Gene expression profiling identifies a subset of adult T-cell acute lymphoblastic leukemia with myeloid-like gene features and over-expression of miR-223.

BACKGROUND: Until recently, few molecular aberrations were recognized in acute lymphoblastic leukemia of T-cell origin; novel lesions have recently been identified and a certain degree of overlap between acute myeloid leukemia and T-cell acute lymphoblastic leukemia has been suggested. To identify novel T-cell acute lymphoblastic leukemia entities, gene expression profiling was performed and clinico-biological features were studied. DESIGN AND METHODS: Sixty-nine untreated adults with T-cell acute lymphoblastic leukemia were evaluated by oligonucleotide arrays: unsupervised and supervised analyses were performed. The up-regulation of myeloid genes and miR-223 expression were validated by quantitative polymerase chain reaction analysis. RESULTS: Using unsupervised clustering, we identified five subgroups. Of these, one branch included seven patients whose gene expression profile resembled that of acute myeloid leukemia. These cases were characterized by over-expression of a large set of myeloid-related genes for surface antigens, transcription factors and granule proteins. Real-time quantitative polymerase chain reaction analysis confirmed over-expression of MPO, CEBPA, CEBPB, GRN and IL8. We, therefore, evaluated the expression levels of miR-223, involved in myeloid differentiation: these cases had significantly higher levels of miR-223 than had the other cases of T-cell acute lymphoblastic leukemia, with values comparable to those observed in acute myeloid leukemia. Finally, these patients appear to have an unfavorable clinical course. CONCLUSIONS: Using gene profiling we identified a subset of adult T-cell acute lymphoblastic leukemia, accounting for 10% of the cases analyzed, which displays myeloid features. These cases were not recognized by standard approaches, underlining the importance of gene profiling in identifying novel acute leukemia subsets. The recognition of this subgroup may have clinical, prognostic and therapeutic implications.

miR-223 is overexpressed in T-lymphocytes of patients affected by rheumatoid arthritis.

miRNAs have recently emerged as key regulators of the immune system, being involved in lymphocyte selection and proliferation, in T(reg) cells differentiation, and in hematopoiesis in general. Rheumatoid arthritis (RA) is an autoimmune pathology the etiology of which is still obscure. Although a multifactorial pathogenesis has been hypothesized, the precise mechanisms leading to the disease are still poorly understood at the molecular level. miRNA expression profile analysis highlighted that miR-223 is the only miRNA that is strikingly deregulated in peripheral T-lymphocytes from RA patients compared with healthy donors. Further analysis by quantitative reverse transcription-polymerase chain analysis confirmed that miR-223 is overexpressed in T-lymphocytes from RA patients (n = 28) compared with healthy donors (n = 10). Moreover, purification of different T-lymphocyte populations from RA patients highlights that miR-223 is expressed at higher levels in naive CD4(+) lymphocytes, whereas its expression is barely detectable in T(h)-17 cells. In summary, our data provide a first characterization of the miRNA expression profiles of peripheral T-lymphocytes of RA patients, identifying miR-223 as overexpressed in CD4(+) naive T-lymphocytes from these individuals. A deeper analysis of the biologic functions and effects of the expression of miR-223 in T-lymphocytes is needed to clarify the exact link between our observation and the disease.

Deletion of the glucose-6-phosphate dehydrogenase gene KlZWF1 affects both fermentative and respiratory metabolism in Kluyveromyces lactis.

In Kluyveromyces lactis, the pentose phosphate pathway is an alternative route for the dissimilation of glucose. The first enzyme of the pathway is the glucose-6-phosphate dehydrogenase (G6PDH), encoded by KlZWF1. We isolated this gene and examined its role. Like ZWF1 of Saccharomyces cerevisiae, KlZWF1 was constitutively expressed, and its deletion led to increased sensitivity to hydrogen peroxide on glucose, but unlike the case for S. cerevisiae, the Klzwf1Delta strain had a reduced biomass yield on fermentative carbon sources as well as on lactate and glycerol. In addition, the reduced yield on glucose was associated with low ethanol production and decreased oxygen consumption, indicating that this gene is required for both fermentation and respiration. On ethanol, however, the mutant showed an increased biomass yield. Moreover, on this substrate, wild-type cells showed an additional band of activity that might correspond to a dimeric form of G6PDH. The partial dimerization of the G6PDH tetramer on ethanol suggested the production of an NADPH excess that was negative for biomass yield.