Recent reports show that increased protein intake in the context of weight loss improves glucose control. The aim of this study was to examine if supplementation of a weight-maintaining diet with essential amino acids (EAA) is effective in improving insulin sensitivity in elderly. Eight insulin-resistant elderly (66 ± 2 (SE) years, 4 females, 4 males) ingested 11 g of EAA two times a day, between meals for 16 weeks. Diet and activity were not otherwise modified. Insulin sensitivity was determined by an oral glucose tolerance test, and body composition was measured by DEXA, at baseline, and every four weeks. One-way repeated measures ANOVA was used. EAA supplementation significantly improved the Matsuda index (p = 0.019). From a baseline value of 3.8 ± 0.4, the Matsuda index increased to 4.0 ± 0.9, 5.6 ± 1.0, 6.1 ± 1.4, and 5.3 ± 0.9 at week 4, 8, 12, and 16, respectively. The effect of EAA supplementation on insulin sensitivity varied between subjects, with the changes in the Matsuda index ranging from −1.76 to 6.73. A positive correlation between the baseline value and the change in Matsuda index was found at 12 weeks (r = 0.762, p = 0.021), whereas a trend was observed after 8 weeks (r = 0.643, p = 0.071). There was also an improvement in lean body mass (p = 0.066) and leg lean mass (p = 0.049) during the study, but no correlation between changes in lean mass and Matsuda index was seen. In conclusion, supplementation of the diet with EAA improves glucose control in insulin-resistant elderly to a variable extent. (Studies performed at GCRC, UTMB, funded by M01 RR 00073 and P30 AG024832)

The pre–T cell receptor (TCR) is expressed early during T cell development and imposes a tight selection for differentiating T cell progenitors. Pre-TCR–expressing cells are selected to survive and differentiate further, whereas pre-TCR− cells are “negatively” selected to die. The mechanisms of pre-TCR–mediated survival are poorly understood. Here, we describe the induction of the antiapoptotic gene BCL2A1 (A1) as a potential mechanism regulating inhibition of pre–T cell death. We characterize in detail the signaling pathway involved in A1 induction and show that A1 expression can induce pre–T cell survival by inhibiting activation of caspase-3. Moreover, we show that in vitro “knockdown” of A1 expression can compromise survival even in the presence of a functional pre-TCR. Finally, we suggest that pre-TCR–induced A1 overexpression can contribute to T cell leukemia in both mice and humans.

Transgenic zebrafish that express GFP under control of the T cell-specific tyrosine kinase (lck) promoter were used to analyze critical aspects of the immune system, including patterns of T cell development and T cell homing after transplant. GFP-labeled T cells could be ablated in larvae by either irradiation or dexamethasone added to the water, illustrating that T cells have evolutionarily conserved responses to chemical and radiation ablation. In transplant experiments, thymocytes from lck-GFP fish repopulated the thymus of irradiated wild-type fish only transiently, suggesting that the thymus contains only short-term thymic repopulating cells. By contrast, whole kidney marrow permanently reconstituted the T lymphoid compartment of irradiated wild-type fish, suggesting that long-term thymic repopulating cells reside in the kidney.

The specific targeting of critical signaling molecules may provide efficient therapies for T-cell acute lymphoblastic leukemia (T-ALL). However, target identification and drug development are limited by insufficient numbers of primary T-ALL cells and by their high rate of spontaneous apoptosis. We established a human interleukin-7 (IL-7)-dependent T-ALL cell line, TAIL7, that maintains several biologic and signaling properties of its parental leukemia cells. TAIL7 cells are pre-T-ALL cells that proliferate in response to IL-7 and IL-4. IL-7 stimulation of TAIL7 cells prevents spontaneous in vitro apoptosis and induces cell activation and cell cycle progression. The signaling events triggered by IL-7 include down-regulation of p27(kip1) and hyperphosphorylation of retinoblastoma protein (Rb). Stimulation of TAIL7 cells by IL-7 leads to phosphorylation of Janus kinase 3 (JAK3), signal transducer and activator of transcription 5 (STAT5), Akt/PKB (protein kinase B), and extracellular-regulated kinase 1 and 2 (Erk1/2). Importantly, specific blockade of JAK3 by its inhibitor WHI-P131 abrogates the IL-7-mediated proliferation and survival of TAIL7 cells, suggesting that activation of JAK3 is critical for IL-7 responsiveness by these cells. Because TAIL7 cells seem to be a biologic surrogate for primary leukemia T cells, this cell line constitutes a valuable tool for the study of the signaling pathways implicated in T-ALL. Exploitation of this cell line should allow the identification of molecular targets and promote the rational design and validation of antileukemia signaling inhibitors.

The Philadelphia translocation, encoding the BCR-ABL1 (BCR-ABL) fusion gene, is typically found in chronic myeloid leukemia (CML) and precursor B-cell acute lymphoblastic leukemia (B-ALL), but is exceptionally rare in T-cell acute lymphoblastic leukemia (T-ALL). To study the potential involvement of ABL1 gene rearrangements in T-cell malignancies, we screened 90 T-ALL cases by fluorescence in situ hybridization (FISH), using BCR and ABL1 probes. No BCR-ABL1 fusion signals were observed, confirming the low frequency of this rearrangement in T-ALL, but we did observe marked amplification (> 10 signals per nucleus) ABL1 of in 5 of 90 (5.5 %) T-ALL patients.

Aberrant expression of transcription factor oncogenes such as HOX11, HOX11L2, TAL1/SCL, LYL1, LMO1, and LMO2 can be detected in lymphoblasts from up to 80% of patients with acute T-cell lymphoblastic leukemia (T-ALL). Transcriptional activation of these oncogenes in leukemic cells typically results from chromosomal rearrangements that place them next to highly active cis-acting transcriptional regulatory elements. However, biallelic activation of TAL1 in some T-ALL cases has been previously proposed. We have used allele-specific mRNA analysis to show that trans-acting mechanisms leading to biallelic overexpression of TAL1 are involved in 10 (42%) of 24 TAL1+ informative T-ALL cases, 2 (17%) of 12 HOX11+ informative cases, and 7 (64%) of 11 LMO2+ informative cases. We propose that aberrant expression of oncogenic transcription factors in a significant fraction of T-ALLs may result from loss of the upstream transcriptional mechanisms that normally down-regulate the expression of these oncogenes during T-cell development.