H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

被引：40

作者：

Godfrey, Laura ^{[1
]}

Crump, Nicholas T. ^{[1
]}

O'Byrne, Sorcha ^{[2
]}

Lau, I-Jun ^{[1
]}

Rice, Siobhan ^{[1
]}

Harman, Joe R. ^{[1
]}

Jackson, Thomas ^{[2
]}

Elliott, Natalina ^{[2
]}

Buck, Gemma ^{[2
]}

Connor, Christopher ^{[3
]}

Thorne, Ross ^{[1
]}

Knapp, David J. H. F. ^{[4
]}

Heidenreich, Olaf ^{[5
,6
]}

Vyas, Paresh ^{[1
,7
]}

Menendez, Pablo ^{[8
,9
,10
]}

Inglott, Sarah ^{[3
]}

Ancliff, Philip ^{[3
]}

Geng, Huimin ^{[11
]}

Roberts, Irene ^{[1
,2
]}

Roy, Anindita ^{[2
]}

Milne, Thomas A. ^{[1
]}

机构：

[1] Univ Oxford, MRC Mol Haematol Unit, MRC Weatherall Inst Mol Med, NIHR Oxford Biomed Res Ctr Haematol Theme, Oxford, England

[2] Univ Oxford, Dept Paediat, Oxford, England

[3] Great Ormond St Hosp Sick Children, London, England

[4] Univ Oxford, Radcliffe Dept Med, MRC Weatherall Inst Mol Med, Oxford, England

[5] Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands

[6] Newcastle Univ, Wolfson Childhood Canc Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[7] Oxford Univ Hosp NHS Fdn Trust, Dept Haematol, Oxford, England

[8] Josep Carreras Leukemia Res Inst, Barcelona, Spain

[9] ICREA, Barcelona, Spain

[10] Ctr Invest Biomed Red Canc CIBERONC ISCIII, Barcelona, Spain

[11] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA

来源：

LEUKEMIA | 2021年 / 35卷 / 01期

基金：

英国惠康基金; 欧洲研究理事会; 英国医学研究理事会;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; EXPRESSION ANALYSIS; PROGNOSTIC MARKERS; FUSION PROTEIN; CHROMATIN; CD133; LINE; METHYLATION; SENSITIVITY; POLYCOMB;

D O I：

10.1038/s41375-020-0808-y

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.

引用

页码：90 / 106

页数：17

共 1 条

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He, Liqun
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