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BCL6 is required for the initiation and maintenance of chronic myeloid leukemia

ABSTRACT: We identified the BCL6 protooncogene as a critical downstream effector of FoxO3A in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for leukemia stem cell maintenance, colony formation and initiation of leukemia in transplant recipients. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia-initiation in xenotransplanted mouse recipients. These findings identify peptide-inhibition of BCL6 as a novel strategy to eradicate leukemia-initiating cells in CML. Identification of BCL6 binding sites in human CML cell line JURL-MK1

ORGANISM(S): Homo sapiens

SUBMITTER: Katerina Hatzi

PROVIDER: E-GEOD-26085 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia.

Hurtz Christian C Hatzi Katerina K Cerchietti Leandro L Braig Melanie M Park Eugene E Kim Yong-mi YM Herzog Sebastian S Ramezani-Rad Parham P Jumaa Hassan H Müller Martin C MC Hofmann Wolf-Karsten WK Hochhaus Andreas A Ye B Hilda BH Agarwal Anupriya A Druker Brian J BJ Shah Neil P NP Melnick Ari M AM Müschen Markus M

The Journal of experimental medicine 20110912 11

Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent ...[more]

PMID: 21911423

Similar Datasets

BCL6 is required for the initiation and maintenance of chronic myeloid leukemia

Project description:We identified the BCL6 protooncogene as a critical downstream effector of FoxO3A in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for leukemia stem cell maintenance, colony formation and initiation of leukemia in transplant recipients. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia-initiation in xenotransplanted mouse recipients. These findings identify peptide-inhibition of BCL6 as a novel strategy to eradicate leukemia-initiating cells in CML.

2011-09-15 | GSE26085 | GEO

BCL6 enables leukemia cells to cope with inhibition of oncogenic tyrosine kinases

Project description:This SuperSeries is composed of the following subset Series: GSE24381: Inhibition of BCL6-dependent gene expression in Philadelphia chromosome positive acute lymphoblastic leukemia GSE24404: Recruitment of BCL6 to target genes in Philadelphia chromosome positive acute lymphoblastic leukemia Refer to individual Series

2011-02-15 | E-GEOD-24426 | biostudies-arrayexpress

Recruitment of BCL6 to target genes in Philadelphia chromosome positive acute lymphoblastic leukemia

Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. Tyrosine kinase inhibitors (TKI) are widely used to treat patients with leukemia driven by BCR-ABL1 and other oncogenic tyrosine kinases. In response to TKI-treatment, BCR-ABL1 ALL cells upregulate BCL6 protein levels by ~90-fold, i.e. to similar levels as in diffuse large B cell lymphoma (DLBCL) with BCL6 translocations. In this study, we used genome tiling arrays to identify BCL6 target genes with specific recruitment of BCL6. Three Ph+ ALL cell lines (BV-173, NALM-1 and TOM-1) in duplicate were either treated with 10µM STI571 (Imatinib) for 24 hours or cultured in absence of STI571.

2011-02-15 | E-GEOD-24404 | biostudies-arrayexpress

BCL6 mediates Chemoresistance in Acute Myeloid Leukemia

Project description:BCL6 is a transcription repressor that plays a crucial role in germinal center formation and lymphomagenesis. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). Heterogeneous levels of BCL6 were found across AML cell lines and primary AML samples. Cells with higher levels of BCL6 were indeed sensitive to treatment with BCL6 inhibitors. Gene expression profiling of AML cells treated with BCL6 inhibitor revealed a subset of target genes that are common with lymphoma cells. Ex vivo treatment of primary AML cells with BCL6 peptide inhibitor (BPI) induced apoptosis and decrease colony forming capacity which correlated with the levels of BCL6 expression . Importantly, inhibition of BCL6 in primary AML cells with either BPI or BCL6 siRNA resulted in significant reduction of leukemia initiating capacity using immunodeficient mice, suggesting ablation of leukemia stem cells (LSC). Such anti-LSC activity was also observed as downregulation of LSC gene signatures using gene expression analyses of cells treated with a BCL6 inhibitor. Importantly, treatment with cytarabine (AraC) induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to AraC. Treatment of AML primary derived xenografts (PDX) revealed that when AraC was combined with BCL6 inhibitor, inhibition of BCL6 significantly potentiated the efficacy of AraC and improved cytotoxic effects by interfering with the leukemia initiating capacity of AML cells. This suggests that pharmacological inhibition of BCL6 might provide a novel therapeutic strategy for ablation of LSCs and overcome chemoresistance in AML.

2020-08-01 | GSE133112 | GEO

Gene expression profiles of mouse BM LSKs, wild-type as well as Ezh2 KO mouse CML leukemia initiating cells (LICs)

Project description:Tyrosine kinase inhibitors (TKIs) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia initiating cells (LICs) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs, required for colony formation, and survival and cell cycle progression of CML cell lines. A critical role for Ezh2 is supported by genetic studies in a mouse CML model. Inactivation of Ezh2 in conventional conditional mice and through CRISPR/Cas9-mediated gene editing prevents initiation and maintenance of disease and survival of LICs, irrespective of BCR/ABL1 mutational status, and extends survival. Expression of the Ezh2 homolog Ezh1 is reduced in Ezh2-deficient CML LICs, creating a scenario resembling complete loss of PRC2. EZH2-dependence of CML LICs raises prospects for improved therapy of TKI-resistant CML and/or eradication of disease by addition of EZH2 inhibitors.

2016-08-18 | GSE85744 | GEO

Gene expression data of BCR-ABL1 transformed myeloid cells from BCL6 wild-type and BCL6 knockout mice treated with and without Imatinib and RI-BPI

2011-08-24 | GSE24813 | GEO

Transcription profiling of chicken Bcl6 deficient DT40 B cell line to investigate the targets of Bcl6 which is required for germinal center formation

Project description:The transcription factor Bcl6 is required for germinal center formation and deregulated expression of Bcl6 has been observed in lymphomas. To gain insight to the function of Bcl6 in terminal differentiation of B cells to plasma cells and to investigate the targets of Bcl6, we established a Bcl6 deficient DT40 B cell line.

2010-02-17 | E-MEXP-2062 | biostudies-arrayexpress

Gene expression data of BCR-ABL1 transformed myeloid cells from BCL6 wild-type and BCL6 knockout mice treated with and without Imatinib and RI-BPI

Project description:To identify differences in the gene regulation between BCL6+/+ and BCL6-/- CML cells a gene expression analysis has been performed. We investigated the gene expression pattern in BCL6+/+ cells in the presence or absence of Imatinib and a combination of Imatinib and RI-BPI (a novel retro-inverso BCL6 peptide inhibitor). In BCL6-/- CML cells, we investigated the gene expression pattern in the presence or absence of Imatinib. BCR-ABL1 transformed myeloid cells from BCL6+/+ mice were cultured in the presence or absence of 10µM Imatinib or 10µM Imatinib and 20µM RI-BPI for 16 hours. BCR-ABL1 transformed myeloid cells from BCL6-/- mice were cultured in the presence or absence of 10µM Imatinib. Two samples for each condition were processed.

2011-08-23 | E-GEOD-24813 | biostudies-arrayexpress

The BCL6 RD2 domain governs commitment of activated B-cells to form germinal centers

Project description:Our data demonstrated that Bcl6 directly binds and represses trafficking receptors S1pr1 and Grp183 by recruiting Hdac2 through the RD2 domain. Deregulation of these genes impairs B-cell migration and may contribute to the Germinal Center failure in Bcl6RD2MUT mice. RNAseq was performed in endogenous BCL6-depleted OCI-LY1 cells rescued with either WT or RD mutant BCL6 (N=3 for each group).

2014-09-14 | E-GEOD-58365 | biostudies-arrayexpress

Bcl6 expression specifies the T follicular helper cell program in vivo

Project description:T follicular helper (Tfh) cells play a pivotal role in germinal center reactions, which requires Bcl6 transcription factor. To analyze their relationships with other effector T cell lineages and their stability in vivo, we developed and analyzed a new Bcl6 reporter mouse alone or together with other lineage reporter systems. Assisted with genome-wide transcriptome analysis, we show substantial plasticity of T cell differentiation in the early phase of immune response. At this stage, CXCR5 appears to be expressed in a Bcl6-independent manner. Once Bcl6 is highly expressed, Tfh cells can persist in vivo and some of them develop into memory cells. Together, our results indicate Bcl6 as a bona fide marker for Tfh polarized program. Three group of samples, with 2 biological replicates within each group and total of 6 samples were analyzed.

2012-09-17 | E-GEOD-40068 | biostudies-arrayexpress

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