ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer

Thoms, Julie A.I.; Birger, Yehudit; Foster, Sam; Knezevic, Kathy; Kirschenbaum, Yael; Chandrakanthan, Vashe; Jonquières, Georg von; Spensberger, Dominik; Wong, Jason; Oram, S. Helen; Kinston, Sarah; Groner, Yoram; Lock, Richard B.; MacKenzie, Karen L.; Göttgens, Berthold; Izraeli, Shai; Pimanda, John E.

doi:10.1182/blood-2010-12-317990

Cited by 88 publications

(100 citation statements)

References 48 publications

(76 reference statements)

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“…To test this hypothesis, we first examined UTX binding to several previously characterized TAL1-activated genes, including RALDH2 (also called ALDH1A2), the proto-oncogene MYB, and genes involved in cell proliferation (e.g., ERG) and apoptosis inhibition (e.g., CD226) (Palii et al 2011b;Thoms et al 2011;Sanda et al 2012). Chromatin immunoprecipitation (ChIP) experiments indicate that UTX is bound to all TAL1 target genes that were examined ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, TAL1 is necessary for the maintenance of leukemia, as shown by the dramatic increase in apoptosis observed in T-ALL cells upon TAL1 knockdown (Palii et al 2011b;Sanda et al 2012). We (Palii et al 2011b) and others (Kusy et al 2010;Thoms et al 2011;Sanda et al 2012) have previously identified TAL1 genomic binding sites in T-ALL, revealing that TAL1 controls the expression of specific genes necessary for cell growth and maintenance of T-ALL. However, the molecular mechanism through which TAL1 regulates transcription of these genes remains unclear.…”

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confidence: 99%

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UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia

et al. 2016

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T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T-ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtypespecific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia

et al. 2016

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“…Using either a vav promoter-driven ERG transgenic approach, or retroviral-mediated ERG overexpression in bone marrow transplant mice, two separate studies have described the development of ERG-induced T-cell leukemias. Both studies also demonstrated that acquired mutations in Notch1 were a common cooperating event (18,19). In addition, retroviral-mediated ERG overexpression in fetal liver cells (FLCs) or post-5-fluorouracil (5FU) bone marrow has been reported to induce development of a non lymphoid disease in bone marrow transplant mice.…”

Section: Mice Homozygous For the Lossof-function Ergmentioning

confidence: 98%

Hematopoietic overexpression of the transcription factor Erg induces lymphoid and erythro-megakaryocytic leukemia

Carmichael

Metcalf

Henley

et al. 2012

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

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The transcription factor encoded by the E-twenty-six (ETS)-related gene, ERG, is an essential regulator of hematopoietic stem cell function and a potent human oncoprotein. Enforced expression of ERG in murine hematopoietic cells leads to the development of a well-characterized lymphoid leukemia and a less well-defined non lymphoid disease. To clarify the latter, we generated murine bone marrow chimeras with enforced Erg expression in engrafted hematopoietic progenitor cells. As expected, these mice developed lymphoid leukemia. However, the previously reported non lymphoid disease that developed was shown to be a uniform, transplantable leukemia with both erythroid and megakaryocytic characteristics. In vivo, this disease had the overall appearance of an erythroleukemia, with an accumulation of immature erythroblasts that infiltrated the bone marrow, spleen, liver, and lung. However, when stimulated in vitro, leukemic cell clones exhibited both erythroid and megakaryocytic differentiation, suggesting that transformation occurred in a bipotential progenitor. Thus, in mice, Erg overexpression induces the development of not only lymphoid leukemia but also erythro-megakaryocytic leukemia.

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“…Those observations might reflect a higher ERG overexpression in non-DS-AMKL driven by other genetic abnormalities, whereas a low, increased ERG expression in DS leukemia could be sufficient to cooperate with other trisomic genes, as demonstrated in our study, such as DYRK1A, CHAF1B and/or HLCS. Since ERG overexpression has been associated with various types of cancer (49) and recently correlated with promotion and maintenance of T acute lymphoblastic leukemia (50,51), additional experiments will be required to ensure that ERG trisomy is directly implicated in DS-AMKL as opposed to oncogenesis in general.…”

Section: Discussionmentioning

confidence: 99%

Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome

Malinge¹,

Bliss-Moreau²,

Kirsammer³

et al. 2012

J. Clin. Invest.

161

196

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Individuals with Down syndrome (DS; also known as trisomy 21) have a markedly increased risk of leukemia in childhood but a decreased risk of solid tumors in adulthood. Acquired mutations in the transcription factor-encoding GATA1 gene are observed in nearly all individuals with DS who are born with transient myeloproliferative disorder (TMD), a clonal preleukemia, and/or who develop acute megakaryoblastic leukemia (AMKL). Individuals who do not have DS but bear germline GATA1 mutations analogous to those detected in individuals with TMD and DS-AMKL are not predisposed to leukemia. To better understand the functional contribution of trisomy 21 to leukemogenesis, we used mouse and human cell models of DS to reproduce the multistep pathogenesis of DS-AMKL and to identify chromosome 21 genes that promote megakaryoblastic leukemia in children with DS. Our results revealed that trisomy for only 33 orthologs of human chromosome 21 (Hsa21) genes was sufficient to cooperate with GATA1 mutations to initiate megakaryoblastic leukemia in vivo. Furthermore, through a functional screening of the trisomic genes, we demonstrated that DYRK1A, which encodes dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A, was a potent megakaryoblastic tumor-promoting gene that contributed to leukemogenesis through dysregulation of nuclear factor of activated T cells (NFAT) activation. Given that calcineurin/NFAT pathway inhibition has been implicated in the decreased tumor incidence in adults with DS, our results show that the same pathway can be both proleukemic in children and antitumorigenic in adults. IntroductionTrisomy 21 is the most common cytogenetic abnormality observed at birth (about 1 out of 700 individuals) and one of the most recurrent aneuploidies seen in leukemia. As an acquired clonal chromosomal change, its incidence varies between 4.1% and 14.8% in hematological disorders and malignant lymphomas (1). Supporting the link between trisomy 21 and abnormal hematopoiesis, epidemiological studies have shown that individuals with Down syndrome (DS) have an increased frequency of leukemia but a lower incidence of solid tumors (2). Whereas recent studies implicated a subset of trisomic genes, including Erg, Ets2, Adamts1, and Dscr1, in tumor growth inhibition, in part through an altered angiogenesis (3-6), the role of trisomy 21, the initiating event in DS leukemogenesis, and the functional implication of specific genes at dosage imbalances that predispose to and/or participate in leukemogenesis remain unclear.Children with DS are at an elevated risk of both acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL) (7). Moreover, epidemiological studies showed that approximately 4%-5% of children with DS are born with transient myeloproliferative disorder (TMD), a clonal preleukemia characterized by an accumulation of immature megakaryoblasts in the fetal liver and peripheral blood (8,9). Although TMD spontaneously disappears in most cases, TMD clones reemerge as AMKL in 20% of cases within 4 to 5 y...

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ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer

Cited by 88 publications

References 48 publications

UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia

UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia

Hematopoietic overexpression of the transcription factor Erg induces lymphoid and erythro-megakaryocytic leukemia

Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome

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