Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma

Richter-Larrea, Jose A.; Robles, Eloy F.; Fresquet, Vicente; Beltrán, Elena; Rullan, Antonio; Agirre, Xabier; Calasanz, Marı́a José; Panizo, Carlos; Richter, José; Hernández, Jesús M.; Román‐Gómez, José; Prósper, Felipe; Martínez-Climent, José A.

doi:10.1182/blood-2010-02-268003

Cited by 100 publications

(104 citation statements)

References 41 publications

(65 reference statements)

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“…128 Moreover, in BL, the BIM and PUMA genes were found to be silenced by epigenetic alterations, such as hyper-methylation. 129,130 Furthermore, the region harbouring the BMF gene is lost in late stage lung and breast cancer. 131 These observations demonstrate that abnormalities in antias well as pro-apoptotic BCL-2 family members can contribute to the development of cancer in humans.…”

Section: Role Of the Bcl-2-regulated Apoptotic Pathway In Human Cancermentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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Section: Role Of the Bcl-2-regulated Apoptotic Pathway In Human Cancermentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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“…In Burkitt lymphoma, epigenetic silencing of Bim by promoter hypermethylation contributes to chemoresistance. 43 To determine whether Bim and Bmf genes are repressed by a similar mechanism in resistant cells, we performed bisulfite DNA sequencing analysis on the promoter regions of Bim and Bmf genes in both parental and WM793-Res cells. CpG methylation was readily detected in the Bim promoter and positions of methylated CpG dinucleotides were identical in both parental and resistant cells (Supplementary Figure 9A).…”

Section: Impaired Erk1/2 Inactivation In Plx4720-resistant Cellsmentioning

confidence: 99%

BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma

Shao

Aplin

2012

Cell Death Differ

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B-RAF is mutated to a constitutively active form in 8% of human cancers including 50% of melanomas. In clinical trials, the RAF inhibitor, PLX4032 (vemurafenib), caused partial or complete responses in 48-81% of mutant B-RAF harboring melanoma patients. However, the average duration of response was 6-7 months before tumor regrowth, indicating the acquisition of resistance to PLX4032. To understand the mechanisms of resistance, we developed mutant B-RAF melanoma cells that displayed resistance to RAF inhibition through continuous culture with PLX4720 (the tool compound for PLX4032). Resistance was associated with a partial reactivation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, recovery of G1/S cellcycle events, and suppression of the pro-apoptotic B-cell leukemia/lymphoma 2 (Bcl-2) homology domain 3 (BH3)-only proteins, Bcl-2-interacting mediator of cell death-extra large (Bim-EL) and Bcl-2 modifying factor (Bmf). Preventing ERK1/2 reactivation with MEK (mitogen-activated protein/extracellular signal-regulated kinase kinase) inhibitors blocked G1-S cell-cycle progression but failed to induce apoptosis or upregulate Bim-EL and Bmf. Treatment with the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid, led to de-repression of Bim-EL and enhanced cell death in the presence of PLX4720 or AZD6244 in resistant cells. These data indicate that acquired resistance to PLX4032/4720 likely involves ERK1/2 pathway reactivation as well as ERK1/2-independent silencing of BH3-only proteins. Furthermore, combined treatment of HDAC inhibitors and MEK inhibitors may contribute to overcoming PLX4032 resistance. Oncogene addiction refers to the dependence of tumor cells on the continued expression of an oncogene for the maintenance of malignant properties.1 It has gained increasing recognition in recent years and provides the rationale for targeted therapeutic strategies. Notable advances are the responses of chronic myelogenous leukemia patients with BCR-ABL (breakpoint cluster region-v-abl abelson murine leukemia viral oncogene homolog 1) translocations to imatinib, breast cancer patients with amplified human epidermal receptor 2 (HER2) to trastuzumab, and mutant epidermal growth factor receptor (EGFR)-harboring nonsmall cell lung carcinomas patients to erlotinib and gefitinib treatments.2-4 A more recent example is the strategy to target mutations in the serine/threonine kinase B-RAF that occur in B50% of melanomas, 30% of thyroid carcinomas, and 14% of colorectal tumors.5 A valine to glutamic acid substitution at codon 600 (V600E) accounts for over 90% of the mutations in B-RAF and activates B-RAF kinase activity toward the MEKextracellular signal-regulated kinase 1/2 (ERK1/2) cascade. B-RAFV600E and MEK (mitogen-activated protein/extracellular signal-regulated kinase kinase) activity are required for melanoma cell proliferation, invasion, and resistance to apoptosis in vitro, 6-11 and tumor xenograft growth in immunocompromised mice. 8,12 Furthermore, conditional melanocyte-specific expr...

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“…[28][29][30][31][32] We first evaluated DNA methylation at the Bim promoter in shSpi-1-A2C and shSpi-1-A2B cells by IP of methylated DNA (MeDIP) using an antibody against 5-methylcytidine. We detected DNA methylation at the Bim promoter between 2.1 and 1.1 kb upstream of the TSS (Figure 6c).…”

Section: Spi-1 Decreases Bim Expression In Preleukaemic Cellsmentioning

confidence: 99%

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

et al. 2013

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Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. Cell Death and Differentiation (2013) 20, 1268-1278; doi:10.1038/cdd.2013.88; published online 12 July 2013Acute myeloid leukaemia (AML) develops through a multistep process driven by the progressive accumulation of mutations, leading to deregulation of cell proliferation and differentiation. Most frequently, abnormalities in cell differentiation are the result of loss-of-function mutations in lineage-specific transcription factors, whereas alterations in cell proliferation are associated with gain-of-function mutations in signalling pathways. 1 Mutations that target components of the spliceosomal machinery 2 and epigenetic regulators 3 have been identified as well, although their functional consequences in leukaemogenesis are not clear. To date, AML treatments are largely determined by the nature of the identified mutated proteins and a major challenge is to design molecules that can target each molecular alteration contributing to transformation. For that, understanding the molecular mechanisms controlled by an oncoprotein is one essential step. We have previously described a mouse model of erythroleukaemia (Spi-1 transgenic mice) that recapitulates the multistep development of human AML. 4 Spi-1 is a master transcription factor of haematopoiesis that is also involved in pre-mRNA splicing regulation. 5 During the preleukaemic stage of the disease, the differentiation blockage of the erythroid progenitors is the first oncogenic mark assoc...

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Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma

Cited by 100 publications

References 41 publications

The BCL-2 protein family, BH3-mimetics and cancer therapy

The BCL-2 protein family, BH3-mimetics and cancer therapy

BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

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