The genetic basis of early T-cell precursor acute lymphoblastic leukaemia

Zhang, Jinghui; Li, Ding; Holmfeldt, Linda; Wu, Gang; Heatley, Sue L.; Payne-Turner, Debbie; Easton, John; Chen, Xiang; Wang, Jianmin; Rusch, Michael; Lu, Charles; Chen, Shann Ching; Wei, Lei; Collins-Underwood, J. Racquel; Ma, Jing; Roberts, Kathryn G.; Pounds, Stanley; Ulyanov, Anatoly; Becksfort, Jared; Gupta, Pankaj; Huether, Robert; Kriwacki, Richard W.; Parker, Matthew; McGoldrick, Daniel; Zhao, David; Alford, Daniel P.; Espy, Stephen; Bobba, Kiran Chand; Song, Guangchun; Pei, Deqing; Cheng, Cheng; Roberts, Stefan; Barbato, Michael I.; Campana, Dario; Coustan‐Smith, Elaine; Shurtleff, Sheila; Raimondi, Susana C.; Kleppe, Maria; Cools, Jan; Shimano, Kristin A.; Hermiston, Michelle L.; Doulatov, Sergei; Eppert, Kolja; Laurenti, Elisa; Notta, Faiyaz; Dick, John E.; Basso, Giuseppe; Hunger, Stephen P.; Loh, Mignon L.; Devidas, Meenakshi; Wood, Brent L.; Winter, Stuart S.; Dunsmore, Kimberly P.; Fulton, Robert S.; Fulton, Lucinda L.; Hong, Xin; Harris, Christopher; Dooling, David J.; Ochoa, Kerri; Johnson, Kimberly; Obenauer, John C.; Evans, William E.; Pui, Ching Hon; Naeve, Clayton W.; Ley, Timothy J.; Mardis, Elaine R.; Wilson, Richard K.; Downing, James R.; Mullighan, Charles G.

doi:10.1038/nature10725

Cited by 1,455 publications

(1,637 citation statements)

References 41 publications

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“…[30][31][32] It is possible that high expression of ERG, BAALC, or WT1 signifies stem cell-like properties that protect these tumors against chemotherapy. In fact, T-ALL/ LBL with an ETP immunophenotype has a genetic profile more akin to normal hematopoietic and myeloid leukemic stem cells 33 and may carry FLT3-ITD mutation, a feature typically associated with AML. 34 TdT is normally expressed in committed T-lymphocytic progenitors.…”

Section: Discussionmentioning

confidence: 99%

Absence of terminal deoxynucleotidyl transferase expression identifies a subset of high-risk adult T-lymphoblastic leukemia/lymphoma

et al. 2013

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Section: Discussionmentioning

confidence: 99%

Absence of terminal deoxynucleotidyl transferase expression identifies a subset of high-risk adult T-lymphoblastic leukemia/lymphoma

et al. 2013

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“…A gain-of-function mutation for EZH2 has been described in large cell lymphoma (28). On the other hand, heterozygous and homozygous mutation and/or deletion of EZH2 has been described in some hematologic malignancies (8)(9)(10)(11)(12)29), but is not typically seen in AML. Understanding of PRC2 biology in cancer is limited by the heterogeneity of clinical samples and the pleiotropy of genetic programs controlled by PRC2.…”

Section: Discussionmentioning

confidence: 99%

“…In the hematopoietic system, forced expression of Ezh2 increases serial transplantation potential in hematopoietic stem cells (6) and enhances transformation in a model of multiple myeloma (7). Intriguingly, heterozygous loss of function of EZH2 has been associated with adverse prognosis in myelofibrosis (8), and heterozygous and homozygous inactivation of EZH2 has been described in myelodysplastic syndromes and more recently in Tlineage lymphoblastic leukemia (9)(10)(11)(12). In contrast, EZH2 alterations appear to be rare events in acute myeloid leukemia (AML).…”

mentioning

confidence: 99%

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

Neff

Sinha

Kluk

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

201

218

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A growing body of data suggests the importance of epigenetic mechanisms in cancer. Polycomb repressive complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers. However, its role in cancer development and progression remains unclear. We used conditional alleles for the PRC2 components enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared with wild-type leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML, but plays a role in leukemia progression. Genome-wide analyses of PRC2-mediated trimethylation of histone 3 demonstrated locus-specific persistence of H3K27me3 despite inactivation of Ezh2, suggesting partial compensation by Ezh1. In contrast, inactivation of the essential PRC2 gene, Eed, led to complete ablation of PRC2 function, which was incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared with Ezh2-null leukemic cells, including down-regulation of Myc target genes and up-regulation of PRC2 targets. Manipulating PRC2 function may be of therapeutic benefit in AML. epigenetics | mouse model | polycomb group proteins | myeloid-lymphoid leukemia protein P olycomb repressive complex 2 (PRC2) has been implicated in development and cancer (1, 2). PRC2 is composed of the core components embryonic ectoderm development (EED), suppressor of zeste 12 (SUZ12), and a SET-domain methyltransferase, either enhancer of zeste 2 (EZH2) or enhancer of zeste 1 (EZH1) (3). The PRC2 complex catalyzes the di-and trimethylation of lysine residue 27 of histone 3 (H3K27me3), a repressive chromatin mark (4). Overexpression of EZH2 has been correlated with prostate cancer progression (5). Follow-up studies have confirmed and expanded these results for other cancer types, mainly solid tumors. In the hematopoietic system, forced expression of Ezh2 increases serial transplantation potential in hematopoietic stem cells (6) and enhances transformation in a model of multiple myeloma (7). Intriguingly, heterozygous loss of function of EZH2 has been associated with adverse prognosis in myelofibrosis (8), and heterozygous and homozygous inactivation of EZH2 has been described in myelodysplastic syndromes and more recently in Tlineage lymphoblastic leukemia (9-12). In contrast, EZH2 alterations appear to be rare events in acute myeloid leukemia (AML). How to reconcile these findings on a mechanistic level is unclear. Given the heterogeneity of clinical samples, elucidating the complex role of PRC2 biology in cancer will be aided by studies in genetically defined animal models (13).Loss of function of PRC2 has been evaluated in several cancer models (14, 15). However, shRNA...

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“…The paradoxical role of EZH2 in tumorigenesis has been observed in several human cancers (16). Although its oncogenic role in promoting cancer progression has been well documented, in certain contexts it also can function as a tumor suppressor (17,20,(58)(59)(60)(61). In addition to leukemia, a tumor-suppressive role for EZH2 has been found in solid tumors such as pancreatic (61) and renal cancer (60).…”

Section: Discussionmentioning

confidence: 99%

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

Mahara

Lee

Feng

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Despite the established oncogenic function of Polycomb repressive complex 2 (PRC2) in human cancers, its role as a tumor suppressor is also evident; however, the mechanism underlying the regulation of the paradoxical functions of PRC2 in tumorigenesis is poorly understood. Here we show that hypoxia-inducible factor 1, α-subunit (HIFI-α) is a crucial modulator of PRC2 and enhancer of zeste 2 (EZH2) function in breast cancer. Interrogating the genomic expression of breast cancer indicates high HIF1A activity correlated with high EZH2 expression but low PRC2 activity in triple-negative breast cancer compared with other cancer subtypes. In the absence of HIFIA activation, PRC2 represses the expression of matrix metalloproteinase genes (MMPs) and invasion, whereas a discrete Ezh2 complexed with Forkhead box M1 (FoxM1) acts to promote the expression of MMPs. HIF1-α induction upon hypoxia results in PRC2 inactivation by selective suppression of the expression of suppressor of zeste 12 protein homolog (SUZ12) and embryonic ectoderm development (EED), leading to a functional switch toward Ezh2/FoxM1-dependent induction of the expression of MMPs and invasion. Our study suggests a tumor-suppressive function of PRC2, which is restricted by HIF1-α, and an oncogenic function of Ezh2, which cooperates with FoxM1 to promote invasion in triple-negative breast cancer.

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The genetic basis of early T-cell precursor acute lymphoblastic leukaemia

Cited by 1,455 publications

References 41 publications

Absence of terminal deoxynucleotidyl transferase expression identifies a subset of high-risk adult T-lymphoblastic leukemia/lymphoma

Absence of terminal deoxynucleotidyl transferase expression identifies a subset of high-risk adult T-lymphoblastic leukemia/lymphoma

Polycomb repressive complex 2 is required for MLL-AF9 leukemia

HIFI-α activation underlies a functional switch in the paradoxical role of Ezh2/PRC2 in breast cancer

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