Oncotarget

Research Papers:

ZNF521 sustains the differentiation block in MLL-rearranged acute myeloid leukemia

Giuseppe Germano _, Giulia Morello, Sanja Aveic, Marica Pinazza, Sonia Minuzzo, Chiara Frasson, Luca Persano, Paolo Bonvini, Giampietro Viola, Silvia Bresolin, Claudia Tregnago, Maddalena Paganin, Martina Pigazzi, Stefano Indraccolo and Giuseppe Basso

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Oncotarget. 2017; 8:26129-26141. https://doi.org/10.18632/oncotarget.15387

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Abstract

Giuseppe Germano1, Giulia Morello1, Sanja Aveic1, Marica Pinazza2, Sonia Minuzzo2, Chiara Frasson3, Luca Persano1, Paolo Bonvini1, Giampietro Viola3, Silvia Bresolin3, Claudia Tregnago3, Maddalena Paganin3, Martina Pigazzi3, Stefano Indraccolo4, Giuseppe Basso3

1Foundation Institute of Pediatric Research Città della Speranza, Padova, Italy

2Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy

3Department of Woman and Child Health, University of Padova, Italy

4Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, Padova, Italy

Correspondence to:

Giuseppe Germano, email: giuseppe.germano@unipd.it

Keywords: ZNF521, acute myeloid leukemia, myeloid differentiation, transcription

Received: August 12, 2016     Accepted: January 31, 2017     Published: February 16, 2017

ABSTRACT

Zinc finger protein 521 (ZNF521) is a multiple zinc finger transcription factor and a strong candidate as regulator of hematopoietic stem cell homeostasis. Recently, independent gene expression profile studies have evidenced a positive correlation between ZNF521 mRNA overexpression and MLL-rearranged acute myeloid leukemia (AML), leaving open the question on the role of ZNF521 in this subtype of leukemia. In this study, we sought to analyze the effect of ZNF521 depletion on MLL-rearranged AML cell lines and MLL-AF9 xenograft primary cells. Knockdown of ZNF521 with short-hairpin RNA (shRNA) led to decreased leukemia proliferation, reduced colony formation and caused cell cycle arrest in MLL-rearranged AML cell lines. Importantly, we showed that loss of ZNF521 substantially caused differentiation of both MLL-rearranged cell lines and primary cells. Moreover, gene profile analysis in ZNF521-silenced THP-1 cells revealed a loss of MLL-AF9-directed leukemic signature and an increase of the differentiation program. Finally, we determined that both MLL-AF9 and MLL-ENL fusion proteins directly interacted with ZNF521 promoter activating its transcription. In conclusion, our findings identify ZNF521 as a critical effector of MLL fusion proteins in blocking myeloid differentiation and highlight ZNF521 as a potential therapeutic target for this subtype of leukemia.


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