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

共 49 条

[1] Evi-1 is a transcriptional target of mixed-lineage leukemia oncoproteins in hematopoietic stem cells [J].

Arai, Shunya ;

Yoshimi, Akihide ;

Shimabe, Munetake ;

Ichikawa, Motoshi ;

Nakagawa, Masahiro ;

Imai, Yoichi ;

Goyama, Susumu ;

Kurokawa, Mineo .

BLOOD, 2011, 117 (23) :6304-6314

[2] High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome [J].

Balgobind, B. V. ;

Zwaan, C. M. ;

Reinhardt, D. ;

Arentsen-Peters, T. J. C. M. ;

Hollink, I. H. I. M. ;

de Haas, V. ;

Kaspers, G. J. L. ;

de Bont, E. S. J. M. ;

Baruchel, A. ;

Stary, J. ;

Meyer, C. ;

Marschalek, R. ;

Creutzig, U. ;

den Boer, M. L. ;

Pieters, R. ;

van den Heuvel-Eibrink, M. M. .

LEUKEMIA, 2010, 24 (12) :2048-2055

[3] EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia [J].

Balgobind, B. V. ;

Lugthart, S. ;

Hollink, I. H. ;

Arentsen-Peters, S. T. J. C. M. ;

van Wering, E. R. ;

de Graaf, S. S. N. ;

Reinhardt, D. ;

Creutzig, U. ;

Kaspers, G. J. L. ;

de Bont, E. S. J. M. ;

Stary, J. ;

Trka, J. ;

Zimmermann, M. ;

Beverloo, H. B. ;

Pieters, R. ;

Delwel, R. ;

Zwaan, C. M. ;

van den Heuvel-Eibrink, M. M. .

LEUKEMIA, 2010, 24 (05) :942-949

[4] MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L [J].

Bernt, Kathrin M. ;

Zhu, Nan ;

Sinha, Amit U. ;

Vempati, Sridhar ;

Faber, Joerg ;

Krivtsov, Andrei V. ;

Feng, Zhaohui ;

Punt, Natalie ;

Daigle, Amanda ;

Bullinger, Lars ;

Pollock, Roy M. ;

Richon, Victoria M. ;

Kung, Andrew L. ;

Armstrong, Scott A. .

CANCER CELL, 2011, 20 (01) :66-78

[5] The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling [J].

Bitoun, Emmanuelle ;

Oliver, Peter L. ;

Davies, Kay E. .

HUMAN MOLECULAR GENETICS, 2007, 16 (01) :92-106

[6] Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia [J].

Bullinger, L ;

Döhner, K ;

Bair, E ;

Fröhling, S ;

Schlenk, RF ;

Tibshirani, R ;

Döhner, H ;

Pollack, JR .

NEW ENGLAND JOURNAL OF MEDICINE, 2004, 350 (16) :1605-1616

[7] EVI1 induces myelodysplastic syndrome in mice [J].

Buonamici, S ;

Li, DL ;

Chi, YQ ;

Zhao, R ;

Wang, XR ;

Brace, L ;

Ni, HY ;

Saunthararajah, Y ;

Nucifora, G .

JOURNAL OF CLINICAL INVESTIGATION, 2004, 114 (05) :713-719

[8] Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1 and in co-localization in nuclear speckles [J].

Chakraborty, S ;

Senyuk, V ;

Sitailo, S ;

Chi, YQ ;

Nucifora, G .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (48) :44936-44943

[9] Malignant transformation initiated by MII-AF9: Gene dosage and critical target cells [J].

Chen, Weili ;

Kumar, Ashish R. ;

Hudson, Wendy A. ;

Li, Quanzhi ;

Wu, Baolin ;

Staggs, Rodney A. ;

Lund, Erik A. ;

Sam, Thien N. ;

Kersey, John H. .

CANCER CELL, 2008, 13 (05) :432-440

[10] Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors [J].

Cozzio, A ;

Passegué, E ;

Ayton, PM ;

Karsunky, H ;

Cleary, ML ;

Weissman, IL .

GENES & DEVELOPMENT, 2003, 17 (24) :3029-3035

← 1 2 3 4 5 →