The t(8;21) fusion protein, AML1–ETO, specifically represses the transcription of the p14ARF tumor suppressor in acute myeloid leukemia

Linggi, Bryan; Müller‐Tidow, Carsten; Locht, Louis van de; Hu, Ming; Nip, John; Serve, Hubert; Berdel, Wolfgang E.; Reijden, Bert van der; Quelle, Dawn E.; Rowley, Janet D.; Cleveland, John L.; Jansen, Joop H.; Pandolfi, Pier Paolo; Hiebert, Scott W.

doi:10.1038/nm726

Cited by 246 publications

(214 citation statements)

References 40 publications

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“…This might also be the case for other fusion oncoproteins, such as PML-RARa (Liu et al, 2006). Also the P14/P19-P53 cell cycle control pathway can be suggested as a connection point for both hypoxia and CBF fusion oncoproteins (Harris, 2002;Lacaud et al, 2002;Linggi et al, 2002).…”

Section: Discussionmentioning

confidence: 89%

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

et al. 2006

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The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1a-aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein.Functional studies show that TEL-ARNT interacts with HIF1a and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1a/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34 þ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.

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Section: Discussionmentioning

confidence: 89%

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

et al. 2006

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“…However, there are only a very limited number of AML1/ETO target genes (for example, p14 arf and C/EBPa), whose regulation was validated in vivo in primary AML blasts Linggi et al, 2002). Three groups have engineered human cell line models of inducible AML1/ETO expression (Burel et al, 2001;Alcalay et al, 2003;Fliegauf et al, 2004).…”

Section: Lat2 Is a Target Gene Of Aml1/etomentioning

confidence: 99%

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

et al. 2011

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The chromosomal translocation (8;21) fuses the hematopoietic transcription factor AML1 (RUNX1) with ETO (RUNX1T1, MTG8), resulting in the leukemia-specific chimeric protein AML1/ETO. This fusion protein has been implicated in epigenetic silencing, recruiting histone deacetylases (HDACs) and DNA methyltransferases to target promoters. Previously, we have identified a novel in vivo AML1/ETO target gene, LAT2 (NTAL/LAB/ WBSCR5), which is involved in FceR I, c-Kit, B-cell and T-cell receptor signalling. We have now addressed the molecular mechanisms of AML1/ETO-mediated LAT2 repression. In Kasumi-1 cells, where AML1/ETO bound to the LAT2 gene, small interfering RNA (siRNA)-mediated AML1/ETO depletion caused upregulation of LAT2, suggesting a possible direct mechanism of repression. Expression of AML1/ETO was associated with a decrease in acetylation of histones H3, H3K9 and H4, and an increase in H3K9 and H3K27 trimethylation. The class I-specific HDAC inhibitors entinostat (MS-275) and mocetinostat (MGCD0103) induced LAT2 expression specifically in AML1/ETO-expressing cells, resulting in induction of several activating histone marks on the LAT2 gene, including trimethylation of histone H3K4. The combination of entinostat and decitabine increased acetylation of histones H3 and H4, as well as LAT2 mRNA expression, in an at least additive fashion. In conclusion, several repressive histone modifications mark the LAT2 gene in the presence of AML1/ETO, and LAT2 gene derepression is achieved by pharmacological inhibition of HDACs.

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“…The Runt domain is involved in DNA binding and heterodimerization with CBFb (Kagoshima et al, 1993) whereas RUNX1T1 can interact with several transcriptional co-repressors (Amann et al, 2001). As a result, the RUNX1-RUNX1T1 fusion protein can recruit transcriptional co-repressor complexes to RUNX1 binding sites and thus represses RUNX1 target genes (Linggi et al, 2002;Follows et al, 2003). However, ectopic expression of RUNX1-RUNX1T1 in human CD34 þ hematopoietic precursor cells induces both the upregulation and downregulation of a number of genes (Mulloy et al, 2005;Tonks et al, 2007), indicating that the expression of this oncoprotein disturbs the entire myeloid gene regulatory network.…”

Section: Introductionmentioning

confidence: 99%

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

et al. 2010

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Correct hematopoietic differentiation requires the tightly regulated execution of lineage-specific and stage-restricted gene expression programs. This process is disturbed in hematological malignancies that typically show incomplete differentiation but often also display a mixed lineage phenotype. Co-expression of lymphoid and myeloid molecules is a well-known feature of acute myeloblastic leukemia (AML) with t(8;21). These cells consistently express the B-cell-specific transcription factor PAX5, and the B-cell-specific cell surface protein CD19. However, the functional consequences of PAX5 expression are unknown. To address this question, we studied the chromatin features of CD19, which is a direct target of PAX5 in cells with and without the t(8;21) chromosomal translocation. We show that CD19 chromatin exists in a poised configuration in myeloid progenitors and that this poised chromatin structure facilitates PAX5-dependent CD19 activation. Our results also show a positive correlation between PAX5 and CD19 expression in t(8;21)-positive AML cells and demonstrate that PAX5 binds to the promoter and enhancer of CD19 gene and remodels chromatin structure at the promoter. This study shows that expression of PAX5 in leukemic cells has functional consequences and points to an important role of a progenitor-specific chromatin configuration in myeloid leukemia.

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The t(8;21) fusion protein, AML1–ETO, specifically represses the transcription of the p14ARF tumor suppressor in acute myeloid leukemia

Cited by 246 publications

References 40 publications

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

Aberrant expression of CD19 in AML with t(8;21) involves a poised chromatin structure and PAX5

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