We recently reported an internal tandem duplication of the receptor-type tyrosine kinases (RTKs), 8,9 ses were also performed to reveal the time when the mutation duplication transformed to overt leukemia within a few months.emerged. Together with the FLT3 mutation, chromosome fin-
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/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...
Summary. We applied the International Prognostic Scoring System (IPSS) to our series of 118 patients with myelodysplastic syndrome (MDS) to determine its validity, and also used univariate and multivariate analyses to evaluate the prognostic significance of TP53 configurations. Sixteen patients with the mutation had a strikingly worse prognosis and the multivariate analysis demonstrated that this alteration was the most significant factor. The prognostic comparison between patients with and without the mutation within each IPSS subgroup showed a significant difference in the intermediate subgroups. A combination of clinical manifestations and genetic configurations provided us with more accurate prognostic information in MDS patients.
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