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.
Highlights
These authors contributed : Inês Pinto, Mafalda Duque
To understand if NOTCH regulated ankyrin repeat protein (NRARP) plays a role in T-cell acute lymphoblastic leukemia (T-ALL) pathogenesis we started by characterizing NRARP expression in T-ALL primary cells and cell lines
Consistent with our observations in cell lines, NRARP forced expression in NOTCH1 mutant/NICD1 high T-ALL samples negatively impacted cell number (Fig. 5a) and viability (Fig. 5b), whereas it had the opposite effect on NOTCH1 wild type/NOTCH1 intracellular domain (NICD) low cases (Fig. 5a, b)
Summary
The outcome of T-ALL patients has improved significantly, the prognosis of patients with resistant or relapsed disease remains dismal [2, 3] This and the high toxicity of the existing therapies underline the need to develop more specific and effective therapeutic strategies [3, 4]. Our previous studies revealed that loss of mir-181ab inhibits leukemia development at least in part by derepressing the expression of Nrarp [13]. These results suggested that deregulation of NRARP may contribute to the pathogenesis of T-ALL. We uncover a dual role for NRARP dependent on NOTCH1 intracellular domain (NICD) levels, with opposite functional outcomes in T-ALL pathogenesis. Our findings establish a new paradigm in what regards the outcomes of the cross talk between Notch and Wnt signaling pathways in T-ALL, with important therapeutic implications
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