Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Elagib, Kamaleldin E.; Goldfarb, Adam N.

doi:10.1016/j.canlet.2006.10.010

Cited by 48 publications

(35 citation statements)

References 55 publications

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“…For that reason, ectopic activation of CD19 and PAX5 most likely occurs at an early stage of hematopoietic differentiation. Several studies indeed suggest that oncogenic transformation by RUNX1/RUNX1T1 occurs at the hematopoietic stem cell or multipotent Lineage promiscuity in t(8;21) AML K Walter et al progenitor stage (Miyamoto et al, 1996Elagib and Goldfarb, 2007). This might also explain why CD19 is co-expressed with CD34 and is downregulated when cells differentiate toward granulocytes (Kita et al, 1992; Supplementary Figure S1).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…This constitutes an interesting model to study the distinct transcriptional responses to AML1-ETO. Indeed, the mechanism by which AML1-ETO can either activate or repress transcription in a cell-and genedependent manner is still largely unexplained (7).…”

Section: Discussionmentioning

confidence: 99%

“…AML1-ETO, the product of the t(8;21) translocation, contains AML1 N-terminal portion, including its DNA binding domain, fused to the almost entire transcriptional corepressor ETO (4,5). While it was proposed initially that AML1-ETO promotes leukemia at least in part by repressing AML1 target gene expression (6), the molecular mechanism of action of AML1-ETO is likely to be more complex since it can both repress or promote transcription depending on the target genes and the cellular context (7).…”

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confidence: 99%

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A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO

Osman

Gobert

Ponthan

et al. 2009

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

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The t(8:21)(q22;q22) translocation is 1 of the most common chromosomal abnormalities linked to acute myeloid leukemia (AML). AML1-ETO, the product of this translocation, fuses the N-terminal portion of the RUNX transcription factor AML1 (also known as RUNX1), including its DNA-binding domain, to the almost entire transcriptional corepressor ETO (also known as MTG8 or RUNX1T1). This fusion protein acts primarily by interfering with endogenous AML1 function during myeloid differentiation, although relatively few genes are known that participate with AML1-ETO during leukemia progression. Here, we assessed the consequences of expressing this chimera in Drosophila blood cells. Reminiscent of what is observed in AML, AML1-ETO specifically inhibited the differentiation of the blood cell lineage whose development depends on the RUNX factor Lozenge (LZ) and induced increased numbers of LZ ؉ progenitors. Using an in vivo RNAi-based screen for suppressors of AML1-ETO, we identified calpainB as required for AML1-ETO-induced blood cell disorders in Drosophila. Remarkably, calpain inhibition triggered AML1-ETO degradation and impaired the clonogenic potential of the human t(8;21) leukemic blood cell line Kasumi-1. Therefore Drosophila provides a promising genetically tractable model to investigate the conserved basis of leukemogenesis and to open avenues in AML therapy.acute myeloid leukemia ͉ genetic model ͉ runx A cute myeloid leukemia (AML) is characterized by the clonal growth of immature blood cells and is often associated with non-random chromosomal translocations that impair the function of key hematopoietic regulators (1). For instance, the t(8:21)(q22;q22) translocation, which is present in 10 to 15% of all cases of AML, affects the transcription factor AML1 (2). AML1 is required at multiple steps of hematopoiesis from the emergence of definitive hematopoietic stem cells to the differentiation of myeloid and lymphoid lineages (3). AML1 is a member of the RUNX family of transcription factors that are characterized by a highly conserved DNA binding domain. AML1-ETO, the product of the t(8;21) translocation, contains AML1 N-terminal portion, including its DNA binding domain, fused to the almost entire transcriptional corepressor ETO (4, 5). While it was proposed initially that AML1-ETO promotes leukemia at least in part by repressing AML1 target gene expression (6), the molecular mechanism of action of AML1-ETO is likely to be more complex since it can both repress or promote transcription depending on the target genes and the cellular context (7).To gain insights into the function and mode of action of AML1-ETO, several animal models for t(8;21) leukemia have been developed using bone marrow transplantation, knock-in or transgenic techniques (8). These models supported the hypothesis that AML1-ETO dominantly suppresses the function of the endogenous AML1 protein in vivo (9-11). In addition, these works indicate that AML1-ETO inhibits myeloid differentiation and promotes self-renewal of hematopoietic progenitors (12-16)...

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“…Leukemia-associated fusion proteins (LAFP), such as PLZF-RARa, PMLRARa, and RUNX1-ETO (referred to as AML1-ETO henceforth), are generated from chromosomal translocations and are involved in blocking differentiation, thus directly driving the malignant phenotype. They do so by recruiting histone deacetylase (HDAC) containing corepressor complexes to the promoters of differentiation genes, resulting in their transcriptional silencing (2,3). HDACs remove acetyl groups from the lysine residues of histones and other proteins.…”

Section: Introductionmentioning

confidence: 99%

Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

Petruccelli

Pettersson

Rincón

et al. 2013

Molecular Cancer Therapeutics

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Histone deacetylase inhibitors (HDI) show activity in a broad range of hematologic and solid malignancies, yet the percentage of patients in any given malignancy who experience a meaningful clinical response remains small. In this study, we sought to investigate HDI efficacy in acute myeloid leukemia (AML) cells expressing leukemia-associated fusion proteins (LAFP). HDIs have been shown to induce apoptosis, in part, through accumulation of DNA damage and inhibition of DNA repair. LAFPs have been correlated with a DNA repairdeficient phenotype, which may make them more sensitive to HDI-induced DNA damage. We found that expression of the LAFPs PLZF-RARa, PML-RARa, and RUNX1-ETO (AML1-ETO) increased sensitivity to DNA damage and apoptosis induced by the HDI vorinostat. The increase in apoptosis correlated with an enhanced downregulation of the prosurvival protein BCL2. Vorinostat also induced expression of the cell-cycle regulators p19INK4D and p21 WAF1 and triggered a G 2 -M cell cycle arrest to a greater extent in LAFP-expressing cells. The combination of LAFP and vorinostat further led to a greater downregulation of several base excision repair (BER) enzymes. These BER genes represent biomarker candidates for response to HDI-induced DNA damage. Notably, repair of vorinostat-induced DNA double-strand breaks was found to be impaired in PLZFRARa-expressing cells, suggesting a mechanism by which LAFP expression and HDI treatment cooperate to cause an accumulation of damaged DNA. These data support the continued study of HDI-based treatment regimens in LAFP-positive AMLs.

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Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Cited by 48 publications

References 55 publications

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

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

A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO

Expression of Leukemia-Associated Fusion Proteins Increases Sensitivity to Histone Deacetylase Inhibitor–Induced DNA Damage and Apoptosis

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