MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia

被引：31

作者：

Riedel, Simone S. ^{[1
,2
]}

Haladyna, Jessica N. ^{[1
,2
]}

Bezzant, Matthew ^{[1
,2
]}

Stevens, Brett ^{[3
]}

Polyea, Daniel A. ^{[3
]}

Sinha, Amit U. ^{[4
,5
,8
]}

Armstrong, Scott A. ^{[4
,5
,9
,10
]}

Wei, Qi ^{[6
]}

Pollock, Roy M. ^{[7
]}

Daigle, Scott R. ^{[7
]}

Jordan, Craig T. ^{[3
]}

Ernst, Patricia ^{[1
,2
]}

Neff, Tobias ^{[1
,2
]}

Bernt, Kathrin M. ^{[1
,2
]}

机构：

[1] Univ Colorado, Sch Med, Div Pediat Hematol Oncol BMT, Aurora, CO USA

[2] Childrens Hosp Colorado, Aurora, CO USA

[3] Univ Colorado Denver, Div Hematol, Aurora, CO USA

[4] Harvard Univ, Childrens Hosp, Div Hematol Oncol, Sch Med,Dana Farber Canc Inst, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA

[6] Childrens Hosp Colorado, Dept Pathol, Aurora, CO USA

[7] Epizyme Inc, Cambridge, MA USA

[8] Basepair, New York, NY USA

[9] Mem Sloan Kettering Canc Ctr, Dept Med, Dept Pediat, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[10] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, 1275 York Ave, New York, NY 10021 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2016年 / 126卷 / 04期

关键词：

RXR-MEDIATED TRANSCRIPTION; H3K79; METHYLATION; GENE-EXPRESSION; MICRORNA EXPRESSION; STEM-CELLS; MN1; GENE; AML; FUSION; TRANSFORMATION; HEMATOPOIESIS;

D O I：

10.1172/JCI80825

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meis1 as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either MII1 or Dot1l in MN1-expressing cells abrogated the cell of origin derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mill or Dot1l impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical MN1(hi) leukemia, and human MN1(hi)/HOXA9(hi) leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in MN1(hi) AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML.

引用

页码：1438 / 1450

页数：13

共 43 条

[1] Hox genes in hematopoiesis and leukemogenesis [J].

Argiropoulos, B. ;

Humphries, R. K. .

ONCOGENE, 2007, 26 (47) :6766-6776

[2] An MLL-dependent network sustains hematopoiesis [J].

Artinger, Erika L. ;

Mishra, Bibhu P. ;

Zaffuto, Kristin M. ;

Li, Bin E. ;

Chung, Elaine K. Y. ;

Moore, Adrian W. ;

Chen, Yufei ;

Cheng, Chao ;

Ernst, Patricia .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (29) :12000-12005

[3] 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

[4]

BUIJS A, 1995, ONCOGENE, V10, P1511

[5] Identification of Regulatory Networks in HSCs and Their Immediate Progeny via Integrated Proteome, Transcriptome, and DNA Methylome Analysis [J].

Cabezas-Wallscheid, Nina ;

Klimmeck, Daniel ;

Hansson, Jenny ;

Lipka, Daniel B. ;

Reyes, Alejandro ;

Wang, Qi ;

Weichenhan, Dieter ;

Lier, Amelie ;

von Paleske, Lisa ;

Renders, Simon ;

Wuensche, Peer ;

Zeisberger, Petra ;

Brocks, David ;

Gu, Lei ;

Herrmann, Carl ;

Haas, Simon ;

Essers, Marieke A. G. ;

Brors, Benedikt ;

Eils, Roland ;

Huber, Wolfgang ;

Milsom, Michael D. ;

Plass, Christoph ;

Krijgsveld, Jeroen ;

Trumpp, Andreas .

CELL STEM CELL, 2014, 15 (04) :507-522

[6] MN1 overexpression is an important step in the development of inv(16) AML [J].

Carella, C. ;

Bonten, J. ;

Sirma, S. ;

Kranenburg, T. A. ;

Terranova, S. ;

Klein-Geltink, R. ;

Shurtleff, S. ;

Downing, J. R. ;

Zwarthoff, E. C. ;

Liu, P. P. ;

Grosveld, G. C. .

LEUKEMIA, 2007, 21 (08) :1679-1690

[7] Histone H3 Lysine 79 Methyltransferase Dot1 Is Required for Immortalization by MLL Oncogenes [J].

Chang, Ming-Jin ;

Wu, Hongyu ;

Achille, Nicholas J. ;

Reisenauer, Mary Rose ;

Chou, Chau-Wen ;

Zeleznik-Le, Nancy J. ;

Hemenway, Charles S. ;

Zhang, Wenzheng .

CANCER RESEARCH, 2010, 70 (24) :10234-10242

[8] Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l [J].

Chen, L. ;

Deshpande, A. J. ;

Banka, D. ;

Bernt, K. M. ;

Dias, S. ;

Buske, C. ;

Olhava, E. J. ;

Daigle, S. R. ;

Richon, V. M. ;

Pollock, R. M. ;

Armstrong, S. A. .

LEUKEMIA, 2013, 27 (04) :813-822

[9] 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

[10] Potent inhibition of DOT1L as treatment of MLL-fusion leukemia [J].

Daigle, Scott R. ;

Olhava, Edward J. ;

Therkelsen, Carly A. ;

Basavapathruni, Aravind ;

Jin, Lei ;

Boriack-Sjodin, P. Ann ;

Allain, Christina J. ;

Klaus, Christine R. ;

Raimondi, Alejandra ;

Scott, Margaret Porter ;

Waters, Nigel J. ;

Chesworth, Richard ;

Moyer, Mikel P. ;

Copeland, Robert A. ;

Richon, Victoria M. ;

Pollock, Roy M. .

BLOOD, 2013, 122 (06) :1017-1025

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