Desmoid tumors are fibroblastic/myofibroblastic proliferations. Previous studies reported that CTNNB1 mutations were detected in 84% and that mutations of the APC gene were found in several cases of sporadic desmoid tumors lacking CTNNB1 mutations. Forty tumors were analyzed by comparative genomic hybridization (CGH). Karyotype and fluorescence in situ hybridization revealed a nonrandom occurrence of trisomy 8 associated with an increased risk of recurrence. We report the first molecular characterization including a large series of patients. We performed array CGH on frozen samples of 194 tumors, and we screened for APC mutations in patients without CNNTB1 mutation. A high frequency of genomically normal tumors was observed. Four relevant and recurrent alterations (loss of 6q, loss of 5q, gain of 20q, and gain of Chromosome 8) were found in 40 out of 46 tumors with chromosomal changes. Gain of Chromosomes 8 and 20 was not associated with an increased risk of recurrence. Cases with loss of 5q had a minimal common region in 5q22.5 including the APC locus. Alterations of APC, including loss of the entire locus, and CTNNB1 mutation could explain the tumorigenesis in 89% of sporadic desmoids tumors and desmoids tumors occurring in the context of Gardner's syndrome. A better understanding of the pathogenetic pathways in the initiation and progression of desmoid tumors requires studies of 8q and 20q gains, as well as of 6q and 5q losses, and study of the Wnt/beta-catenin pathway.

The TEL-JAK2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. TEL-JAK2 transgenic expression in the mouse lymphoid lineage results in fatal and rapid T-cell leukemia/lymphoma. In the present report we show that T-cell leukemic cells from ESR␣-TEL-JAK2 transgenic mice present an aberrant CD8 ؉ differentiation phenotype, as determined by the expression of stage-specific cell surface markers and lineage-specific genes. TEL-JAK2 transforms immature CD4 ؊ CD8 ؊ double-negative thymocytes, as demonstrated by the development of T-cell leukemia with full penetrance in a Rag2-deficient genetic background. This disease is similar to the bona fide TEL-JAK2 disease as assessed by phenotypic and gene profiling analyses. Pre-TCR signaling synergizes with TEL-JAK2 to transform immature thymocytes and initiate leukemogenesis as shown by (1) the delayed leukemia onset in Rag2-, CD3⑀-and pT␣-deficient mice, (2) the occurrence of recurrent chromosomal alterations in pre-TCR-deficient leukemia, and (3) the correction of delayed leukemia onset in Rag2-deficient TEL-JAK2 mice by an H-Y TCR␣␤ transgene that mimics pre-TCR signaling. Although not affecting leukemia incidence and mouse survival, TCR␣␤ expression was shown to facilitate leukemic cell expansion in secondary lymphoid organs. IntroductionIn the thymus, T cells develop from a common CD4 Ϫ CD8 Ϫ double-negative (DN) progenitor into 2 main lineages, ␣␤ and ␥␦, which are defined by the selection of productive rearrangements in the respective T-cell receptor (TCR) loci (for a review, see Aifantis et al 1 ). In mice, DN thymocytes are divided in 4 categories according to CD25 and CD44 expression: DN1 (CD25 Ϫ CD44 ϩ ), DN2 (CD25 ϩ CD44 ϩ ), DN3 (CD25 ϩ CD44 Ϫ ), and DN4 (CD25 Ϫ CD44 Ϫ ). Rag-mediated rearrangement of the TCR␤ locus at the DN3 stage leads to cell surface expression of a functional TCR␤ chain, which assembles with the surrogate pT␣ chain and CD3-signaling proteins to form the pre-TCR complex. Constitutive survival, proliferation, and differentiation signals emanating from the pre-TCR allow T cells to pass through the ␤-selection checkpoint and mature to the DN4, CD4 Ϫ CD8 ϩ immature single-positive (ISP) and CD4 ϩ CD8 ϩ double-positive (DP) stages. The ␤-selected cells rearrange their TCR␣ locus, and only the minority of cells expressing a functional TCR␣␤ complex at the cell surface will either undergo negative selection and die or undergo positive selection and become mature CD4 or CD8 single-positive (SP) thymocytes.Chromosomal rearrangements or point mutations in oncogenes or tumor suppressor genes occur in hematopoietic stem cells (HSCs), uncommitted and committed lymphoid progenitors, or developing thymocytes, thus leading to T-cell leukemia. Chromosomal translocations involving the juxtaposition of protooncogenes to the promoter and enhancer sequences of TCR loci result in deregulated oncogene expression. Chromosomal translocations can also create fusion genes encoding fu...

A family with dominant X-linked chondrodysplasia was previously described. The disease locus was ascribed to a 24 Mb interval in Xp11.3-q13.1. We have identified a variant (c.*281A>T) in the 3' untranslated region (UTR) of the HDAC6 gene that totally segregates with the disease. The variant is located in the seed sequence of hsa-miR-433. Our data showed that, in MG63 osteosarcoma cells, hsa-miR-433 (miR433) down-regulated both the expression of endogenous HDAC6 and that of an enhanced green fluorescent protein-reporter mRNA bearing the wild-type 3'-UTR of HDAC6. This effect was totally abrogated when the reporter mRNA bore the mutated HDAC6 3'-UTR. The HDAC6 protein was found to be over-expressed in thymus from an affected male fetus. Concomitantly, the level of total alpha-tubulin, a target of HDAC6, was found to be increased in the affected fetal thymus, whereas the level of acetylated alpha-tubulin was found to be profoundly decreased. Skin biopsies were obtained from a female patient who presented a striking body asymmetry with hypotrophy of the left limbs. The mutated HDAC6 allele was expressed in 31% of left arm-derived fibroblasts, whereas it was not expressed in the right arm. Overexpression of HDAC6 was observed in left arm-derived fibroblasts. Altogether these results strongly suggest that this HDAC6 3'-UTR variant suppressed hsa-miR-433-mediated post-transcriptional regulation causing the overexpression of HDAC6. This variant is likely to constitute the molecular cause of this new form of X-linked chondrodysplasia. This represents to our knowledge the first example of a skeletal disease caused by the loss of a miRNA-mediated post-transcriptional regulation on its target mRNA.