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The signaling axis atypical protein kinase C l/i-Satb2 mediates leukemic transformation of B-cell progenitors

ABSTRACT: The signaling axis atypical protein kinase C l/i-Satb2 mediates leukemic transformation of B-cell progenitors

PROVIDER: PRJNA495366 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7985800.fastq.gz	Fastqsanger.gz
	SRR7985800_1.fastq.gz	Fastqsanger.gz
	SRR7985800_2.fastq.gz	Fastqsanger.gz
	SRR7985801.fastq.gz	Fastqsanger.gz
	SRR7985801_1.fastq.gz	Fastqsanger.gz

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The signaling axis atypical protein kinase C l/i-Satb2 mediates leukemic transformation of B-cell progenitors

Project description:Oncogene driven transformation of leukemic progenitors results in B-acute lymphoblastic leukemia. Genetic deletions at specific hotspots are driven by recombination of epigenetically repressed loci and cause B cell transformation, and epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. The upstream signals driving epigenetic silencing have not been elucidated. BCR-ABL leukemias are initiated by leukemic stem cells/progenitors, and their modeling in vivo represents an opportunity for the identification of the epigenetic progress contributing to lineage leukemogenesis. We have found that primary human and murine BCR-ABL+ leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKCz behaves as a leukemic suppressor, aPKCl/i is critically required for oncogenic progenitor proliferation, survival, and B cell differentiation arrest, but not for normal B cell lineage differentiation. We found that in vitro and in vivo B cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKCl/i-dependent Etv5/Satb2 chromatin repressive signaling complex. Thus genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias in vitro and in vivo. Therefore, the aPKCl/i-SATB2 signaling cascade is required for leukemic BCR-ABL+ B-cell progenitor transformation and is amenable to non-BCR-ABL kinase inhibition.

2018-10-10 | GSE121018 | GEO

The signaling axis atypical protein kinase C ?/?-Satb2 mediates leukemic transformation of B-cell progenitors.

Project description:Epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. BCR-ABL leukemias result from leukemic stem cell/progenitor transformation and represent an opportunity to identify epigenetic progress contributing to lineage leukemogenesis. Primary human and murine BCR-ABL+ leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKC? behaves as a leukemic suppressor, aPKC?/? is critically required for oncogenic progenitor proliferation, survival, and B-cell differentiation arrest, but not for normal B-cell lineage differentiation. In vitro and in vivo B-cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKC ?/?-Erk dependent Etv5/Satb2 chromatin repressive signaling complex. Genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias. Therefore, the aPKC?/?-SATB2 signaling cascade is required for leukemic BCR-ABL+ B-cell progenitor transformation and is amenable to non-tyrosine kinase inhibition.

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ChIP-seq for Satb2 in E15 cortex

Project description:The goal of the study was to identify the binding site of SATB2 in wild-ype cortex by performing ChIP-seq using SATB2 antibody. E15 cortical tissues were dissected, lysed and fixed. Chromatin was prepared by sonication. Sequences bound by SATB2 protein was precipitated using a SATB2 antibody. Sequencing was performed on Illumina Genome Analyzer II. SATB2 binding peaks were called using MACS. ChIP for Satb2, followed by sequencing on Illumina Genome Analyzer II platform

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CBFA2T3-GLIS2 oncogenic fusion is sufficient for leukemic transformation

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Role of Satb1 and Satb2 in embryonic stem cells

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Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation

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PML-RARa induces dynamic changes in genome architecture during leukemic transformation

Project description:Acute Promyelocytic Leukemia (APL) is a fatal subtype of leukemia driven by the translocation between genes encoding the Promyelocytic Leukemia (PML) protein and the Retinoic Acid Receptor alpha (RARa) protein. We use mouse hematopoietic progenitor cells expressing PML-RARa and dissect the dynamic changes in the epigenome, transcriptome and genome architecture triggered by the expression of this oncogenic transcription factor during leukemic transformation. We find that PML-RARa induces a continuum of topologic and transcriptional alterations, mostly affecting distal regulatory elements. Furthermore, we identify Klf4 ― a master regulator of hematopoietic differentiation ― as an early mis-regulated gene during leukemogenesis, and deconstruct the dynamic alterations in long-range interactions, histone modifications and transcriptional output triggered by PML-RARa expression at the Klf4 locus. Our study provides a comprehensive overview of the dynamic genomic and transcriptomic alterations induced by PML-RARa, which ultimately block hematopoietic differentiation and induce leukemic transformation.

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Genetic changes during leukemic transformation to secondary acute myeloid leukemia from myeloproliferative neoplasms

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