Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2r gamma(null) mice carrying a complete null mutation of the cytokine gamma c upon the SCID background. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle-dependent cytotoxic therapy. Global transcriptional profiling identified LS cell-specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.

and 5 The Jackson Laboratory, Bar Harbor, Maine, USA The presence of rare malignant stem cells supplying a hierarchy of malignant cells has recently been reported. In human acute myelogenous leukemia (AML), the leukemia stem cells (LSCs) have been phenotypically restricted within the CD34 þ CD38À fraction. To understand the origin of malignant cells in primary human B-precursor acute lymphocytic leukemia (B-ALL), we established a novel in vivo xenotransplantation model. Purified CD34 þ CD38 þ CD19 þ , CD34 þ CD38ÀCD19 þ and CD34 þ CD38ÀCD19À bone marrow (BM) or peripheral blood (PB) cells from three pediatric B-ALL patients were intravenously injected into sublethally irradiated newborn NOD/ SCID/IL2rc null mice. We found that both CD34 þ CD38 þ CD19 þ and CD34 þ CD38ÀCD19 þ cells initiate B-ALL in primary recipients, whereas the recipients of CD34 þ CD38ÀCD10À CD19À cells showed normal human hematopoietic repopulation. The extent of leukemic infiltration into the spleen, liver and kidney was similar between the recipients transplanted with CD34 þ CD38 þ CD19 þ cells and those transplanted with CD34 þ CD38ÀCD19 þ cells. In each of the three cases studied, transplantation of CD34 þ CD38 þ CD19 þ cells resulted in the development of B-ALL in secondary recipients, demonstrating self-renewal capacity. The identification of CD34 þ CD38 þ CD19 þ self-renewing B-ALL cells proposes a hierarchy of leukemia-initiating cells (LICs) distinct from that of AML. Recapitulation of patient B-ALL in NOD/SCID/IL2rc null recipients provides a powerful tool for directly studying leukemogenesis and for developing therapeutic strategies.

The present study provides direct evidence of the distribution of BM-derived cells in the mouse cornea. Immunohistochemical study showed that some of these cells are BM-derived antigen-presenting cells such as dendritic cells and macrophages. Some elements of BM-derived cells may continue to exist in the corneal stroma.

To obtain insights into the cardiomyogenic potential of hematopoietic tissue, we intravenously (i.v.) injected purified hematopoietic stem/progenitor cells into newborn recipients that may fully potentiate the developmental plasticity of stem cells. Transplantation of mouse bone marrow (BM) lineage antigen-negative (Lin-) cells resulted in the generation of the cells that displayed cardiomyocyte-specific antigenic profiles and contractile function when transplanted into syngeneic newborn recipients. To clarify the mechanism underlying the cardiomyogenic potential, green fluorescent protein (GFP)-labeled BM Lin-ScaI+ hematopoietic progenitors were transplanted into neonatal mice constitutively expressing cyan fluorescence protein (CFP). Lambda image acquisition and linear unmixing analysis using confocal microscopy successfully separated GFP and CFP, and revealed that donor GFP+ cardiomyocytes coexpressed host-derived CFP. We further reconstituted human hemopoietic- and immune systems in mice by injecting human cord blood (CB)-derived Lin-CD34+CD38- hematopoietic stem cells (HSCs) into neonatal T cell(-)B cell(-)NK cell- immune-deficient NOD/SCID/IL2rgamma(null) mice. Fluoroescence in situ hybridization analysis of recipient cardiac tissues demonstrated that human and murine chromosomes were colocalized in the same cardiomyocytes, indicating that cell fusion occurred between human hematopoietic progeny and mouse cardiomyocytes. These syngeneic- and xenogeneic neonatal transplantations provide compelling evidence that hematopoietic stem/progenitor cells contribute to the postnatal generation of cardiomyocytes through cell fusion, not through transdifferentiation.

Objectives: The relationship between atrial fibrillation (AF) and gastroesophageal reflux disease (GERD) remains controversial, and investigations into this relationship have been based on small series. This multicenter survey evaluated the relationship between these diseases. Methods: The study enrolled 188 consecutive subjects (110 males and 78 females, mean age 60.4 ± 0.9 years) treated as outpatients. Patients were classified by the frequency scale for symptoms of GERD (F-scale) after obtaining informed consent for screening for GERD. Scores on this questionnaire were correlated to baseline characteristics obtained from medical records. The cutoff value for a diagnosis of GERD was set at 8.0 points. Results: Total scores on the F-scale were significantly greater in female subjects (p = 0.004) and in patients with AF (p = 0.019) compared to the other subjects. Univariate and multivariate analysis of the prevalence of GERD demonstrated that GERD was not related to gender, hypertension, dyslipidemia or coronary artery disease and that AF alone showed a significant (p < 0.001) correlation with GERD. Conclusions: This multicenter questionnaire survey demonstrated that among traditional cardiovascular risk factors, AF was an independent risk factor for GERD. A large cohort study to assess the potential relationship between GERD and AF is warranted.