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

被引：20

作者：

Germano, Giuseppe ^{[1
]}

Morello, Giulia ^{[1
]}

Aveic, Sanja ^{[1
]}

Pinazza, Marica ^{[2
]}

Minuzzo, Sonia ^{[2
]}

Frasson, Chiara ^{[3
]}

Persano, Luca ^{[1
]}

Bonvini, Paolo ^{[1
]}

Viola, Giampietro ^{[3
]}

Bresolin, Silvia ^{[3
]}

Tregnago, Claudia ^{[3
]}

Paganin, Maddalena ^{[3
]}

Pigazzi, Martina ^{[3
]}

Indraccolo, Stefano ^{[4
]}

Basso, Giuseppe ^{[3
]}

机构：

[1] Fdn Inst Pediat Res Citta Speranza, Padua, Italy

[2] Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy

[3] Univ Padua, Dept Woman & Child Hlth, Padua, Italy

[4] Ist Oncol Veneto IRCCS, Immunol & Mol Oncol Unit, Padua, Italy

来源：

ONCOTARGET | 2017年 / 8卷 / 16期

关键词：

ZNF521; acute myeloid leukemia; myeloid differentiation; transcription; GENE-EXPRESSION PROFILE; ACUTE LYMPHOBLASTIC-LEUKEMIA; HUMAN HEMATOPOIETIC-CELLS; FINGER PROTEIN 521; STEM-CELLS; PARTNER GENES; PROGENITORS; HOXA9; LEUKEMOGENESIS; DISTINCT;

D O I：

10.18632/oncotarget.15387

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 shorthairpin 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.

引用

页码：26129 / 26141

页数：13

共 53 条

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