Long-term persistence of Ag-experienced CD8 cells, a class of T lymphocytes with cytotoxic function, contributes to immunological memory against intracellular pathogens. After Ag clearance, memory CD8 cells are maintained over time by a slow proliferation, primarily cytokine driven. In this article, we show that the bone marrow (BM) is the crucial organ where such basal division of memory CD8 cells occurs. BM memory CD8 cells contain a higher percentage of proliferating cells than their corresponding cells in either spleen or lymph nodes from C57BL/6 mice. This occurs both in the case of memory-phenotype CD44high CD8 cells and in the case of Ag-specific memory CD8 cells. Importantly, the absolute number of Ag-specific memory CD8 cells dividing in the BM largely exceeds that in spleen, lymph nodes, liver, and lung taken together. In the BM, Ag-specific memory CD8 cells express lower levels of CD127, i.e., the α-chain of IL-7R, than in either spleen or lymph nodes. We interpret these results as indirect evidence that Ag-specific memory CD8 cells receive proliferative signals by IL-7 and/or IL-15 in the BM and propose that the BM acts as a saturable “niche” for the Ag-independent proliferation of memory CD8 cells. Taken together, our novel findings indicate that the BM plays a relevant role in the maintenance of cytotoxic T cell memory, in addition to its previously described involvement in long-term Ab responses.

As a consequence of transformation, cancer cells generally lose some of their differentiative properties. Thus, alterations interfering with the genetic mechanisms required to maintain embryonic determination could lead to tumorigenesis. Homeobox genes are a network of genes encoding nuclear proteins containing DNA-binding homeodomains that are highly conserved throughout evolution. They are expressed in a stage-related fashion in the developing embryo and, in adult life, in normal tissues. In mice and humans, homeobox genes of the HOX family are organized in 4 clusters on different chromosomes which have presumably evolved by duplication of a primordial gene cluster. Strikingly, the order of genes within each cluster is also highly conserved throughout evolution, suggesting that the physical organization of HOX genes might be essential for their expression. Recent reports indicate that homeobox mutant mice display morphological abnormalities or show neoplastic alterations, and that growth factors can turn on homeobox genes. We have studied the expression of the Antennapedia-like HOX genes in normal human kidney and in renal carcinomas. The great majority of the HOX genes analyzed are expressed in a peculiar manner in normal kidney: blocks of genes, even entire HOX loci, are coordinately regulated. Alterations in HOX gene expression in renal carcinoma can be observed in 2 genes of the HOX-2 locus, HOX-2A and HOX-2E, which are actively expressed in normal kidney and silent in cancer biopsies. The HOX-3H gene is not expressed in normal kidney whereas the HOX-3H transcripts are present in renal carcinomas. Homeobox genes within the 4 HOX loci can be aligned on the basis of the maximal sequence homology of their homeodomains: this alignment defines 13 paralogous gene groups. In renal carcinomas, genes of group 10 (HOX-1D, 2F, 3E, 4B) display a marked difference in their transcript classes when compared to those of normal kidney. Our findings suggest an association between altered HOX gene expression and kidney cancer.

Hematopoiesis is a continuous process in which precursor cells proliferate and differentiate throughout life. However, the molecular mechani that govern this process are not clearly defined. Homeobox-containing genes, encoding DNA-binding homeodomains, are a network of genes highly conserved throughout evolution. They are organized in clusters expressed in the developing embryo with a positional hierarchy. We have analyzed expression of the four human HOX loci in erythroleukemic, promyelocytic, and monocytic cell lines to investigate whether the physical organization of human HOX genes reflects a regulatory hierarchy involved in the differentiation process of hematopoietic cells. Our results demonstrate that cells representing various stages of hematopoietic differentiation display differential patterns ofHOX gene expression and that HOX genes are coordinately switched on or off in blocks that may include entire loci. The entire HOX4 locus is silent in all lines analyzed and almost all the HOX2 genes are active in erythroleukemic cells and turned off in myeloid-restricted cells. Our observations provide information about the regulation of HOX genes and suggest that the coordinate regulation of these genes may play an important role in lineage determination during early steps of hematopolesis.

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Transcription factors are crucial to an understanding of the molecular basis of neoplasia. Horneobox‐containing genes are a family of transcriptional regulators encoding DNA‐binding ho‐meodomains, involved in the control of normal development. Class‐1 human homeobox‐containing genes (HOX genes) display a peculiar chromosomal organization, perhaps directly related to their function. Aberrant expression of homeobox‐genes has been associated with both morphological abnormalities and oncogenesis. We have recently observed that alterations in HOX gene expression are detectable in kidney and colon cancer when compared to the corresponding normal organs. Here we have analyzed the expression of HOX genes in primary and metastatic human small‐cell lung cancer (SCLC) xenografted in nude mice, in order to investigate whether HOX gene expression correlates with the histology and stage of SCLC progression. The results show that different SCLCs display differential patterns of HOX gene expression. Furthermore, in SCLC, the number of actively expressed HOX genes might be substantially lower in metastatic cancers than in primary tumors. The alteration in HOX gene expression in SCLCs mainly concerns the HOX B and C loci. This finding suggests that downregulation of HOX genes may play a role in small‐cell lung cancer progression, possibly through their implication in tumor suppression.