Purpose: Our recent study revealed that CD55-high population in breast cancer cell line was resistant to apoptosis and formed colonies in vitro more efficiently than CD55-low population. The present study was conducted to examine whether CD55-high population in breast cancer cell line possesses higher tumorigenic potential in vivo and presence of CD55-high cells in breast cancer affects clinicopathologic behavior of patients. Experimental Design: CD55-high and CD55-low population was sorted from breast cancer cell line, injected into immunodeficient mice, and the resultant tumor volume was measured. CD55 expression was immunohistochemically examined in clinical samples from 74 cases with breast cancers, and cases with >1% of tumor cells showing high level of CD55 expression were categorized as CD55 high. Results: The xenotransplanted tumor volume derived from CD55-high population was significantly larger than that from CD55-low population. Fifty (67.6%) of 74 cases of breast cancer were CD55-high. A significant correlation was observed between CD55-high character and relapse rate (P < 0.001). Univariate analysis showed that tumor size (P = 0.005) and CD55 expression (P = 0.005) were unfavorable prognostic factors. Multivariate analysis revealed that the tumor size (P = 0.013) and CD55 expression (P = 0.011) were independent prognostic factors. Conclusions: CD55 play an important role in tumorigenesis of breast cancer, and presence of small population of cells with strong CD55 expression would be sufficient to predict poor prognosis of patients.

Genome-wide DNA replication timing (RT) profiles reflect the global 3D chromosome architecture of cells. They also provide a comprehensive and unique megabase-scale picture of the cellular epigenetic state. Thus normal differentiation involves reproducible changes in RT and transformation generally perturbs these, although the potential effects of altered RT on the properties of transformed cells remain largely unknown. A major challenge to interrogating these issues in human acute lymphoid leukemia (ALL) is the low proliferative activity of most of the cells, which may be further reduced in cryopreserved samples and difficult to overcome in vitro. In contrast, the ability of many human ALL cell populations to expand when transplanted in highly immunodeficient mice is well documented. To examine the stability of DNA RT profiles of serially passaged xenografts of primary human B- and T-ALL cells, we first devised a method that circumvents the need for BrdU incorporation to distinguish early versus late S-phase cells. Using this and more standard protocols, we found consistent strong retention in xenografts of the original patient-specific RT features, for all 8 primary human ALL cases surveyed (7 B-ALLs and one T-ALL). Moreover, in a case where genomic analyses indicated changing subclonal dynamics in serial passages, the RT profiles tracked concordantly. These results show that DNA RT is a relatively stable feature of human ALLs propagated in immunodeficient mice. In addition, they suggest the power of this approach for future interrogation of the origin and consequences of altered DNA RT in these diseases.

Objective. Statins, which are used as cholesterollowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs.Methods. We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFN␣ production, and intracellular signaling.Results. Statins inhibited IFN␣ production profoundly and tumor necrosis factor ␣ production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFN␣ production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFN␣ production by PDCs from SLE patients and SLE serum-induced IFN␣ production.Conclusion. Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.Statins, inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, represent the most important cholesterol-lowering agents used to treat hypercholesterolemia. Recent clinical and experimental evidence indicates that statins have pleiotropic effects that include antiinflammatory and immunomodulatory properties, as shown by reduced rates of graft rejection in statin-treated patients after heart transplantation (1), beneficial effects in autoimmune encephalomyelitis or multiple sclerosis (2,3), decreased leukocyte recruitment and edema formation in animal models of acute inflammation (4), and delayed disease progression in the

The majority of cases of intravascular lymphomatosis (IVL) is derived from B cells. However, IVL may also arise from T cells, or more rarely NK cells. The clinicopathological findings in six cases of NK‐cell IVL (NK‐IVL), including one new case, were summarised and compared with B‐cell IVL (B‐IVL) and T‐cell IVL (T‐IVL). Earlier onset of disease and female predominance were found in NK‐IVL. NK‐IVL was typically Epstein–Barr virus (EBV)‐positive, whereas EBV was rarely detected in B‐IVL. Cutaneous manifestations were common in NK‐IVL with constant EBV infection. B‐IVL showed a more favourable prognosis than T‐ or NK‐IVL. Irrespective of immunophenotype, however, IVL showed a less favourable prognosis than ordinary lymphomas within the same immunophenotype. In summary, IVL of the B‐, T‐ and NK‐cell phenotypes is clinicopathologically distinct and shows similarities to their more common counterparts, i.e. diffuse large B‐cell lymphoma, peripheral T‐cell lymphoma, unspecified and extranodal NK/T‐cell lymphoma, nasal type.

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Highlights d The composition of focal adhesions mediating niche interactions is altered in LSCs d ILK is a focal adhesion component required for LSC selfrenewal in vivo d ILK inhibition sensitizes therapy-resistant patient LSCs to standard chemotherapy d The mitochondrial metabolism of quiescent LSCs is perturbed by ILK inhibition

Xenograft models are transforming our understanding of the output capabilities of primitive human hematopoietic cells in vivo. However, many variables that affect posttransplantation reconstitution dynamics remain poorly understood. Here, we show that an equivalent level of human chimerism can be regenerated from human CD34+ cord blood cells transplanted intravenously either with or without additional radiation-inactivated cells into 2- to 6-month-old NOD-Rag1−/−-IL2Rγc−/− (NRG) mice given a more radioprotective conditioning regimen than is possible in conventionally used, repair-deficient NOD-Prkdcscid/scid-IL2Rγc−/−(NSG) hosts. Comparison of sublethally irradiated and non-irradiated NRG mice and W41/W41 derivatives showed superior chimerism in the W41-deficient recipients, with some differential effects on different lineage outputs. Consistently superior outputs were observed in female recipients regardless of their genotype, age, or pretransplantation conditioning, with greater differences apparent later after transplantation. These results define key parameters for optimizing the sensitivity and minimizing the intraexperimental variability of human hematopoietic xenografts generated in increasingly supportive immunodeficient host mice.

Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of miRNAs in regulating drug resistance and leukemic stem cell (LSCs) fate, we performed global transcriptome profiling in treatment-naïve chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor; its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in pre-clinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185 and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL may provide a valuable strategy for overcoming drug resistance in patients.