Wnt/β-catenin signaling is critically required for the development and maintenance of leukemia stem cells (LSCs) in acute myeloid leukemia (AML) by constitutive activation of myeloid regeneration-related pathways. Cell-intrinsic activation of canonical Wnt signaling propagates in the nucleus by β-catenin translocation, where it induces expression of target oncogenes such as JUN, MYC and CCND1. As the Wnt/β−catenin pathway is now well established to be a key oncogenic signaling pathway promoting leukemic myelopoiesis, targeting it would be an effective strategy to impair LSC functionality. Although the effects of the adenosine analogue cordycepin in repressing β-catenins and destabilizing the LSC niche have been highlighted, the cellular and molecular effects on AML–LSC have not been fully clarified. In the present study, we evaluated the potency and efficacy of cordycepin, a selective repressor of Wnt/β-catenin signaling with anti-leukemia properties, on the AC133+ LSC fraction. Cordycepin effectively reduces cell viability of the AC133+ LSCs in the MUTZ−2 cell model and patient-derived cells through the induction of apoptosis. By Wnt-targeted RNA sequencing panel, we highlighted the re-expression of WIF1 and DKK1 among others, and the consequent downregulation of MYC and PROM1 (CD133) following MUTZ−2 cell exposure to increasing doses of cordycepin. Our results provide new insights into the molecular circuits involved in pharmacological inhibition mediated by cordycepin reinforcing the potential of targeting the Wnt/β-catenin and co-regulatory complexes in AML.

Abazari, N., Stefanucci, M., Bossi, L., Trojani, A., Cairoli, R., Beghini, A. (2023). Cordycepin (3′dA) Induces Cell Death of AC133+ Leukemia Cells via Re-Expression of WIF1 and Down-Modulation of MYC. CANCERS, 15(15) [10.3390/cancers15153931].

Cordycepin (3′dA) Induces Cell Death of AC133+ Leukemia Cells via Re-Expression of WIF1 and Down-Modulation of MYC

Cairoli, R;
2023

Abstract

Wnt/β-catenin signaling is critically required for the development and maintenance of leukemia stem cells (LSCs) in acute myeloid leukemia (AML) by constitutive activation of myeloid regeneration-related pathways. Cell-intrinsic activation of canonical Wnt signaling propagates in the nucleus by β-catenin translocation, where it induces expression of target oncogenes such as JUN, MYC and CCND1. As the Wnt/β−catenin pathway is now well established to be a key oncogenic signaling pathway promoting leukemic myelopoiesis, targeting it would be an effective strategy to impair LSC functionality. Although the effects of the adenosine analogue cordycepin in repressing β-catenins and destabilizing the LSC niche have been highlighted, the cellular and molecular effects on AML–LSC have not been fully clarified. In the present study, we evaluated the potency and efficacy of cordycepin, a selective repressor of Wnt/β-catenin signaling with anti-leukemia properties, on the AC133+ LSC fraction. Cordycepin effectively reduces cell viability of the AC133+ LSCs in the MUTZ−2 cell model and patient-derived cells through the induction of apoptosis. By Wnt-targeted RNA sequencing panel, we highlighted the re-expression of WIF1 and DKK1 among others, and the consequent downregulation of MYC and PROM1 (CD133) following MUTZ−2 cell exposure to increasing doses of cordycepin. Our results provide new insights into the molecular circuits involved in pharmacological inhibition mediated by cordycepin reinforcing the potential of targeting the Wnt/β-catenin and co-regulatory complexes in AML.
Articolo in rivista - Articolo scientifico
AC133+; AML; cordycepin; MYC; WIF1;
English
2-ago-2023
2023
15
15
3931
open
Abazari, N., Stefanucci, M., Bossi, L., Trojani, A., Cairoli, R., Beghini, A. (2023). Cordycepin (3′dA) Induces Cell Death of AC133+ Leukemia Cells via Re-Expression of WIF1 and Down-Modulation of MYC. CANCERS, 15(15) [10.3390/cancers15153931].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/433618
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