Using a combination of molecular cytogenetic and large-scale expression analysis in human T-cell acute lymphoblastic leukemias (T-ALLs), we identified and characterized a new recurrent chromosomal translocation, targeting the major homeobox gene cluster HOXA and the TCRB locus. Real-time quantitative polymerase chain reaction (RQ-PCR) analysis showed that the expression of the whole HOXA gene cluster was dramatically dysregulated in the HOXA-rearranged cases, and also in MLL and CALM-AF10 -related T-ALL cases, strongly suggesting that HOXA genes are oncogenic in these leukemias. Inclusion of HOXA-translocated cases in a general molecular portrait of 92 T-ALLs based on large-scale expression analysis shows that this rearrangement defines a new homogeneous subgroup, which shares common biologic networks with the TLX1-and TLX3-related cases. Because T-ALLs derive from T-cell progenitors, expression profiles of the distinct T-ALL subgroups were analyzed with respect to those of normal human thymic subpopulations. Inappropriate use or perturbation of specific molecular networks involved in thymic differentiation was detected. Moreover, we found a significant association between T-ALL oncogenic subgroups and ectopic expression of a limited set of genes, including several developmental genes, namely HOXA, TLX1, TLX3, NKX3-1, SIX6, and TFAP2C. These data strongly support the view that the abnormal expression of developmental genes, including the prototypical homeobox genes HOXA, is critical in T-ALL oncogenesis. IntroductionT-cell acute lymphoblastic leukemias (T-ALLs) are highly malignant tumors representing 10% to 15% of pediatric and 25% of adult ALLs in humans. 1,2 T-ALL cells derive from partially differentiated thymocytes. These cells originate from pluripotent progenitors that are progressively committed to the ␣ or ␥␦ T-cell lineages in the thymus. 3 Somatic V(D)J recombination rearranges the T-cell-receptor (TCR) gene segments, generating protein products that allow cells to pass through several cellular processes, so-called -selection and selection. 4,5 Hence, V(D)J recombination both directly compromises genome integrity and indirectly controls cellular functions considered to be critical for oncogenesis, such as cell cycle, proliferation, and apoptosis. 6 However, T-ALLs remain rare, consistent with efficient control mechanisms that can only be overcome by accumulation of oncogenic events. Several classes of proto-oncogenes can be activated by chromosomal rearrangements or epigenetic mechanisms in T-ALL. [7][8][9] The resulting oncoproteins include basic helix-loop-helix proteins (TAL1/SCL, TAL2, LYL1), homeodomain-containing proteins (TLX1/HOX11, TLX3/HOX11L2), and LIM only proteins (LMO1, LMO2), which are likely to be involved in transcription factor complexes. 8,10 In addition, chromosomal alterations or DNA mutations can activate genes involved in signal transduction and thymus differentiation, such as NOTCH1 and LCK, [11][12][13] or can lead to gene fusion (MLL-ENL, CALM-AF10, NUP214-ABL1). [14][15][...
Tapasin is critical for efficient loading and surface expression of most HLA class I molecules. The high level surface expression of HLA-B*2705 on tapasin-deficient 721.220 cells allowed the influence of this chaperone on peptide repertoire to be examined. Comparison of peptides bound to HLA-B*2705 expressed on tapasin-deficient and -proficient cells by mass spectrometry revealed an overall reduction in the recovery of B*2705-bound peptides isolated from tapasin-deficient cells despite similar yields of B27 heavy chain and β2-microglobulin. This indicated that a proportion of suboptimal ligands were associated with B27, and they were lost during the purification process. Notwithstanding this failure to recover these suboptimal peptides, there was substantial overlap in the repertoire and biochemical properties of peptides recovered from B27 complexes derived from tapasin-positive and -negative cells. Although many peptides were preferentially or uniquely isolated from B*2705 in tapasin-positive cells, a number of species were preferentially recovered in the absence of tapasin, and some of these peptide ligands have been sequenced. In general, these ligands did not exhibit exceptional binding affinity, and we invoke an argument based on lumenal availability and affinity to explain their tapasin independence. The differential display of peptides in tapasin-negative and -positive cells was also apparent in the reactivity of peptide-sensitive alloreactive CTL raised against tapasin-positive and -negative targets, demonstrating the functional relevance of the biochemical observation of changes in peptide repertoire in the tapasin-deficient APC. Overall, the data reveal that tapasin quantitatively and qualitatively influences ligand selection by class I molecules.
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