Date Published: November 15, 2011
Publisher: Hindawi Publishing Corporation
Author(s): F. Marchesi, K. Girardi, G. Avvisati.
Translocation t(4;11)(q21;q23) leading to formation of MLL-AF4 fusion gene is found in about 10% of newly diagnosed B-cell acute lymphoblastic leukemia (ALL) in adult patients. Patients expressing this chromosomal aberration present typical biological, immunophenotypic, and clinical features. This form of leukemia is universally recognized as high-risk leukemia and treatment intensification with allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) could be a valid option to improve prognosis, but data obtained from the literature are controversial. In this review, we briefly describe pathogenetic, clinical, and prognostic characteristics of adult t(4;11)(q21;q23)/MLL-AF4 positive ALL and provide a review of the clinical outcome reported by the most important cooperative groups worldwide.
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 chromosomal aberrations 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 characteristic immunophenotypic 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.
Mixed-Lineage-Leukemia (MLL) gene is one of the most frequently involved 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), in particular 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 and Hox genes) . MLL encodes a 500 kD protein that contains multiple conserved functional domains including three AT hooks (near the N-terminal portion of MLL), four central zinc finger 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 . MLL localization and stabilization depend on a proteolytic post-translational process activated by taspase1, a specialized protease cleaving the MLL protein into N-terminal 320 kD (MLLn) and C-terminal 180 kD (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 .
t(4;11)(q21;q23)/MLL-AF4 positive adult ALL remains an attractive leukemic subtype because of special pathogenetic and clinical aspects with respect to the other ALL forms. Prognosis of this form of ALL in adults patients remains poor despite several ongoing clinical and biological studies to improve clinical outcome. One of the most important questions in this setting remains the role of HSCT as consolidation treatment in first CR; even though this approach is the most used [52, 57], data obtained by international cooperative groups worldwide are controversial.