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1.
Blood ; 138(15): 1345-1358, 2021 10 14.
Article in English | MEDLINE | ID: mdl-34010414

ABSTRACT

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFß-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.


Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Core Binding Factor beta Subunit/genetics , Gene Expression Regulation, Leukemic , Leukemia, Myeloid, Acute/genetics , Proto-Oncogene Proteins/genetics , Trans-Activators/genetics , Antisense Elements (Genetics)/genetics , Cell Line, Tumor , Gene Fusion , Humans , Oncogene Proteins, Fusion/genetics , Promoter Regions, Genetic , RUNX1 Translocation Partner 1 Protein/genetics , Tumor Cells, Cultured
3.
Cell Death Dis ; 6: e1806, 2015 Jul 09.
Article in English | MEDLINE | ID: mdl-26158512

ABSTRACT

Human induced pluripotent stem (iPS) cells can be derived from lineage-restricted cells and represent an important tool to develop novel patient-specific cell therapies and research models for inherited and acquired diseases. Recently, patient-derived iPS cells, containing donor genetic background, have offered a breakthrough approach to study human genetics of neurodegenerative diseases. By offering an unlimited source of patient-specific disease-relevant cells, iPS cells hold great promise for understanding disease mechanisms, identifying molecular targets and developing phenotypic screens for drug discovery. This review will discuss the potential impact of using iPS cell-derived models in multiple sclerosis (MS) research and highlight some of the current challenges and prospective for generating novel therapeutic treatments for MS patients.


Subject(s)
Cell Differentiation/genetics , Cell- and Tissue-Based Therapy , Induced Pluripotent Stem Cells , Multiple Sclerosis/therapy , Cell Lineage , Humans , Multiple Sclerosis/genetics , Precision Medicine
4.
Blood Cancer J ; 4: e211, 2014 May 09.
Article in English | MEDLINE | ID: mdl-24813079

ABSTRACT

Reprogramming somatic cells into induced pluripotent stem (iPS) cells is nowadays approaching effectiveness and clinical grade. Potential uses of this technology include predictive toxicology, drug screening, pathogenetic studies and transplantation. Here, we review the basis of current iPS cell technology and potential applications in hematology, ranging from disease modeling of congenital and acquired hemopathies to hematopoietic stem and other blood cell transplantation.


Subject(s)
Induced Pluripotent Stem Cells/physiology , Animals , Hematology/methods , Hematopoietic Stem Cell Transplantation/methods , Humans , Induced Pluripotent Stem Cells/cytology
5.
Ann Oncol ; 18(9): 1523-8, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17761709

ABSTRACT

BACKGROUND: Polymorphisms in genes involved in detoxification and DNA-repair pathways may modify the individual's risk for genomic damage, and, as a consequence, the risk of developing malignant diseases. PATIENTS AND METHODS: We performed a case-control study including 160 cases of acute myeloid leukaemia (AML) and 162 matched controls to test the impact of six genomic polymorphisms on the risk to develop AML and/or therapy-related AML. RESULTS: We found a significantly higher prevalence of the polymorphic variants RAD51-G135C and CYP3A4-A-290G genes in AML cases, when compared with controls (P = 0.02 and P = 0.04), increasing the risk of AML 2.1-folds (95% CI: 1.1-4.0) and 3.2-fold (95% CI: 1.1-11.5), respectively. Carriers of both the RAD51-G135C and CYP3A4-A-290G variants were at highest AML risk (P = 0.003; OR:13,6; 95% CI: 2.0-585.5), suggesting a synergistic effect between these polymorphisms. CONCLUSIONS: These results suggest that polymorphic variants in DNA-repair and detoxification enzymes may co-operate in modulating the individual's risk of AML.


Subject(s)
DNA Repair Enzymes/genetics , Leukemia, Myeloid, Acute/enzymology , Metabolic Detoxication, Phase II/genetics , Metabolic Detoxication, Phase I/genetics , Polymorphism, Genetic , Adult , Aged , Aged, 80 and over , Case-Control Studies , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/genetics , DNA-Binding Proteins/genetics , Female , Gene Frequency , Glutathione Transferase/genetics , Humans , Isoenzymes/genetics , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , NAD(P)H Dehydrogenase (Quinone)/genetics , Rad51 Recombinase/genetics , Risk Factors
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