NRARP displays either pro- or anti-tumoral roles in T-cell acute lymphoblastic leukemia depending on Notch and Wnt signaling

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis in patients with resistant or relapsed disease. Although NOTCH is a known driver in T-ALL, its clinical inhibition has significant limitations. Our previous studies suggested that NRARP, a negative regulator of Notch signaling, could have a suppressive role in T-ALL. Here, we report that NRARP levels are significantly increased in primary T-ALL cells suggesting that NRARP is not sufficient to block NOTCH oncogenic signals. Interestingly, although NRARP overexpression blocks NOTCH1 signaling and delays the proliferation of T-ALL cells that display high levels of Notch1 signaling, it promotes the expansion of T-ALL cells with lower levels of Notch1 activity. We found that NRARP interacts with lymphoid enhancer-binding factor 1 (LEF1) and potentiates Wnt signaling in T-ALL cells with low levels of Notch. Together these results indicate that NRARP plays a dual role in T-ALL pathogenesis, regulating both Notch and Wnt pathways, with opposite functional effects depending on Notch activity. Consistent with this hypothesis, mice transplanted with T-cells co-expressing NOTCH1 and NRARP develop leukemia later than mice transplanted with T-NOTCH1 cells. Importantly, mice transplanted with T-cells overexpressing NRARP alone developed leukemia with similar kinetics to those transplanted with T-NOTCH1 cells. Our findings uncover a role for NRARP in T-ALL pathogenesis and indicate that Notch inhibition may be detrimental for patients with low levels of Notch signaling, which would likely benefit from the use of Wnt signaling inhibitors. Importantly, our findings may extend to other cancers where Notch and Wnt play a role.

Network-based integrated analysis for toxic effects of high-concentration formaldehyde inhalation exposure through the toxicogenomic approach

“…S2 ). Although the functions of NRARP and its association with formaldehyde have not been fully understood, it interacts with Notch and WNT signaling in angiogenesis 54 and presents dual pro- or antitumor activity 55 . The Notch1 gene positively regulates Nrarp 56 and is upregulated in the long-term exposure (5 days to 13 weeks) DEG results.…”

The multiple ways Wnt signaling contributes to acute leukemia pathogenesis

“…NRARP delays the proliferation of T‐ALL cells with highly activated Notch. On the other hand, NRARP interacts with LEF‐1 in cells showing lower levels of Notch activity and potentiates Wnt signaling 130 . These data suggest that Notch and Wnt signaling can independently promote leukemogenesis, opening a new road on T‐ALL biology, especially in cases with wild‐type NOTCH1 .…”

Molecular Pathways and Druggable Targets in Head and Neck Squamous Cell Carcinoma

“…So far, a dual biological activity of Notch signalling has been reported in solid tumours. Preliminary reports of NOTCH1 mutations in T cell acute lymphoblastic leukaemia (TALL) and chronic hematopoietic cancers were implicated as oncogenic [ 84 , 85 , 86 , 87 ]. Genome sequencing of HNSCC suggested NOTCH1 acts as a tumour suppressor gene, and was the second most frequently mutated with an incidence of 15–19% [ 15 , 16 ].…”