Histone acetyl transferases (HATs) play distinct roles in many cellular processes and are frequently misregulated in cancers. Here, we study the regulatory potential of MYST1-(MOF)-containing MSL and NSL complexes in mouse embryonic stem cells (ESCs) and neuronal progenitors. We find that both complexes influence transcription by targeting promoters and TSS-distal enhancers. In contrast to flies, the MSL complex is not exclusively enriched on the X chromosome, yet it is crucial for mammalian X chromosome regulation as it specifically regulates Tsix, the major repressor of Xist lncRNA. MSL depletion leads to decreased Tsix expression, reduced REX1 recruitment, and consequently, enhanced accumulation of Xist and variable numbers of inactivated X chromosomes during early differentiation. The NSL complex provides additional, Tsix-independent repression of Xist by maintaining pluripotency. MSL and NSL complexes therefore act synergistically by using distinct pathways to ensure a fail-safe mechanism for the repression of X inactivation in ESCs.DOI: http://dx.doi.org/10.7554/eLife.02024.001

No abstract

No abstract

T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy of lymphoblasts committed to T-cell lineage. Dismal outcomes (15-30%) in case of T-LBL relapses warrants for establishing risk-based treatment in future. This is a first comprehensive, systematic, integrated genome-wide analysis including relapse cases aimed towards identifying molecular markers of prognostic relevance for T-LBL. NOTCH1 was identified as putative driver for T-LBL. Activated NOTCH/PI3K-AKT signaling axis and alterations in cell cycle regulators constitutes the core oncogenic program for T-LBL. Mutated KMT2D was identified as a prognostic marker. The cumulative incidence of relapse was 47±17% in patients with KMT2D mutations compared with 14±3% in KMT2D wildtype. Structural analysis of the mutated domains of KMT2D revealed plausible impact on the structure and functional consequences. These findings provide new insights into the pathogenesis of T-LBL including high translational potential. The ongoing trial LBL 2018 (NCT04043494) allows prospective validation and subsequent fine-tuning of the stratification criteria for T-LBL risk groups to improve survival of the pediatric patients.

The main challenges in the treatment of T-cell lymphoblastic lymphoma (T-LBL) in children and adolescents are twofold: to increase survival rates in concert with reduction of acute and long-term toxicities including the rate of secondary malignancies. The need for molecular and prognostic markers in T-LBL is crucial to allow for systematic treatment optimization and may serve as targets for new treatment approaches.