Affymetrix SNP6.0 array data for PAX5 amplified acute lymphoblastic leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE99813 | GEO | 2017/06/09
SECONDARY ACCESSION(S): PRJNA389710
REPOSITORIES: GEO
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Project description:One of the most frequently mutated proteins in human B-lineage leukemia, mutated in about one third of all cases, is the transcription factor PAX5. While reduced function of PAX5 has a clear connection to human malignancy there is limited evidence of a direct impact on the development and function of B-cell progenitors. One possible explanation to this comes from the finding that PAX5 mutated B-ALL display complex karyotypes and additional mutations, indicating that PAX5 might be just one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we used BioID technology to identify associated proteins. This revealed 239 proteins out of which several could be found mutated in human B-ALL. Most prominently we identified IKZF1, commonly mutated, and RUNX1, involved in the formation of ETV6-AML1 fusion protein formation, among the interaction partners. ChIP-seq as well as PLAC-seq analysis supported the idea that these factors share regulatory elements in human B-ALL cells. Gene expression and mutation analysis of both mouse models and primary human leukemia suggested that these factors form a functional gene regulatory network targeted by multiple mutations in human B-ALL. Keywords: Expression profiling by high throughput sequencing
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Project description:Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) shown to have a dismal outcome on standard therapy. For improved diagnosis and prognosis of these patients, the initiating genetic events need to be elucidated. To investigate the genetic basis, the genomes of 94 iAMP21 patients were interrogated by genomic arrays, FISH and MLPA. Detailed mapping of chromosome 21 refined the common region of amplification (CRA) to 5.1 Mb; including the RUNX1 gene, miR-802 and genes mapping to the Down Syndrome Critical Region. Over a quarter of copy number alterations targeted chromosome 21, including telomeric deletions in 88% of patients. Global analysis by genomic arrays identified recurrent abnormalities affecting genes in key pathways. The frequency of these abnormalities were determined by FISH and/or MLPA; IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%) and RB1 (37%). Study of the clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 instability. This study provides convincing evidence that chromosome 21 instability is the only abnormality common to all iAMP21 patients and the initiating event is likely hidden within the complex structural rearrangements of this abnormal chromosome. DNA copy number analysis of 17 diagnostic and 1 relapse acute lymphoblastic leukaemia samples was performed using agilent 185K microarrays. These samples were hybridised against gender matched reference DNA.
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Project description:One of the most frequently mutated proteins in human B-lineage leukemia is the transcription factor PAX5 mutated in about one third of all cases. While reduced function of PAX5 has a clear link to human malignancy there is limited evidence for that the this directly impact the development of function of B-cell progenitors. One possible explanation to this comes from the finding that PAX5 mutated B-ALL display complex karyotypes and additional mutations. This suggestsindicating that PAX5 might be one component of a larger transcription factor network targeted in B-ALL. To investigate the functional network associated with PAX5 we identified proteins associated with this transcription factor using BioID technology. This identified more than 239 proteins several of which could be found mutated in human B-ALL. Most prominently we identified IKZF1, commonly mutated, and RUNX1, involved in the formation of ETV6-AML1 fusion protein formation, among the interaction partners. CHIPChIP-seq as well as PLAC-seq analysis supported the idea that these factors share regulatory elements in human B-ALL cells. Gene expression and mutation analysis of both mouse models and primary human leukemia suggested that these factors form a functional gene regulatory network targeted by multiple mutations in human B-ALL. In summary, we here present a model where a transcription factor can work through redeployment of other factors and not only through sites that it binds itself.
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Project description:Heterochromatin has a high density of DNA and low rates of gene transcription.H3k9me3 is a conserved histone modification, and is best known for its role in constitutive heterochromatin formation.H1155, which is a neuroendocrine large cell lung cancer cell line, has a dense nucleus and a high level of occupancy of H3K9me3. PAX5 is a neurogenesis and B lymphocyte development transcription factor, and endogenous expressed in neuroendocrine carcinoma, including H1155 cell line. To assess whether PAX5 promotes heterochromatin formation in H1155, we knock out PAX5 in H1155 cell (KO-PAX5) by CRISPR/Cas9 and use H3K9me3 to performed ChIP-seq.
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