Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells.

DNA methyltransferase 3A (DNMT3A) mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Transplantation studies have elucidated an important role for Dnmt3a in stem cell self-renewal and in myeloid differentiation. Here, we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Mx1-Cre-mediated Dnmt3a ablation led to the development of a lethal, fully penetrant MPN with myelodysplasia (MDS/MPN) characterized by peripheral cytopenias and by marked, progressive hepatomegaly. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. The MDS/MPN induced by Dnmt3a ablation was transplantable, including the marked hepatomegaly. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Gene expression and DNA methylation analyses of progenitor cell populations identified differential regulation of hematopoietic regulatory pathways, including fetal liver hematopoiesis transcriptional programs. These data demonstrate that Dnmt3a ablation in the hematopoietic system leads to myeloid transformation in vivo, with cell-autonomous aberrant tissue tropism and marked extramedullary hematopoiesis (EMH) with liver involvement. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo.

Effects of aging upon the expression of differentiation and class II MHC antigens on the surface of T lymphocytes from normal human subjects.

This study documents differences in the expression of differentiation antigens and Class II MHC encoded antigens on the T and B cells of young, adult, and older healthy humans as measured by their density on the cell surface. Marker densities were calculated by fluorescence intensity vector analysis, using two-color flow cytometry. Relative changes in marker densities with increasing age were calculated by expressing younger group marker density values as 100%. The following statistically significant changes were observed with advancing age: (1) Increased density of HLA-DR markers on CD3+ and CD8+ cells and CD4 markers in the "adult" group (ages > 34 < or = 59 years) (1.5-fold, 0.5-fold, and 0.4-fold increases, respectively) when compared with the "young" group (ages < or = 34 years); (2) decreased density of HLA-DR markers on CD3+ and CD8+ cells and CD8 markers in the "older" group (ages > or = 60 years) (0.2-fold, 0.5-fold, and 0.4-fold decreases, respectively) when compared with the adult group. However, when the "older" group was compared to the young group, the density of HLA-DR markers on CD3 cells and the density of CD4 markers and CD8CD57 markers were significantly higher (1-fold, 0.4-fold, and 0.8-fold) and the CD8 markers were lower (0.4-fold). The size score of individual T cell subsets, as measured by forward light scatter, was uniformly smaller in the older age group when compared with the young group (29.5 +/- 4.0% SD); it was also smaller than in the adult group (16.5 +/- 2.7% SD). These observations may be of relevance to the decreased level of host immunologic responsiveness observed with increasing age.

Current status of immunological monitoring in the renal allograft recipient.

With the appropriate combined use of different immune monitoring techniques, it is possible to derive sensitive diagnostic parameters for the transplant surgeon. However, the core biopsy or cytological examination of the graft continues to represent the gold standard for evaluating the specificity and sensitivity of these methods. With the development of newer monoclonal antibodies and a better understanding of the impact of immune processes on the behavior of various activation linked, T cell associated surface antigens, one may be able to secure further valuable information, with enhanced diagnostic and prognostic accuracy.