The E3 ubiquitin ligase WWP1 sustains the growth of acute myeloid leukaemia

A G Sanarico, C Ronchini, A Croce, E M Memmi, U A Cammarata, A De Antoni, S Lavorgna, M Divona, L Giacò, G E M Melloni, A Brendolan, G Simonetti, G Martinelli, P Mancuso, F Bertolini, F Lo Coco, G Melino, P G Pelicci, F Bernassola

Research output: Contribution to journalArticlepeer-review


The E3 ubiquitin ligase (E3) WWP1 is an oncogenic factor implicated in the maintenance of different types of epithelial cancers. The role of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) in haematological neoplasms remains unknown. Acute myeloid leukaemia (AML) is characterized by the expansion of malignant myeloid cells blocked at different stages of differentiation. Here we report that the expression of WWP1 is significantly augmented in a large cohort of primary AML patients and in AML cell lines, compared with haematopoietic cells from healthy donors. We show that WWP1 inactivation severely impairs the growth of primary AML blasts and cell lines in vitro. In vivo, we observed a reduced leukaemogenic potential of WWP1-depleted AML cells upon transplantation into immunocompromised mice. Mechanistically, WWP1 inactivation induces the accumulation of its protein substrate p27Kip1, which ultimately contributes to G0/G1 cell cycle arrest of AML blasts. In addition, WWP1 depletion triggers the autophagy signalling and reduces survival of leukaemic cells. Collectively, our findings provide molecular insights into the anti-cancer potential of WWP1 inhibition, suggesting that this E3 is a promising biomarker and druggable target in AML.

Original languageEnglish
Pages (from-to)911-919
Number of pages9
Issue number4
Publication statusPublished - Apr 2018


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