EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs

被引：59

作者：

Bindels, Eric M. J. ^{[1
]}

Havermans, Marije ^{[1
]}

Lugthart, Sanne ^{[1
]}

Erpelinck, Claudia ^{[1
]}

Wocjtowicz, Elizabeth ^{[2
]}

Krivtsov, Andrei V. ^{[3
,4
]}

Rombouts, Elwin ^{[1
]}

Armstrong, Scott A. ^{[3
,4
]}

Taskesen, Erdogan ^{[1
]}

Haanstra, Jurgen R. ^{[1
]}

Beverloo, H. Berna ^{[5
]}

Doehner, Hartmut ^{[6
]}

Hudson, Wendy A. ^{[7
]}

Kersey, John H. ^{[7
]}

Delwel, Ruud ^{[1
]}

Kumar, Ashish R. ^{[2
,7
]}

机构：

[1] Erasmus Univ, Med Ctr, Dept Hematol, NL-3015 GE Rotterdam, Netherlands

[2] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA

[3] Childrens Hosp, Dana Farber Canc Inst, Div Hematol Oncol, Dept Pediat Oncol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Boston, MA USA

[5] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands

[6] Univ Ulm, Dept Internal Med 3, D-7900 Ulm, Germany

[7] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA

来源：

BLOOD | 2012年 / 119卷 / 24期

基金：

美国国家卫生研究院;

关键词：

ACUTE MYELOID-LEUKEMIA; HIGH BRE EXPRESSION; TRANSCRIPTIONAL ELONGATION; H3K79; METHYLATION; STEM-CELLS; MLL; GENE; BINDING; INTERACTS; CHROMATIN;

D O I：

10.1182/blood-2011-11-393827

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The proto-oncogene EVI1 (ecotropic viral integration site-1), located on chromosome band 3q26, is aberrantly expressed in human acute myeloid leukemia (AML) with 3q26 rearrangements. In the current study, we showed, in a large AML cohort carrying 11q23 translocations, that similar to 43% of all mixed lineage leukemia (MLL)-rearranged leukemias are EVI1(pos). High EVI1 expression occurs in AMLs expressing the MLL-AF6, -AF9, -AF10, -ENL, or -ELL fusion genes. In addition, we present evidence that EVI1(pos) MLL-rearranged AMLs differ molecularly, morphologically, and immunophenotypically from EVI1(neg) MLL-rearranged leukemias. In mouse bone marrow cells transduced with MLL-AF9, we show that MLL-AF9 fusion protein maintains Evi1 expression on transformation of Evi1(pos) HSCs. MLL-AF9 does not activate Evi1 expression in MLL-AF9-transformed granulocyte macrophage progenitors (GMPs) that were initially Evi1(neg). Moreover, shRNA-mediated knockdown of Evi1 in an Evi1(pos) MLL-AF9 mouse model inhibits leukemia growth both in vitro and in vivo, suggesting that Evi1 provides a growth-promoting signal. Using the Evi1(pos) MLL-AF9 mouse leukemia model, we demonstrate increased sensitivity to chemotherapeutic agents on reduction of Evi1 expression. We conclude that EVI1 is a critical player in tumor growth in a subset of MLL-rearranged AMLs. (Blood. 2012; 119(24):5838-5849)

引用

页码：5838 / 5849

页数：12

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