Abstract
Leukemia-initiating cells play critical role in relapse, resistance to therapies and metastases but the mechanism remains largely elusive. We report that β-catenin is over-expressed in almost all T-ALL patients and flow sorted β-cateninhigh fractions are highly resistant to therapy, leading to liver metastases in nude mice as well as dysregulated lncRNAs. Pharmacological inhibition through XAV-939 as well as si-RNA mediated inhibition of β-catenin is initially effective in re-sensitization to therapy, however, prolonged inhibition shifts dependency from β-catenin to Notch signaling, with particularly high levels of receptors Notch 1 and Notch 2. The results are verifiable in a cohort of T-ALL patients comprising of responders vs. those who have progressed, with β-catenin, Notch 1 and Notch 2 elevated in progressed patients. Further, in patients-derived cells, silencing of Notch 1 or Notch 2 does not counter resistance to β-catenin inhibition, rather pharmacological pan-Notch inhibition is needed to overcome resistance and its effect on in vitro tumor sphere formations as well as in vivo liver metastases. Thus, wnt and Notch signaling are part of a regulatory loop mutually compensating for each other in T-ALL, while ensuring the maintenance of stem cell phenotype.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is aggressive, as its name suggests, progresses rather quickly
Our results indicate an intricate relationship between wnt and Notch signaling that helps maintain the stemness in T-ALL patients
In one of the first studies on the subject (Guo et al, 2007), it was reported that β-catenin stabilization predisposes thymocytes to malignant transformation. β-catenin is an essential factor in the canonical wnt signaling pathway wherein activated wnt signaling and binding of wnt ligand to its cognitive receptor leads to accumulation of β-catenin in cytoplasm followed by its translocation to the nucleus where it functions as a transcription factor
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is aggressive, as its name suggests, progresses rather quickly. With almost 50% survival after 5 years, the prognosis is rather poor in patients with relapsed disease (Marks and Rowntree, 2017) This calls for better understanding of factors that can potentially lead to T-ALL relapse and progression. Cancer stem cells and the process of “stemness” have long been associated with cancer relapse (Ahmad, 2013; Suresh et al, 2016; Peitzsch et al, 2017; Khandekar et al, 2019; Yin et al, 2021). This is even true for T-ALL with the realization of existence as well as Compensatory Signaling in T-ALL a role of stem cells in relapse, drug resistance and metastasis (Tremblay and Curtis, 2014; Tan et al, 2017), the mechanistic details remain largely unexplored
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