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Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia

ABSTRACT: Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia

PROVIDER: PRJNA541266 | ENA |

REPOSITORIES: ENA

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Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia

Project description:We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.

2019-05-07 | GSE130743 | GEO

Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia.

Project description:Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones.

| S-EPMC6606637 | biostudies-literature

Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia

Project description:Study EGAS00001003627

| EGAS00001003627 | EGA

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. Identification of BCL6 binding sites in human CML cell line JURL-MK1

2011-09-15 | E-GEOD-26085 | biostudies-arrayexpress

HOXB-AS3 expressions promote cell proliferation

Project description:We knock down HOXB-AS3 with shRNA in OCI/AML3 cell line to investigate the downstream pathways of HOXB-AS3 in the cell proliferation.

2019-07-16 | GSE114823 | GEO

The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia

Project description:In this work we dissect the functional role of the HOXB-AS3 long non coding RNA in patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. HOXB-AS3 was found to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.

2019-10-16 | PXD015520 | Pride

Modeling mammalian spermatogonial differentiation and meiotic initiation in vitro

Project description:In mammalian testes, premeiotic spermatogonia respond to retinoic acid by completing an essential lengthy differentiation program before initiating meiosis. The molecular and cellular changes directing these developmental processes remain largely undefined. This wide gap in knowledge is due to two critical unresolved technical challenges: (1) lack of robust and reliable in vitro models to study differentiation and meiotic initiation; and (2) lack of methods to isolate large and pure populations of male germ cells at each stage of differentiation and at meiotic initiation. Here, we report a facile in vitro differentiation and meiotic initiation system that can be readily manipulated, including the use of chemical agents that cannot be safely administered to live animals. In addition, we present a transgenic mouse model enabling fluorescence-activated cell sorting-based isolation of millions of spermatogonia at specific developmental stages as well as meiotic spermatocytes

2022-10-28 | PXD037781 | JPOST Repository

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

Project description:PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

| PRJNA356748 | ENA

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

2011-09-15 | GSE26085 | GEO

An enhancer cluster promotes NPCs formation from ESCs through maintaining HoxB activation by long-range chromatin interaction

Project description:Homeobox B cluster genes (HoxB) are important marker genes for neural progenitor cells (NPCs) formation from embryonic stem cells (ESCs). However, mechanisms of HoxB activation in NPCs remain largely unknown. Here, we find an enhancer cluster (EnC) interacting with the HoxB locus by PLAC-seq analysis. CRISPR/Cas9-mediated EnC deletion significantly inhibited HoxB expression, indicating that the EnC is required for HoxB activation in NPCs. Transcriptome analysis revealed that differentiation-related master control genes and NPCs formation-related signaling pathways were significantly inhibited suggesting that the EnC is essential for NPCs formation. In summary, our results reveal a new mechanism about HoxB activation depending on EnC is crucial for NPCs formation.

2020-10-13 | GSE159378 | GEO

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