Id2 and E Proteins Orchestrate the Initiation and Maintenance of MLL-Rearranged Acute Myeloid Leukemia

被引：29

作者：

Ghisi, Margherita ^{[1
,2
]}

Kats, Lev ^{[1
,3
]}

Masson, Frederick ^{[4
,5
,6
,7
]}

Li, Jason ^{[3
,8
]}

Kratina, Tobias ^{[6
,7
]}

Vidacs, Eva ^{[1
]}

Gilan, Omer ^{[1
,3
]}

Doyle, Maria A. ^{[9
]}

Newbold, Andrea ^{[1
,3
]}

Bolden, Jessica E. ^{[7
,10
]}

Fairfax, Kirsten A. ^{[7
,10
]}

de Graaf, Carolyn A. ^{[7
,10
]}

Firth, Matthew ^{[6
,7
]}

Zuber, Johannes ^{[11
]}

Dickins, Ross A. ^{[2
]}

Corcoran, Lynn M. ^{[6
,7
]}

Dawson, Mark A. ^{[1
,3
]}

Belz, Gabrielle T. ^{[6
,7
]}

Johnstone, Ricky W. ^{[1
,3
]}

机构：

[1] Peter MacCallum Canc Ctr, Canc Therapeut Program, St Andrews Pl, East Melbourne, Vic 3002, Australia

[2] Monash Univ, Australian Ctr Blood Dis, Melbourne, Vic 3004, Australia

[3] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia

[4] Olivia Newton John Canc Res Inst, Canc Inflammat Lab, Heidelberg, Vic 3084, Australia

[5] La Trobe Univ, Sch Canc Med, Heidelberg, Vic 3084, Australia

[6] Walter & Eliza Hall Inst Med Res, Mol Immunol Div, Parkville, Vic 3052, Australia

[7] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia

[8] Peter MacCallum Canc Ctr, Bioinformat Core, St Andrews Pl, East Melbourne, Vic 3002, Australia

[9] Peter MacCallum Canc Ctr, Res Comp Facil, St Andrews Pl, East Melbourne, Vic 3002, Australia

[10] Walter & Eliza Hall Inst Med Res, Mol Med Div, 1G Royal Parade, Parkville, Vic 3052, Australia

[11] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, Dr Bohr Gasse 7, A-1030 Vienna, Austria

来源：

CANCER CELL | 2016年 / 30卷 / 01期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

STEM-CELLS; SELF-RENEWAL; EXPRESSION; PROGNOSIS; PROGRAM; PROGENITOR; PREDICTS; GENES;

D O I：

10.1016/j.ccell.2016.05.019

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8;21) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8; 21) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.

引用

页码：59 / 74

页数：16

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