Genomic analysis of relapsed Acute Lymphoblastic Leukaemia in children
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Vikki Rand
PROVIDER: E-GEOD-43060 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Identification of de novo copy number abnormalities arising in relapsed paediatric ALL in matched presentation and relapse samples. We identified deletions of BACH2, (BTB and CNC homology 1, basic leucine zipper transcription factor 2) at relapse. To study the role of Bach2 in pre-B ALL in a genetic experiment, we transformed pre-B cells from Bach2–/– mice with BCR-ABL1. Our findings identify Bach2 as a novel tumor suppressor upstream of p53 in pre-B ALL.
2013-12-21 | GSE43060 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating of paediatric malignancies and one for which no effective therapy exists. A major contributor to the failure of therapeutic trials is the assumption that biologic properties of brainstem tumours in children are identical to cerebral high-grade gliomas of adults. A better understanding of the biology of DIPG itself is needed in order to develop agents targeted more specifically to these childrenâs disease. Here we address this lack of knowledge by performing the first high-resolution SNP-based DNA microarray analysis of a series of DIPGs. Eleven samples (nine post-mortem and two pre-treatment surgical samples), the largest series thus far examined, were hybridized to Affymetrix SNP arrays (250k or 6.0). The study was approved by the Research Ethics Board at our institution (Hospital for Sick Children, Toronto, Ontario, Canada). All Array findings were validated using quantitative-PCR, fluorescence in-situ hybridization, immunohistochemistry and/or microsatellite analysis. Analysis of DIPG copy number alterations showed recurrent changes distinct from those of paediatric supratentorial high-grade astrocytomas. 36% of DIPGs had gains in PDGFRA and all showed PDGF-R-α expression. Gains in PARP-1 were identified in 3 cases. Pathway analysis revealed genes with loss of heterozygosity were enriched for DNA repair pathways. Our data provides the first, comprehensive high-resolution genomic analysis of paediatric DIPG. Our findings of recurrent involvement of the PDGFR pathway as well as defects in DNA repair pathways coupled with gain of PARP-1 highlight two potential, biologically-based, therapeutic targets directed specifically at this devastating disease. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from snap frozen biopsy and autopsy brain tissue from DIPG patients. Copy number analysis of Affymetrix 250K and 6.0 SNP arrays was performed for 11 paediatric DIPG samples, 7 matched normal brain samples, and HapMap samples.
2010-06-16 | E-GEOD-18828 | biostudies-arrayexpress
Project description:The B cell-specific BACH2 transcription factor is required for affinity maturation of mature B cells. Here, we show that Bach2 mediates negative selection at the pre-B cell receptor checkpoint and functions as a critical safeguard against leukemogenesis. Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments, and thus lack pre-B cell receptor expression. Upon productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends negative selection through BCL6-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, Bach2-mediated checkpoint control is frequently compromised and low levels of Bach2 expression represent a strong independent predictor of poor clinical outcome. Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53. Upon transformation with Myc, Bach2-/- pre-B cells fail to upregulate p53, form large colonies and initiate fatal leukemia in transplant recipient mice. ChIP-seq and gene expression analyses revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and multiple other checkpoint control genes. These findings identify Bach2 as a key activator of p53 in pre-B cells, which is critical to maintain stringency of the pre-B cell receptor checkpoint and an important barrier against leukemic transformation. ChIP-seq using BACH2 and BCL6 antibodies in OCI-Ly7 cells
2013-06-27 | E-GEOD-44420 | biostudies-arrayexpress
Project description:The B cell-specific BACH2 transcription factor is required for affinity maturation of mature B cells. Here, we show that Bach2 mediates negative selection at the pre-B cell receptor checkpoint and functions as a critical safeguard against leukemogenesis. Bach2-mediated activation of p53 is required for stringent elimination of pre-B cells that failed to productively rearrange immunoglobulin VH-DJH gene segments, and thus lack pre-B cell receptor expression. Upon productive VH-DJH gene rearrangement, pre-B cell receptor signaling ends negative selection through BCL6-mediated repression of p53. In patients with pre-B acute lymphoblastic leukemia, Bach2-mediated checkpoint control is frequently compromised and low levels of Bach2 expression represent a strong independent predictor of poor clinical outcome. Bach2+/+ pre-B cells resist leukemic transformation by Myc through Bach2-dependent upregulation of p53. Upon transformation with Myc, Bach2-/- pre-B cells fail to upregulate p53, form large colonies and initiate fatal leukemia in transplant recipient mice. ChIP-seq and gene expression analyses revealed that BACH2 competes with BCL6 for promoter binding and reverses BCL6-mediated repression of p53 and multiple other checkpoint control genes. These findings identify Bach2 as a key activator of p53 in pre-B cells, which is critical to maintain stringency of the pre-B cell receptor checkpoint and an important barrier against leukemic transformation.
2013-06-27 | GSE44420 | GEO
Project description:Affymetrix SNP 250K array data for paediatric high grade gliomas
| PRJNA255983 | ENA
Project description:In order to investigate the function of Bach2 in pre-B ALL, we isolated bone marrow cells from wildtype and Bach2 knockout mice of C57Bl6 background and transformed them with BCR-ABL1. We compared the gene expression profiles of Bach2 wildtype and knockout pre-B ALL cells, both with and without imatinib treatment (2uM for 16h).
2013-07-11 | E-GEOD-30883 | biostudies-arrayexpress
Project description:The role of FoxP3+ regulatory T (Treg) cells in the maintenance of immunological tolerance is well established. Recently, genome-wide association studies (GWAS) in humans have associated polymorphisms within the BACH2 locus encoding the transcription factor BTB and CNC homology 1, basic leucine zipper transcription factor 2 (Bach2) with diverse allergic and autoimmune diseases including asthma, multiple sclerosis, Crohn's disease, celiac disease, generalized vitiligo and type 1 diabetes. Common to these diseases is a failure to adequately maintain immunological tolerance. However, a role for Bach2 in this process has not been established. Here, by assessing the phenotype of mice in which the Bach2 gene is disrupted, we demonstrate a non-redundant role for Bach2 in the prevention of a spontaneous lethal inflammatory disorder predominantly affecting the lung and gut with excessive T helper 2 (Th2) responses and formation of circulating autoantibodies. Bach2 was necessary for efficient induction of FoxP3 expression both during thymopoesis and upon stimulation of naïve peripheral CD4+ T cells under Treg polarizing conditions in vitro. Consequently, in bone marrow reconstitution experiments, Bach2 expression within the haematopoetic system was necessary for suppression of lethal autoimmunity in a manner that was FoxP3 dependent. These findings demonstrate a requirement for Bach2 in early lineage commitment of both thymic and induced Treg cells and point to shared mechanisms that underlie diverse allergic and autoimmune disorders that may serve as targets in the development of novel therapeutic strategies. Six samples were collected from separate mice: three Ly5.1+ wildtype thymocyte samples (biological replicates) and three Ly5.1- Bach2 knockout thymocyte samples (biological replicates).
2013-11-01 | E-GEOD-42598 | biostudies-arrayexpress
Project description:Through a diversity of functional lineages, cells of the innate and adaptive immune system either drive or constrain immune reactions within tumors. Thus, while the immune system has a powerful ability to recognize and kill cancer cells, this function is often suppressed preventing clearance of disease. The transcription factor (TF) BACH2 controls the differentiation and function of multiple innate and adaptive immune lineages, but its role in regulating tumor immunity is not known. Here, we demonstrate that BACH2 is required to establish immunosuppression within tumors. We found that growth of subcutaneously implanted tumors was markedly impaired in Bach2-deficient mice and coincided with intratumoral activation of both innate and adaptive immunity but was dependent upon adaptive immunity. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-γ. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression. These findings demonstrate that BACH2 is a key component of the molecular programme of tumor immunosuppression and identify a new target for development of therapies aimed at reversing immunosuppression in cancer. Analysis of tumor-infiltrating lymphocytes in Bach2-deficient mice revealed high frequencies of CD4+ and CD8+ effector cells expressing the inflammatory cytokine IFN-γ. Lymphocyte activation coincided with reduction in the frequency of intratumoral CD4+ Foxp3+ regulatory T (Treg) cells. Mechanistically, Treg-dependent inhibition of CD8+ T cells was required for BACH2-mediated tumor immunosuppression.
2016-06-01 | E-GEOD-74653 | biostudies-arrayexpress
Project description:The aim was to investigate how BCL6 genotype affects Bach2 dependent gene expression changes. We compared gene expression profiles of BCL6+/+ and BCL6-/- BCR-ABL1 transformed pre-B cells after inducible overexpression of Bach2.
2013-07-11 | E-GEOD-41042 | biostudies-arrayexpress
Project description:Novel therapeutic strategies are needed for paediatric patients affected by Acute Myeloid Leukaemia (AML), especially for high-risk patients, characterized by high relapse incidence. MicroRNAs (miRs) have been extensively studied as biomarkers in cancer and haematological disorders, and their expression has been correlated to the presence of recurrent molecular abnormalities, expression of oncogenes, as well as to prognosis/clinical outcome. In this work, we identified different miRs expression signatures related both to presence of MLL and FLT3-ITD rearrangements and to paediatric AML patients clinical outcome. Notably, miR-221/222 resulted as a possible relapse-risk related miR. Thus, we investigated miR-221/222 expression modulation by using BRD4 and HAT inhibitors (JQ1 and curcumin), alone or in association. JQ1 modulates miR 221/222 expression in AML with a synergic effect when associated with curcumin. Moreover, we observed changes in the expression of CDKN1B, a known target of miR-221/222, increase in apoptosis and impaired colony forming capacity of AML cell lines and CD34+ AML primary cultures. Altogether, these findings suggest that several miRs expression signatures may be potentially useful as risk stratification indicators and relapse prediction markers of paediatric AML. Epigenetic drugs, deserving additional research for enhancing activity, bioavailability and safety, could represent a novel therapeutic strategy for high-risk paediatric AML patients
2022-07-30 | GSE209871 | GEO