T-cell acute lymphoblastic leukemia (T-ALL) is caused by the accumulation of multiple mutations combined with the ectopic expression of transcription factors in developing T cells. However, the molecular basis underlying cooperation between transcription factor expression and additional oncogenic mutations in driving T-ALL has been difficult to assess due to limited robust T-cell model systems. Here we utilize a new ex vivo pro-T-cell model to study oncogenic cooperation. Using a systems biological approach we first dissect the pro-T-cell signaling network driven by interleukin-7, stem cell factor and Notch1 and identify key downstream Akt, Stat, E2f and Myc genetic signaling networks. Next, this pro-T-cell system was used to demonstrate that ectopic expression of the TAL1 transcription factor and Pten deletion are bona-fide cooperating events resulting in an increased stem cell signature, upregulation of a specific E2f signaling network and metabolic reprogramming with higher influx of glucose carbons into the tricarboxylic acid cycle. This ex vivo pro-T-cell system thereby provides a powerful new model system to investigate how normal T-cell signaling networks are perturbed and/or hijacked by different oncogenic events found in T-ALL.

Mucosa‐associated lymphoid tissue 1 (Malt1) regulates immune cell function by mediating the activation of nuclear factor κB (NF‐κB) signaling through both its adaptor and proteolytic function. Malt1 is also a target of its own protease activity and this self‐cleavage further contributes to NF‐κB activity. Until now, the functional distinction between Malt1 self‐cleavage and its general protease function in regulating NF‐κB signaling and immune activation remained unclear. Here we demonstrate, using a new mouse model, the importance of Malt1 self‐cleavage in regulating expression of NF‐κB target genes and subsequent T cell activation. Significantly, we further establish that Treg homeostasis is critically linked to Malt1 function via a Treg intrinsic and extrinsic mechanism. TCR‐mediated Malt1 proteolytic activity and self‐cleavage was found to drive Il2 expression in conventional CD4+ T cells, thereby regulating Il2 availability for Treg homeostasis. Remarkably, the loss of Malt1‐mediated self‐cleavage alone was sufficient to cause a significant Treg deficit resulting in increased anti‐tumor immune reactivity without associated autoimmunity complications. These results establish for the first time that inhibition of MALT1 proteolytic activity could be a viable therapeutic strategy to augment anti‐tumor immunity.

BackgroundThe CNOT3 protein is a subunit of the CCR4-NOT complex, which is involved in mRNA degradation. We recently identified CNOT3 loss-of-function mutations in patients with T-cell acute lymphoblastic leukemia (T-ALL).MethodsHere, we use different Drosophila melanogaster eye cancer models to study the potential tumor suppressor function of Not3, the CNOT3 orthologue, and other members of the CCR4-NOT complex.ResultsOur data show that knockdown of Not3, the structural components Not1/Not2, and the deadenylases twin/Pop2 all result in increased tumor formation. In addition, overexpression of Not3 could reduce tumor formation. Not3 downregulation has a mild but broad effect on gene expression and leads to increased levels of genes involved in DNA replication and ribosome biogenesis. CycB upregulation also contributes to the Not3 tumor phenotype. Similar findings were obtained in human T-ALL cell lines, pointing out the conserved function of Not3.ConclusionsTogether, our data establish a critical role for Not3 and the entire CCR4-NOT complex as tumor suppressor.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0650-0) contains supplementary material, which is available to authorized users.