The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications
Introduction
Acute leukemia is a heterogeneous disease that is classified based on the presence of specific cytogenetic abnormalities as well as the morphology according to French–American–British (FAB) classification and immunophenotype of the leukemic cells [1], [2], [3]. Each chromosomal change and its molecular abnormality identify the distinct subgroup with predictable clinical features and therapeutic outcomes [4], [5], [6], [7]. The genes associated with these chromosomal translocations in leukemias frequently encode transcription factors that play pivotal roles in normal hematopoietic cell development [8], [9]. One of the most frequent chromosome abnormalities in acute myeloblastic leukemias (AMLs) is t(8;21)(q22;q22) [10], [11]. AML1/RUNX1 was initially identified as a gene in the breakpoint of the t(8;21) [12]. AML1 was subsequently shown to encode the α subunit of heterodimeric transcription factor polyomavirus enhancer binding protein 2 (PEBP2), also known as core binding factor (CBF), which contained a domain with a high homology to the Drosophila melanogaster pair-rule segmentation gene, runt [12], [13], [14], [15], [16], [17]. AML1 binds to the consensus DNA sequence TGT/cGGT, which is present in a number of promoters and enhancers of viral and cellular genes, through its Runt domain. Its affinity for DNA is increased by heterodimerization through the Runt domain with a β subunit called PEBP2β/CBFβ [14], [15], [16], [17]. AML1 is normally expressed in all lineages of hematopoietic cells and acts as a regulator of the expression of various genes specific to hematopoiesis [18], [19], [20], [21]. Furthermore, targeting mice lacking either Aml1 or Pebp2β/Cbfβ are embryonic lethal due to the complete absence of fetal liver hematopoiesis, indicating that AML1/PEBP2β is essential for definitive hematopoiesis of all lineages [22], [23], [24], [25], [26].
Subsequent studies have revealed that the genes encoding this transcription factor complex is frequently involved in other distinct chromosomal translocations associated with human leukemias (Fig. 1). AML1 is altered by the t(12;21)(p13;q22) in pediatric acute lymphoblastic leukemia (ALL) [27], [28] and by several rare translocations in AML [29], [30], [31]. PEBP2β has also been demonstrated to be the target of the inv(16)(p13q22) in AML with FAB M4Eo morphology [1], [32], [33], [34], [35]. Although these leukemias represent a wide range of clinical features, morphologic and immunologic phenotype, the recurrent involvement of the AML1/PEBP2β complex in leukemias suggests underlying pathogenesis. Each of these translocations generates fusion proteins that retain the Runt domain and are predicted to interfere with the normal activity of AML1/PEBP2β. How do the leukemia-associated fusion proteins perturb the normal function of AML1 and contribute to leukemogenesis? In this review, current understanding of the role of the AML1 in leukemogenesis will be summarized.
Section snippets
Structure and function of the AML1
PEBP2/CBF was first identified and purified based on its ability to interact with the enhancer core sites of polyomavirus or Molony murine leukemia virus [36], [37]. PEBP2 is a Runt domain family of heterodimeric transcription factors containing a common PEBP2β subunit and one of three PEBP2α subunits [14], [15], [16], [17], [38], [39]. The nomenclature committee of the Human Genome Organization has recently adopted the following symbols to designate the genes for Runt-related transcription
AML1 as a key regulator of hematopoiesis
The development of the hematopoietic system is regulated by a series of transcription factors that control both the generation of hematopoietic stem cells and the lineage commitment and differentiation of the progenitor cells. The first blood cells, which arise from the extraembryonic lateral plate, appear in the yolk sac of mouse embryos and are primarily primitive nucleated erythrocytes and macrophages [111]. This first transient wave of primitive hematopoiesis is followed shortly thereafter
AML1 involved in several types of acute leukemia with chromosome translocation
The AML1 gene has been noted for its frequent involvement in chromosomal translocations associated with leukemia (Fig. 1). The translocations involving AML1 produce chimeric proteins such as AML1-MTG8 (ETO) in de novo AML with t(8;21)(q22;q22) [12], [125], [126] and TEL (ETV6)-AML1 in pediatric ALL with t(12;21)(p13;q22) [27], [28] (Fig. 2). AML1 also contributes to fusion genes produced by t(3;21)(q26;q22) and t(16;21)(q24;q22) in therapy-related leukemia (TRL) and acute transformation from
Mutations of the AML1 gene also involved in leukemia
Several isoforms of the AML1 proteins, including AML1a, AML1b, AML1c and AML1ΔN are produced by alternative splicing [48], [49], [50]. AML1a that lacks a transactivation domain has a higher DNA-binding affinity, but cannot activate transcription. These isoforms could lead to profound changes in the transcriptional activity of AML1. Transfected AML1a suppresses G-CSF-induced differentiation and stimulates proliferation of 32Dcl3 cells, but AML1b exhibits antagonistic effects [49]. Furthermore,
AML1 as a new therapeutic target in leukemia
Approximately 60% of patients with AML associated with t(8;21) or inv(16) who are treated with antileukemic agents have achieved long-term remission, compared with a 30% in remaining AML [6], [7], [34]. Pediatric patients with PBC-ALL carrying t(12;21) have approximately 95% chance for achieving long-term remission, compared with 70% for the remainder [19]. Antimetabolic agents such as cytosine arabinoside may induce a pathway leading to apoptosis, which is more active in leukemia cells having
Conclusions
AML1 fusion proteins as a consequence of chromosomal translocations associated with leukemias function as a transcriptional repressor. AML1-MTG8 maintains the DNA-binding Runt domain, but the C-terminal HAT interacting region of AML1 has been replaced by the coding sequence of MTG8 including its self-association and nuclear corepressor interacting regions. AML1 fusion proteins interact with N-CoR and mSin3, which are required for recruitment of the HDACs, and induce transcriptional repression
Reviewers
Misao Ohki, PhD, Cancer Genomics Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Dr Alan D. Friedman, Cancer Research Building, Room 255, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
Acknowledgments
The author is very grateful to Drs Y. Ito, K. Shigesada, M. Osato, H.S. Scott, H. Mitsuya, and all contributors to this work for their kind help. This work is supported in part by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science and Culture, Grants-in-Aid for Cancer Research from Japanese Ministry of Health and Welfare.
Norio Asou received his MD and PhD from Kumamoto University School of Medicine, Kumamoto, Japan. He is presently Associate Professor at the Department of Internal Medicine II, Kumamoto University School of Medicine. His research focuses on the pathogenesis and treatment of human leukemias.
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Norio Asou received his MD and PhD from Kumamoto University School of Medicine, Kumamoto, Japan. He is presently Associate Professor at the Department of Internal Medicine II, Kumamoto University School of Medicine. His research focuses on the pathogenesis and treatment of human leukemias.