Crosstalk between β-catenin and WT1 signalling activity in acute myeloid leukemia

Payne, Megan; Tsaponina, Olga; Caalim, G; Greenfield, Hayley M.; Milton-Harris, Leanne; Mancini, Erika J.; Blair, Allison; Heesom, KJ; Tonks, Alex; Darley, RL; Roberts, SG; Morgan, Rhys G.

doi:10.1101/2021.11.06.467095

Cited by 1 publication

(1 citation statement)

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“…Proteomic studies have revealed for the first time that β-catenin also interacts with Wilms tumour protein (WT1), in an RNA-independent manner. Interestingly, these studies demonstrated that β-catenin also co-localised with WT1 in the nucleus during Wnt activation [ 37 , 38 ]. Since this was confirmed in the HL-60 cells, in addition to primary samples, and that we have shown inhibition of β-catenin in multiple AML cell lines, it would be interesting to distinguish whether NUC-7738 also inhibits WT1 and whether this heightens the anti-leukemic response.…”

Section: Discussionmentioning

confidence: 99%

NUC-7738 regulates β-catenin signalling resulting in reduced proliferation and self-renewal of AML cells

Shahid

Elshani

et al. 2022

PLoS ONE

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Acute myeloid leukemia (AML) stem cells are required for the initiation and maintenance of the disease. Activation of the Wnt/β-catenin pathway is required for the survival and development of AML leukaemia stem cells (LSCs) and therefore, targeting β-catenin is a potential therapeutic strategy. NUC-7738, a phosphoramidate transformation of 3’-deoxyadenosine (3’-dA) monophosphate, is specifically designed to generate the active anti-cancer metabolite 3’-deoxyadenosine triphosphate (3’-dATP) intracellularly, bypassing key limitations of breakdown, transport, and activation. NUC-7738 is currently in a Phase I/II clinical study for the treatment of patients with advanced solid tumors. Protein expression and immunophenotypic profiling revealed that NUC-7738 caused apoptosis in AML cell lines through reducing PI3K-p110α, phosphorylated Akt (Ser473) and phosphorylated GSK3β (Ser9) resulting in reduced β-catenin, c-Myc and CD44 expression. NUC-7738 reduced β-catenin nuclear expression in AML cells. NUC-7738 also decreased the percentage of CD34+ CD38- CD123+ (LSC-like cells) from 81% to 47% and reduced the total number and size of leukemic colonies. These results indicate that therapeutic targeting of the PI3K/Akt/GSK3β axis can inhibit β-catenin signalling, resulting in reduced clonogenicity and eventual apoptosis of AML cells.

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Section: Discussionmentioning

confidence: 99%