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][...

Interleukin 7 (IL-7) and its receptor, formed by IL-7Rα (encoded by IL7R) and γc, are essential for normal T-cell development and homeostasis. Here we show that IL7R is an oncogene mutated in T-cell acute lymphoblastic leukemia (T-ALL). We find that 9% of individuals with T-ALL have somatic gain-of-function IL7R exon 6 mutations. In most cases, these IL7R mutations introduce an unpaired cysteine in the extracellular juxtamembrane-transmembrane region and promote de novo formation of intermolecular disulfide bonds between mutant IL-7Rα subunits, thereby driving constitutive signaling via JAK1 and independently of IL-7, γc or JAK3. IL7R mutations induce a gene expression profile partially resembling that provoked by IL-7 and are enriched in the T-ALL subgroup comprising TLX3 rearranged and HOXA deregulated cases. Notably, IL7R mutations promote cell transformation and tumor formation. Overall, our findings indicate that IL7R mutational activation is involved in human T-cell leukemogenesis, paving the way for therapeutic targeting of IL-7R-mediated signaling in T-ALL.