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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24404 | GEO | 2011/02/15

SECONDARY ACCESSION(S): PRJNA133747

REPOSITORIES: GEO

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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

Inhibition of BCL6-dependent gene expression 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 analyzed the gene expression changes after treatment with Imatinib or Imatinib + RI-BPI.

2011-03-01 | GSE24381 | GEO

Inhibition of BCL6-dependent gene expression 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 analyzed the gene expression changes after treatment with Imatinib or Imatinib + RI-BPI. Three Ph+ ALL cell lines (BV-173, SUP-B15 and TOM-1) were treated in the presence or absence of 10 μM STI571 (Imatinib) or in the presence of both 10 μM STI571 and 20 μM RI-BPI for 24 hours.

2011-03-01 | E-GEOD-24381 | biostudies-arrayexpress

Effect of imatinib on 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. In this study, the tyrosine kinase inhibitor imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of Ph+ ALL cell lines were analyzed in response to imatinib treatment.

2010-09-10 | GSE23743 | GEO

Effect of imatinib on 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. In this study, the tyrosine kinase inhibitor imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of Ph+ ALL cell lines were analyzed in response to imatinib treatment. Four Ph+ ALL cell lines (BV-173, NALM-1, SUP-B15, and TOM1) were either treated with 10µM STI571 (Imatinib) for 16 hours or cultured in absence of STI571.

2010-09-10 | E-GEOD-23743 | biostudies-arrayexpress

Effect of Imatinib on chronic myelogenous leukemia

Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which is present in almost every patient with chronic myeloid leukemia. In this study, the tyrosine kinase inhibitor Imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of CML cell lines were analyzed in response to Imatinib treatment.

2010-10-10 | GSE24493 | GEO

SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms

Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1+, but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.

2017-06-06 | GSE99656 | GEO

Transcription profiling of human BCR-ABL1-transformed acute lymphoblastic leukemia cells reveals Activation-induced cytidine deaminase acts as a mutator

Project description:The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of ALL with a particularly unfavorable prognosis. Acute lymphoblastic leukemia (ALL) cells are derived from B cell precursors in most cases and typically carry rearranged immunglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph-positive ALLs as compared to 6 of 80 Ph-negative ALLs. Forced expression of BCR-ABL1 in Ph-negative ALL cells and inhibition of the BCR-ABL1-kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph-positive ALL, IGH V region genes and BCL6 were mutated in many Ph-positive but unmutated in most Ph-negative cases. In addition, AID introduced DNA-single-strand breaks within the tumor suppressor gene CDKN2B in Ph-positive ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph-positive ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset. Experiment Overall Design: To study the gene expression profile of two Ph-positive ALL cell lines (BV173 and SUP-B15) in the presence or absence of 10 Î¼mol/l STI571 for 16 hours

2008-06-15 | E-GEOD-7182 | biostudies-arrayexpress

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

Project description:Ph+ acute lymphoblastic leukemia (ALL) is characterized by the expression of an oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors result in elevated expression of IL7R which enable the survival of transformed cells when IL7 was added together with the kinase inhibitors. Importantly, treatment with anti-IL7R antibodies prevents leukemia development in xenotransplantation models using patient-derived Ph+ ALL cells. Our results suggest that the association between IL7R and CXCR4 serves as molecular platform for BCR-ABL1 induced transformation and development of Ph+ ALL. Targeting this platform with anti-IL7R antibody eliminates Ph+ ALL cells including those with resistance to commonly used ABL1 kinase inhibitors. Thus, anti-IL7R antibodies may provide alternative treatment options for ALL in general and may suppress incurable drug-resistant leukemia forms.

2020-05-19 | GSE150784 | GEO

Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1-transformed acute lymphoblastic leukemia cells

Project description:The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of ALL with a particularly unfavorable prognosis. Acute lymphoblastic leukemia (ALL) cells are derived from B cell precursors in most cases and typically carry rearranged immunglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph-positive ALLs as compared to 6 of 80 Ph-negative ALLs. Forced expression of BCR-ABL1 in Ph-negative ALL cells and inhibition of the BCR-ABL1-kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph-positive ALL, IGH V region genes and BCL6 were mutated in many Ph-positive but unmutated in most Ph-negative cases. In addition, AID introduced DNA-single-strand breaks within the tumor suppressor gene CDKN2B in Ph-positive ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph-positive ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset. Keywords: gene expression array-based (RNA / in situ oligonucleotide)

2007-04-03 | GSE7182 | GEO

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