Defining the molecular basis of oncogenic cooperation between TAL1 expression and Pten deletion in T-ALL using a novel pro-T-cell model system

Abstract

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.

STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells

“…Interestingly, we found that STAT5 could bind near the MCL1 gene, albeit without leading to its transcriptional activation (supplemental Figure 4), which is in agreement with the fact that IL-7 does not upregulate Mcl-1 protein in these cells (supplemental Figure 6). Genes upregulated by IL-7 in a STAT5-dependent manner in TAIL7 cells include HRH2, APOL4, and CA6, as well as, expectedly, OSM, IKZF4, PIM1, SOCS2, and CISH, [45][46][47][48][49] whereas among the top downregulated genes, we found BCL6, NLRP6, and IL10 ( Figure 5D; supplemental Figure 4). We validated these results by qPCR analysis of IL-7-treated TAIL7 cells in the presence or absence of S5i.…”

“…63 In T-ALL, IL-7 rapidly activates PI3K/Akt, MEK/ERK, and JAK/STAT pathways, 1,17,18,64 which contrasts with the heterogeneous ability of IL-7 to activate MEK/ERK pathway, and the delayed kinetics of Akt activation, in normal T-cells. 48,65,66 In fact, all 3 pathways are activated not only by IL-7 binding to its receptor, leading to heterodimerization of IL-7Ra with gc chain, 1,64 but also by mutational activation of IL-7Ra, which occurs in 9% to 10% of T-ALL cases, relies on receptor homodimerization, and does not require the ligand. 20,[67][68][69] We previously showed that MEK/ERK pathway is dispensable for IL-7-induced viability, growth, or proliferation of T-ALL cells cultured in vitro, 17 whereas PI3K/Akt signaling plays a critical role in mediating IL-7 proleukemia effects.…”

Clinical and biological features of PTPN2-deleted adult and pediatric T-cell acute lymphoblastic leukemia

“…We hypothesize that PTEN and PTPN2 pathways could be functionally incompatible, as recently demonstrated for TAL1 and IL7R/JAK-STAT signaling cascades. 33 Functional experiments are needed to understand the mutual exclusion of these 2 phosphatase alterations in T-ALL.…”

Oncogenic transcriptional program driven by TAL1 in T-cell acute lymphoblastic leukemia

“…Additionally, recent genomic studies have provided a comprehensive catalog of chromosomal and genetic abnormalities involved in T-ALL, including mutations of epigenetic regulators (e.g., PHF6, EZH2, SUZ12), the PI3K-PTEN-AKT pathway (e.g., PTEN, PIK3R1), the JAK-STAT pathway (e.g., JAK3, IL7R), ribosomal genes (e.g., RPL10), USP7, BCL11B, and NRAS genes, for example [35,36]. It should be noted that although it is not exclusive, some of these abnormalities are more frequently found in specific subgroup(s) of T-ALL (e.g., PTEN mutations in TAL-positive cases) [35,37,38], suggesting a potential collaborating effect between type A and type B abnormalities. Please also refer to several recent review articles for more details regarding genetic abnormalities [24][25][26].…”

“…Additionally, recent genome-wide studies have revealed that several genes are more frequently mutated in the TAL1positive T-ALL subgroup than in other subgroups [35]. For instance, mutations in the genes mediating the PI3K-PTEN-AKT-mTOR pathway, including PTEN, are observed in approximately half of TAL1-postive human T-ALL cases [35,37,38], while these mutations are less frequently found in TAL1-negative cases. This finding suggests potential collaborating effects or a requirement of this pathway and could also coincide with the fact that TAL1 affects the mTOR pathway in normal HSCs via the repression of DDIT4 [53].…”