Differentiation status in neuroblastoma strongly affects clinical outcomes and inducing differentiation is a treatment strategy in this disease. However, the molecular mechanisms that control neuroblastoma differentiation are not well understood. Here we show that high-level HOXC9 expression is associated with neuroblastoma differentiation and is prognostic for better survival in neuroblastoma patients. HOXC9 induces growth arrest and neuronal differentiation in neuroblastoma cells by directly targeting both cell cycle-promoting and neuronal differentiation genes. HOXC9 expression is upregulated by retinoic acid (RA) and knockdown of HOXC9 expression confers resistance to RA-induced growth arrest and differentiation. Moreover, HOXC9 expression is epigenetically silenced in RA-resistant neuroblastoma cells and forced HOXC9 expression is sufficient to inhibit their proliferation and tumorigenecity. These findings identify HOXC9 as a key regulator of neuroblastoma differentiation and suggest a therapeutic strategy for RA-resistant neuroblastomas through epigenetic activation of HOXC9 expression.
Normal development of the immune system requires regulated processing of NF-B2 p100 to p52, which activates NF-B2 signaling. Constitutive production of p52 has been suggested as a major mechanism underlying lymphomagenesis induced by NF-B2 mutations, which occur recurrently in a variety of human lymphoid malignancies. To test the hypothesis, we generated transgenic mice with targeted expression of p52 in lymphocytes. In contrast to their counterparts expressing the tumor-derived NF-B2 mutant p80HT, which develop predominantly B cell tumors, p52 transgenic mice are not prone to lymphomagenesis. However, they are predisposed to inflammatory autoimmune disease characterized by multiorgan infiltration of activated lymphocytes, high levels of autoantibodies in the serum, and immune complex glomerulonephritis. p52, but not p80HT, represses Bim expression, leading to defects in apoptotic processes critical for elimination of autoreactive lymphocytes and control of immune response. These findings reveal distinct signaling pathways for actions of NF-B2 mutants and p52 and suggest a causal role for sustained NF-B2 activation in the pathogenesis of autoimmunity.NF-B2 is a member of the NF-B family of transcription factors that also includes NF-B1 (p105/p50), RelA (p65), RelB, and c-Rel (1). The full-length NF-B2 protein p100 contains an N-terminal Rel homology domain, responsible for dimerization, nuclear translocation, and DNA binding. Its C-terminal region contains an ankyrin repeat domain with IB activity. Under basal conditions, NF-B2 p100 forms inhibitory complexes with Rel proteins (2-4). Phosphorylation of the C terminus of p100 by IB kinase ␣ and NF-B inducing kinase leads to proteolytic processing of p100 to p52 (5, 6). The resulting p52-Rel protein heterodimers then translocate into the nucleus and activate transcription of their target genes. This alternative NF-B signaling pathway is activated by engagement of the receptors for B cell-activating factor, lymphotoxin-, and CD40 ligand (3,(7)(8)(9). Previous studies with NF-B2Ϫ/Ϫ mice demonstrate a crucial role of NF-B2 in B cell development and secondary lymphoid organogenesis. These mice present a marked decrease in the peripheral B cell population and an absence of discrete perifollicular marginal and mantle zones and of germinal centers in the spleen (10, 11). More recently, it has been shown that NF-B2 signaling is essential for the development of medullary thymic epithelial cells that function as antigen-presenting cells in negative selection of autoreactive T cell clones (12).The NF-B2 gene is recurrently mutated in a variety of human lymphoid malignancies, including T-cell lymphoma, chronic lymphocytic leukemia, multiple myeloma, and B cell lymphoma (13). A cardinal feature of these genetic alterations is the generation of C-terminally truncated NF-B2 mutants that lack various portions of the ankyrin repeat domain (14 -20). To determine whether NF-B2 mutation can directly initiate lymphomagenesis, we generated transgenic mice with targeted expression in l...
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