserved functional domains including three AT hooks (near the N-terminal portion of MLL), four central zincfinger domains, and 210-aminoacid C-terminal SET domain. The last is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation [2]. MLL localization and stabilization depend on a proteolytic post-translational process activated by taspase1, a specialized protease cleaving the MLL proteininto N-terminal 320kD (MLLn) and C-terminal 180kD (MLLc) fragments. These fragments are responsible for the transcriptional regulation of specific target genes, including many of the HOX genes, that are key regulators of normal and malignant hematopoiesis [3].
Several chromosomal aberrations can occur to the MLL gene, with two main action mechanisms: reciprocal translocations, resulting inin-frame fusion transcripts with various partner genes, and partial tandem duplication (PTD) of gene [4]. MLL gene translocations result in a chimeric fusion protein in which the N-terminal portion of the MLL gene is fused to the C-terminal portion of the gene fusion partners; the methyltransferase domain of MLL (SET domain) is invariably lost in MLL-fusion protein. These fusion genes may alter thenormal cellular proliferation and differentiation processes, favoring leukemogenesis [5]. Several studies demonstrated that 11q23 is susceptible to double strand breaks resulting from inhibition of topoisomerase II [6]; this specific susceptibility can explain the high incidence of MLL aberrations occurring in secondary acute leukemias (i.e., therapy-related acute myeloid leukemia, especially aftertreatment with topoisomerase II inhibitors). Two distinct breakpoint cluster regions in theMLL gene could be distinguished: bcr1 and bcr2. Bcr1 encompasses approximately 3.5kb from the start of intron 8 up to the first approximately 600bp of intron 11, and bcr2 included approximately 200bp immediately at the 5' boundary of exon 12. Ninety-five percent of breaks occurred within these 2 regions...