It has been well established that a number of transcription factors play critical roles in regulating the fate of hematopoietic stem cell populations. One of them is the leukemia-associated transcription factor acute myeloid leukemia 1 (AML1; also known as runt-related transcription factor 1, or RUNX1). This gene was originally cloned from the breakpoint of the t(8;21) reciprocal chromosome translocation and was later recognized as one of the most frequent targets of leukemia-associated gene aberrations. Gene-targeting experiments revealed that transcriptionally active AML1 is essential for the establishment of definitive hematopoiesis. More specifically, this gene functions in the emergence of the hematopoietic progenitor cells from the hemogenic endothelium by budding in the aorta-gonad-mesonephros region, and its expression points to the sites with strong potential for the emergence of hematopoietic stem cells. This review discusses aspects of the biologic properties of AML1 in early hematopoietic development.
AML1 is one of the most frequently mutated genes associated with human acute leukemia and encodes the DNA-binding subunit of the heterodimering transcriptional factor complex, core-binding factor (CBF) (or polyoma enhancer binding protein 2 [PEBP2]). A null mutation in either AML1 or its dimerizing partner, CBF, results in embryonic lethality secondary to a complete block in fetal liver hematopoiesis, indicating an essential role of this transcription complex in the development of definitive hematopoiesis. The hematopoietic phenotype that results from the loss of AML1 can be replicated in vitro with a two-step culture system of murine embryonic stem (ES) cells. Using this experimental system, we now demonstrate that this hematopoietic defect can be rescued by expressing the PEBP2␣B1 (AML1b) isoform under the endogenous AML1-regulatory sequences through a knock-in (targeted insertion) approach. Moreover, we demonstrate that the rescued AML1؊/؊ ES cell clones contribute to lymphohematopoiesis within the context of chimeric animals. Rescue requires the transcription activation domain of AML1 but does not require the C-terminal VWRPY motif, which is conserved in all AML1 family members and has been shown to interact with the transcriptional corepressor, Groucho/transducin-like Enhancer of split. Taken together, these data provide compelling evidence that the phenotype seen in AML1-deficient mice is due solely to the loss of transcriptionally active AML1.Hematopoietic development in mammals is supported by two discrete cellular populations which are believed to be derived from distinct cellular origins (5, 22). In the mouse, for example, the first wave of primitive hematopoiesis emerges around day 7.5 postcoitus (E 7.5) in the yolk sac and consists primarily of large nucleated primitive erythrocytes, which diminish midgestation. By contrast, around E 9.5, the second wave of hematopoiesis emerges in the fetal liver and consists of so-called definitive hematopoietic cells, including enucleated erythrocytes containing adult-type globin molecules, myeloid cells, and lymphoid progenitors. The site of this second wave of hematopoiesis is subsequently shifted to the bone marrow and spleen prior to birth.Recent studies have revealed that a number of transcriptional factors play critical roles in regulating the fate of the hematopoietic stem cell populations. These factors are divided into two groups: one contains factors which regulate both primitive and definitive hematopoiesis, and the other contains factors whose activities are required for the development of some or all of the definitive hematopoietic lineages (reviewed in reference 44). The acute myeloid leukemia (AML) 1 gene, AML1, belongs to the latter group and is unique in that loss of this gene in mice results in the complete absence of all definitive hematopoietic lineages (37, 51).AML1 was originally cloned from the breakpoint of chromosome 21 in t(8;21)(q22;q22), which is associated with 40% of the AML cases of the French-British-American classification M2 subt...
AML1/Runx1 is a frequent target of leukemia-associated gene aberration, and it encodes a transcription factor essential for definitive hematopoiesis. We previously reported that the AML1 molecules with trans-activation subdomains retained can rescue in vitro hematopoietic defects of AML1-deficient mouse embryonic stem (ES) cells when expressed by using a knock-in approach. Extending this notion to in vivo conditions, we found that the knock-in ES cell clones with AML1 mutants, which retain trans-activation subdomains but lack C-terminal repression subdomains including the conserved VWRPY motif, contribute to hematopoietic tissues in chimera mice. We also found that germline mice homozygous for the mutated AML1 allele, which lacks the VWRPY motif, exhibit a minimal effect on hematopoietic development, as was observed in control knock-in mice with full-length AML1. On the other hand, reduced cell numbers and deviant CD4 expression were observed during early T-lymphoid ontogeny in the VWRPY-deficient mice, whereas the contribution to the thymus by the corresponding ES cell clones was inadequate. These findings demonstrate that AML1 with its trans-activating subdomains is essential and sufficient for hematopoietic development in the context of the entire mouse. In addition, its transrepression activity, depending on the Cterminal VWRPY motif, plays a role in early thymocyte development. IntroductionVertebrate hematopoietic development is characterized by the sequential appearance of two cell populations, further defined as primitive and definitive hematopoiesis. 1 In mice, for example, primitive hematopoiesis is first seen in the form of blood islands in the yolk sac of the 7.5-day-old (E7.5) mouse embryo. It is thought that this cell population is directly differentiated from hemangioblasts, a bipotent precursor. Primitive hematopoiesis consists predominantly of a large and nucleated erythroid population containing embryonic-type hemoglobin. In contrast to the restricted and temporal development of this first wave, which diminishes at midgestation, definitive hematopoiesis originates from the aorta-gonad-mesonephros (AGM) region, where stem cells with long-term repopulating ability of multilineage hematopoiesis emerge at approximately E9.5, as a result of budding, from the ventral endothelial cells of the great vessels. 2,3 The stem cells then migrate into the fetal liver and proliferate to rapidly establish the definitive hematopoiesis of all lineages, including progenitors for T-and B-lymphoid populations. Active sites for definitive hematopoiesis are transferred to bone marrow and spleen before birth and function throughout life within these organs.These stem cells are equipped with a number of critical transcription factors that play pivotal roles in determining the fate of the cells at discrete developmental stages. Most of these molecules have been identified by isolating DNA-binding proteins to known cis-regulatory elements of lineage-specific genes or by cloning the DNA targets of leukemia-associated chrom...
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