Fate mapping reveals separate origins of T cells and myeloid lineages in the thymus.

The cellular differentiation pathway originating from the bone marrow leading to early T lymphocytes remains poorly understood. The view that T cells branch off from a lymphoid-restricted pathway has recently been challenged by a model proposing a common progenitor for T cell and myeloid lineages. We generated interleukin-7 receptor alpha (Il7r) Cre recombinase knockin mice and traced lymphocyte development by visualizing the history of Il7r expression. Il7r fate mapping labeled all T cells but few myeloid cells. More than 85% of T cell progenitors were Il7r reporter(+) and, hence, had arisen from an Il7r-expressing pathway. In contrast, the overwhelming majority of myeloid cells in the thymus were derived from Il7r reporter(-) cells. Thus, lymphoid-restricted progenitors are the major route to T cells, and distinct origins of lymphoid and myeloid lineages represent a fundamental hallmark of hematopoiesis.

Gene expression factors as predictors of genetic risk and survival in chronic lymphocytic leukemia.

BACKGROUND: A variety of surrogate markers for genetic features and outcome have been described in chronic lymphocytic leukemia based on gene expression analyses. Previous studies mostly focused on individual markers and selected disease characteristics, which makes it difficult to estimate the relative value of the novel markers. Therefore, in the present study a comprehensive approach was chosen investigating 18 promising, partly novel expression markers in a well characterized cohort of patients with long clinical follow-up and full genetic information (IGHV status, genomic abnormalities). DESIGN AND METHODS: Expression markers were evaluated using real-time quantitative reverse transcriptase polymerase chain reaction in CD19(+)-purified samples from 151 patients. Multivariate analyses were performed to test the markers' ability to identify patients at genetic risk and as prognostic markers in the context of established prognostic factors. RESULTS: For individual markers, ZAP70 expression provided the highest rate (81%) of correct assignment of patients at genetic risk (IGHV unmutated, V3-21 usage, 11q- or 17p-), followed by LPL and TCF7 (76% both). The assignment rate was improved to 88% by information from a four-gene combination (ZAP70, TCF7, DMD, ATM). In multivariate analysis of treatment-free survival, IGHV mutation status and expression of ADAM29 were of independent prognostic value besides disease stage. With regards to overall survival, expression of ATM, ADAM29, TCL1, and SEPT10 provided prognostic information in addition to that derived from clinical and genetic factors. CONCLUSIONS: Gene expression markers are suitable for screening but not as surrogates for the information from genetic risk factors. While many individual markers may be associated with outcome, only a few are of independent prognostic significance. With regard to prognosis estimation, the genetic prognostic factors cannot be replaced by the expression markers.