Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors.

Unfavorable patient survival coincides with lineage plasticity observed in human acute leukemias. These cases are assumed to arise from hematopoietic stem cells, which have stable multipotent differentiation potential. However, here we report that plasticity in leukemia can result from instable lineage identity states inherited from differentiating progenitor cells. Using mice with enhanced c-Myc expression, we show, at the single-cell level, that T-lymphoid progenitors retain broad malignant lineage potential with a high capacity to differentiate into myeloid leukemia. These T-cell-derived myeloid blasts retain expression of a defined set of T-cell transcription factors, creating a lymphoid epigenetic memory that confers growth and propagates myeloid/T-lymphoid plasticity. Based on these characteristics, we identified a correlating human leukemia cohort and revealed targeting of Jak2/Stat3 signaling as a therapeutic possibility. Collectively, our study suggests the thymus as a source for myeloid leukemia and proposes leukemic plasticity as a driving mechanism. Moreover, our results reveal a pathway-directed therapy option against thymus-derived myeloid leukemogenesis and propose a model in which dynamic progenitor differentiation states shape unique neoplastic identities and therapy responses.

Similarity in targets with REST points to neural and glioblastoma related miRNAs.

There are groups of genes that need coordinated repression in multiple contexts, for example if they code for proteins that work together in a pathway or in a protein complex. Redundancy of biological regulatory networks implies that such coordinated repression might occur at both the pre- and post-transcriptional level, though not necessarily simultaneously or under the same conditions. Here, we propose that such redundancy in the global regulatory network can be detected by the overlap between the putative targets of a transcriptional repressor, as identified by a ChIP-seq experiment, and predicted targets of a microRNA (miRNA). To test this hypothesis, we used publicly available ChIP-seq data of the neural transcriptional repressor RE1 silencing transcription factor (REST) from 15 different cell samples. We found 20 miRNAs, each of which shares a significant amount of predicted targets with REST. The set of predicted associations between these 20 miRNAs and the overlapping REST targets is enriched in known miRNA targets. Many of the detected miRNAs have functions related to neural identity and glioblastoma, which could be expected from their overlap in targets with REST. We propose that the integration of experimentally determined transcription factor binding sites with miRNA-target predictions provides functional information on miRNAs.