Role of the Polycomb Repressive Complex 2 in Acute Promyelocytic Leukemia

Villa, Raffaella; Pasini, Diego; Gutiérrez, Arantxa; Morey, Lluís; Occhionorelli, Manuela; Viré, Emmanuelle; Nomdedeu, Josep; Jenuwein, Thomas; Pelicci, Pier Giuseppe; Minucci, Saverio; Fuks, François; Helin, Kristian; Croce, Luciano Di

doi:10.1016/j.ccr.2007.04.009

Cited by 228 publications

(192 citation statements)

References 52 publications

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“…Functional dissection of protein complexes associated with oncogenic transcription factors, which often represent the initiating events in acute leukemia (24), is critical for understanding the transformation mechanisms and identifying potential therapeutic targets for intervention of self-renewal pathways corrupted in cancer stem cells (20,22,(25)(26)(27). CBF␤, which plays an important role for wild-type AML1 functions, in part by increasing its DNA binding ability (28) and stability (29), has been thought to be a critical component and potential target for AE-mediated transformation (1,10).…”

Section: Discussionmentioning

confidence: 99%

Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

Kwok

Zeisig

Qiu

et al. 2009

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

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Although both heterodimeric subunits of core binding factors (AML1/RUNX1 and CBF␤) essential for normal hematopoiesis are frequently mutated to form different chimeric fusion proteins in acute leukemia, the underlying molecular mechanisms and structural domains required for cellular transformation remain largely unknown. Despite the critical role of CBF␤ for wild-type AML1 function and its direct involvement in chromosomal translocation, we demonstrate that both the expression and interaction with CBF␤ are superfluous for AML1-ETO (AE)-mediated transformation of primary hematopoietic cells. Similarly, the hetero-oligomeric interaction with transcriptional repressor ETO family proteins and the highly conserved NHR1 domain in AE fusion are also dispensable for transforming activity. In contrast, AE-mediated transformation is critically dependent on the DNA binding and homo-oligomeric properties of the fusion. Abolishment of homooligomerization by a small-molecule inhibitor could specifically suppress AML1 fusion-mediated transformation of primary hematopoietic cells. Together, these results not only identify the essential molecular components but also potential avenues for therapeutic targeting of AE-mediated leukemogenesis.A ML1/RUNX1 and CBF␤ are 2 critical transcription factors essential for generation of hematopoietic stem cells (HSCs) (1, 2). Mice deficient in AML1 or CBF␤ have almost identical phenotypes; they completely lack definitive hematopoiesis and die at approximately embryonic day 12.5. In acute myeloid leukemia in which leukemic stem cells have been functionally identified, AML1 and CBF␤ represent the most commonly mutated targets (1, 2). t(8;21) resulting in AML1-ETO (AE) fusion can be found in up to 40% of AML-M2; and inv(16) leading to CBF␤-SHMMC fusion constitutes approximately 30% of AML-M4. AML1 is also fused to TEL as a result of t(12;21) in approximately 25% of childhood leukemia, the most common form of childhood cancers. Although animal modeling clearly indicates that AML1 fusions per se are not sufficient for induction of full-blown leukemia, they function to enhance self-renewal and expand targeted HSCs and early progenitors for cooperative secondary mutations to take place (3-5).While enhanced self-renewal has emerged as a critical feature associated with various oncogenic transcription factors involved in acute leukemia (6-8), much less is known about the underlying molecular mechanisms. It is clear that most, if not all, of the transcription factors do not work as monomers but need to complex with various proteins for full activity and specificity, although the molecular composition of the associated transcriptional complexes required for self-renewal remains largely unknown. At the molecular level, AE encodes the DNA-binding runt homology domain (RHD) fused in-frame with almost the entire transcriptional repressor protein ETO containing 4 different Nervy homology regions (NHRs) (Fig. 1A), suggesting a gain of transcriptional repressor function by the oncogenic fusion (9). A well-reco...

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Section: Discussionmentioning

confidence: 99%

Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

Kwok

Zeisig

Qiu

et al. 2009

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

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“…The PMLRARAa fusion protein characteristic of promyelocyte leukemia was recently shown to bind and recruit EZH2, the catalytic component of the PRC2 complex. 76 Overexpression of PRC1 complex components, such as BMI1, has been correlated with adverse outcomes in several hematopoietic malignancies. [77][78][79][80][81][82] However, little is known about the actual mechanisms involved, but with the advent of genome-wide studies this is likely to change in the near future.…”

Section: H3k27 Methylationmentioning

confidence: 99%

Chromatin maps, histone modifications and leukemia

Neff

Armstrong

2009

Leukemia

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“…4,6 In APL cells, PML-RARA forms homodimers, multimeric complexes and heterodimers with retinoid X receptor that all bind to retinoic acid responsive element and repress transcription at physiological levels of RA through recruitment of co-repressor complexes containing HDACs, DNA methyltransferases and polycomb histone methyltransferases. 4,[7][8][9][10] At pharmacological levels, however, RA reverses PML-RARA mediated repression of RARA target genes resulting in terminal neutrophil differentiation of APL cells. 4,5 Although these findings highlight the progress in our understanding of how PML-RARA represses transcription at the molecular level, little is currently known regarding the gene-expression signature that emerges as a consequence of PML-RARA and secondary genetic aberrations in human APL.…”

Section: Introductionmentioning

confidence: 99%

A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

et al. 2010

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Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges as a consequence of the t(15;17) translocation, acts as a transcriptional repressor that blocks neutrophil differentiation at the promyelocyte (PM) stage. In this study, we used publicly available microarray data sets and identified signatures of genes dysregulated in APL by comparison of gene expression profiles of APL cells and normal PMs representing the same stage of differentiation. We next subjected our identified APL signatures of dysregulated genes to a series of computational analyses leading to (i) the finding that APL cells show stem cell properties with respect to gene expression and transcriptional regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost. In a broader perspective, our study provides strong evidence that genomic strategies might be used in a clinical setting to prospectively identify candidate drugs that subsequently are validated in vitro to define the most effective drug combination for individual cancer patients on a rational basis.

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Role of the Polycomb Repressive Complex 2 in Acute Promyelocytic Leukemia

Cited by 228 publications

References 52 publications

Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

Chromatin maps, histone modifications and leukemia

A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

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