A challenge for the development of therapies selectively targeting leukemic stem cells in acute myeloid leukemia (AML) is their similarity to normal hematopoietic stem cells (HSCs). Here we demonstrate that the leukemia-propagating cell in murine CALM/AF10-positive AML differs from normal HSCs by B220 surface expression and immunoglobulin heavy chain rearrangement. Furthermore, depletion of B220+ cells in leukemic transplants impaired development of leukemia in recipients. As in the murine model, human CALM/AF10-positive AML was characterized by CD45RA (B220)-positive, IG DH-JH rearranged leukemic cells. These data demonstrate in a murine leukemia model that AML can be propagated by a transformed progenitor with lymphoid characteristics, which can be targeted by antibodies that do not crossreact with normal HSCs.

The nuclear factor-kappaB (NF-B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-B-deficient and NF-B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)H epatocellular carcinoma (HCC) is the most frequent type of liver cancer and one of the most prevalent causes of cancer mortality worldwide. These tumors arise at sites of chronic liver injury, inflammation, and hepatocyte proliferation provoked by several causes such as chronic hepatitis B and C viral infection, chronic alcohol consumption, and aflatoxin B1-contaminated food. 1,2 Despite remarkable improvements in diagnosis, only limited therapeutic options exist, most of them with minimal clinical benefit. 2 Moreover, there is

To elucidate the molecular events responsible for tumorigenesis and progression of ependymomas, we analyzed molecular alterations on the gene expression level in a series of newly diagnosed ependymal neoplasms (n ‫؍‬ 39). To this aim, tumor RNA was hybridized to microarrays comprising 2600 different genes with relevance to mitosis, cell-cycle control, oncogenesis, or apoptosis. For CLU, IGF-2, and RAF-1, which are apparent candidate genes because they had been previously described to be involved in tumorigenesis of other human malignancies, we found a high expression on the mRNA as well as the protein level. We identified gene expression signatures for the differentiation of tumors with respect to location, grade, and patient age. Spinal ependymomas were characterized by high-expression levels of HOXB5, PLA2G, and CDKN2A and tumors in young patients (<16 years of age) by high-expression levels of LDHB and STAM. Notably, we were able to classify supratentorial grade II and III tumors with 100% accuracy, whereas this did not apply for infratentorial Ependymal tumors arise from the ependymal lining of the cerebral ventricles and from the remnants of the central canal of the spinal cord. This neoplasm constitutes ϳ3 to 5% of all intracranial malignancies and is the third most common brain tumor in children and young adults. 1,2 In ependymomas, the morphological features and biological behavior vary considerably. Patients with spinal tumor location have usually a favorable prognosis after gross total resection, whereas local tumor progression is the predominant reason for death in patients with intracranial ependymomas, resulting in a 5-year overall survival of ϳ60%. [3][4][5] Because ependymomas are characterized by tremendous variability in clinical behavior, the understanding of the complex changes taking place at the genomic level might lead to more precise understanding of the tumor biology. Cytogenetic studies revealed numerous chromosomal aberrations in ependymomas. In particular, a 30 to 50% incidence of aberrations involving chromosome 22, including monosomy 22 as well as deletions of 22q, prevailed the most frequent finding. 6 -8 Recently, Hirose and co-workers 7 reported on different patterns of chromosomal abnormalities with respect to tumor location detected by comparative genomic hybridization. In intracranial tumors, gain of 1q and losses on 6q, 9, and 13 were frequent, whereas gains on chromosome 7 were recognized almost exclusively in spinal cord tumors and were associated with various other chromosomal aberrations including frequent loss of 22q, suggesting that intracranial and spinal cord ependymomas progress along substantially different pathways. As a hereditary form, neurofibromatosis type 2 is associated with spinal ependymomas, indicating a functional role of the NF2 tumor suppressor gene in these tumors. 9,10 In contrast to adults in which spinal tumors predominate, ϳ90% of all pediatric ependymomas are of intraSupported by the Bundesministerium fü r Bildung und Forschung (FKZ 01 KW 9937 and...