Epigenetic Effects of IDH1/IDH2 Mutations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-33-SCI-33 ◽  
Author(s):  
Ari M. Melnick ◽  
Ross L Levine ◽  
Maria E Figueroa ◽  
Craig B. Thompson ◽  
Omar Abdel-Wahab
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Malignant Transformation ◽  
Covalent Modification ◽  
Specific Gene ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Hematopoietic Stem

Abstract Abstract SCI-33 Epigenetic deregulation of gene expression through aberrant DNA methylation or histone modification plays an important role in the malignant transformation of hematopoietic cells. In particular, acute myeloid leukemias (AMLs) can be classified according to epigenetic signatures affecting DNA methylation or histone modifications affecting specific gene sets. Heterozygous somatic mutations in the loci encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in ∼20% of AMLs and are accompanied by global DNA hypermethylation and hypermethylation and silencing of a number of specific gene promoters. IDH1/2 mutations are almost completely mutually exclusive with somatic loss-of-function mutations in TET2, which hydroxylates methylcytosine (mCpG). DNA hydroxymethylation can function as an intermediate step in mCpG demethylation. TET2 mutant de novo AMLs also display global and promoter specific hypermethylation partially overlapping with IDH1/2 mutant cases. Mutations in the IDH1/2 loci result in a neomorphic enzyme that generates the aberrant oncometabolite 2-hydroxyglutarate (2HG) using α-ketoglutarate (αKG) as a substrate. 2HG can disrupt the activity of enzymes that use αKG as a cofactor, including TET2 and the jumonji family of histone demethylases. Expression of mutant IDH isoforms inhibits TET2 hydroxymethylation and jumonji histone demethylase functions. IDH and TET2 mutant AMLs accordingly exhibit reduced levels of hydroxymethylcytosine and a trend towards increased histone methylation. Mutant IDH or TET2 loss of function causes differentiation blockade and expansion of hematopoietic stem cells and TET2 knockout results in a myeloproliferative phenotype in mice. Hydroxymethylcytosine is in abundance in hematopoietic stem cells and displays specific distribution patterns, yet the function of this covalent modification is not fully understood. Recent data link TET2 with the function of cytosine deaminases as a pathway towards DNA demethylation, which has implications as well for B cell lymphomas and CML lymphoid blast crisis, which are linked with the actions of activation induced cytosine deaminase. Altogether, the available data implicate mutations in IDH1/2 and TET2 in promoting malignant transformation in several tissues, by disrupting epigenomics programming and altering gene expression patterning. Disclosures: Thompson: Agios Pharmaceuticals: Consultancy.

scholarly journals Spatial genome re-organization between fetal and adult hematopoietic stem cells

2019 ◽  
Author(s):  
C Chen ◽  
W Yu ◽  
J Tober ◽  
P Gao ◽  
B He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Target Genes ◽  
Three Dimensional ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Dynamic Interactions ◽  
Hematopoietic Stem ◽  
3D Genome ◽  
Chromatin Interactions

AbstractFetal hematopoietic stem cells (HSCs) undergo a developmental switch to become adult HSCs. The functional properties of the HSCs change dramatically during this switch, including their cycling behavior, hematopoietic lineage outputs and proliferation rate. The relationship between three-dimensional (3D) genome organization, epigenomic state, and transcriptome is poorly understood during this critical developmental transition. Here we conducted a comprehensive survey of the 3D genome, epigenome and transcriptome of fetal and adult HSCs in mouse. We found that chromosomal compartments and topologically associating domains (TAD) are largely conserved between fetal and adult HSCs. However, there is a global trend of increased compartmentalization and TAD boundary strength in adult HSCs. In contrast, dynamics of intra-TAD chromatin interactions is much higher and more widespread, involving over a thousand gene promoters and distal enhancers. Such dynamic interactions target genes involved in cell cycle, metabolism, and hematopoiesis. These developmental-stage-specific enhancer-promoter interactions appear to be mediated by different sets of transcription factors in fetal and adult HSCs, such as TCF3 and MAFB in fetal HSCs, versus NR4A1 and GATA3 in adult HSCs. Loss-of-function studies of TCF3 confirms the role of TCF3 in mediating condition-specific enhancer-promoter interactions and gene regulation in fetal HSCs. In summary, our data suggest that the fetal-to-adult transition is accompanied by extensive changes in intra-TAD chromatin interactions that target genes underlying the phenotypic differences between fetal and adult HSCs.

scholarly journals Liver-Specific Gene Expression in Cultured Human Hematopoietic Stem Cells

Stem Cells ◽  
2003 ◽  
Vol 21 (1) ◽  
pp. 98-104 ◽  
Author(s):  
Henning C. Fiegel ◽  
Michael V. Lioznov ◽  
Lourdes Cortes-Dericks ◽  
Claudia Lange ◽  
Dietrich Kluth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Specific Gene ◽  
Hematopoietic Stem ◽  
Specific Gene Expression

scholarly journals Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lars Velten ◽  
Benjamin A. Story ◽  
Pablo Hernández-Malmierca ◽  
Simon Raffel ◽  
Daniel R. Leonce ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Single Cell ◽  
Lineage Tracing ◽  
Specific Gene ◽  
Leukemic Stem Cells ◽  
Hematopoietic Stem ◽  
Mutational Status

AbstractCancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.

scholarly journals Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+ subpopulations

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 2906-2912 ◽  
Author(s):  
D Haase ◽  
M Feuring-Buske ◽  
S Konemann ◽  
C Fonatsch ◽  
C Troff ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Hematopoietic Stem Cells ◽  
Malignant Transformation ◽  
Cell Sorting ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogenous disease according to morphology, immunophenotype, and genetics. The retained capacity of differentiation is the basis for the phenotypic classification of the bulk population of leukemic blasts and the identification of distinct subpopulations. Within the hierarchy of hematopoietic development and differentiation it is still unknown at which stage the malignant transformation occurs. It was our aim to analyze the potential involvement of cells with the immunophenotype of pluripotent stem cells in the leukemic process by the use of cytogenetic and cell sorting techniques. Cytogenetic analyses of bone marrow aspirates were performed in 13 patients with AML (11 de novo and 2 secondary) and showed karyotype abnormalities in 10 cases [2q+, +4, 6p, t(6:9), 7, +8 in 1 patient each and inv(16) in 4 patients each]. Aliquots of the samples were fractionated by fluorescence-activated cell sorting of CD34+ cells. Two subpopulations, CD34+/CD38-(early hematopoietic stem cells) and CD34+/CD38+ (more mature progenitor cells), were screened for karyotype aberations as a marker for leukemic cells. Clonal abnormalities and evaluable metaphases were found in 8 highly purified CD34+/CD38-populations and in 9 of the CD34+/CD38-specimens, respectively. In the majority of cases (CD34+/CD38-, 6 of 8 informative samples; CD34+/CD38+, 5 of 9 informative samples), the highly purified CD34+ specimens also contained cytogenetically normal cells. Secondary, progression-associated chromosomal changes (+8, 12) were identified in the CD34+/CD38-cells of 2 patients. We conclude that clonal karyotypic abnormalities are frequently found in the stem cell-like (CD34+/CD38-) and more mature (CD34+/CD38+) populations of patients with AML, irrespective of the phenotype of the bulk population of leukemic blasts and of the primary or secondary character of the leukemia. Our data suggest that, in AML, malignant transformation as well as disease progression may occur at the level of CD34+/CD38-cells with multilineage potential.

scholarly journals Haploinsufficiency of Dnmt1 Impairs Leukemia Stem Cell Function Through Derepression of Bivalent Chromatin Domains,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3459-3459
Author(s):  
Jennifer J. Trowbridge ◽  
Amit U. Sinha ◽  
Scott A. Armstrong ◽  
Stuart H. Orkin
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Dna Methyltransferase ◽  
Cell Function ◽  
Gene Signature ◽  
Conditional Knockout ◽  
Specific Gene ◽  
Epigenetic Mechanisms ◽  
Chromatin Domains ◽  
Hematopoietic Stem

Abstract Abstract 3459 Leukemia stem cells (LSCs) are an attractive target in treatment of many types of blood cancers. There remains an incomplete understanding of the epigenetic mechanisms driving LSC formation and maintenance, and how this compares to the epigenetic regulation of normal hematopoietic stem cells (HSCs). One of the major epigenetic modifications, DNA methylation, is catalyzed by the DNA methyltransferase enzymes Dnmt1, Dnmt3a and Dnmt3b. We observed decreased expression of Dnmt3a and Dnmt3b in LSCs isolated from a model of MLL-AF9-induced acute myeloid leukemia (AML) compared to normal HSCs. In contrast, expression of Dnmt1 was maintained in LSCs compared to HSCs, suggesting that Dnmt1 may have a critical function in the formation and maintenance of LSCs. Supporting this hypothesis, we found that conditional knockout of Dnmt1 fully ablates the development of AML. Furthermore, haploinsufficiency of Dnmt1 (Dnmt1fl/+ Mx-Cre) was sufficient to delay progression of leukemogenesis and impair LSC self-renewal. Strikingly, haploinsufficiency of Dnmt1 did not functionally alter normal hematopoiesis or HSCs, suggesting an enhanced dependence of LSCs on DNA methylation. Mechanistically, we observed that haploinsufficiency of Dnmt1 in LSCs resulted in derepression of genes that had been silenced by MLL-AF9-mediated transformation and marked by bivalent H3K27me3/H3K4me3 chromatin domains. These results suggest that the formation and maintenance of LSCs depends not only upon activation of a leukemogenic program, but also upon silencing of a specific gene signature that is active in HSCs through crosstalk between two epigenetic mechanisms, polycomb-mediated repression and DNA methylation-mediated repression. This silenced gene signature includes known and candidate tumor suppressor genes as well as genes involved in lineage restriction. These studies present evidence that distinct epigenetic regulatory mechanisms are dominant in LSCs compared to HSCs and provide novel gene candidates for targeted reactivation in AML therapy. Disclosures: Armstrong: Epizyme: Consultancy.

scholarly journals A highly efficient reporter system for identifying and characterizing in vitro expanded hematopoietic stem cells

2021 ◽  
Author(s):  
James Lok Chi Che ◽  
Daniel Bode ◽  
Iwo Kucinski ◽  
Alyssa H Cull ◽  
Fiona Bain ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Gene Expression Signature ◽  
The Body ◽  
Molecular Profile ◽  
Functional Screening ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Single Clone

Hematopoietic stem cells (HSCs) cultured outside the body are the fundamental component of a wide range of cellular and gene therapies. Recent efforts have achieved more than 200-fold expansion of functional HSCs, but their molecular characterization has not been possible due to the substantial majority of cells being non-HSCs and single cell-initiated cultures displaying substantial clone-to-clone variability. Using the Fgd5 reporter mouse in combination with the EPCR surface marker, we report exclusive identification of HSCs from non-HSCs in expansion cultures. Linking single clone functional transplantation data with single clone gene expression profiling, we show that the molecular profile of expanded HSCs is similar to actively cycling fetal liver HSCs and shares a gene expression signature with functional HSCs from all sources, including Prdm16, Fstl1 and Palld. This new tool can now be applied to a wide-range of functional screening and molecular experiments previously not possible due to limited HSC numbers.

scholarly journals Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells

2010 ◽  
Vol 10 (1) ◽  
pp. 12 ◽  
Author(s):  
Leilei Tang ◽  
Saskia M Bergevoet ◽  
Christian Gilissen ◽  
Theo de Witte ◽  
Joop H Jansen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Gene Expression Profile ◽  
Abc Transporter ◽  
Expression Profile ◽  
Transporter Gene ◽  
Hematopoietic Stem

Comparative gene expression analysis of zebrafish and mammals identifies common regulators in hematopoietic stem cells

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. e1-e9 ◽  
Author(s):  
Isao Kobayashi ◽  
Hiromasa Ono ◽  
Tadaaki Moritomo ◽  
Koichiro Kano ◽  
Teruyuki Nakanishi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Side Population ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Junction ◽  
Hematopoietic Stem

Abstract Hematopoiesis in teleost fish is maintained in the kidney. We previously reported that Hoechst dye efflux activity of hematopoietic stem cells (HSCs) is highly conserved in vertebrates, and that Hoechst can be used to purify HSCs from teleost kidneys. Regulatory molecules that are strongly associated with HSC activity may also be conserved in vertebrates. In this study, we identified evolutionarily conserved molecular components in HSCs by comparing the gene expression profiles of zebrafish, murine, and human HSCs. Microarray data of zebrafish kidney side population cells (zSPs) showed that genes involved in cell junction and signal transduction tended to be up-regulated in zSPs, whereas genes involved in DNA replication tended to be down-regulated. These properties of zSPs were similar to those of mammalian HSCs. Overlapping gene expression analysis showed that 40 genes were commonly up-regulated in these 3 HSCs. Some of these genes, such as egr1, gata2, and id1, have been previously implicated in the regulation of HSCs. In situ hybridization in zebrafish kidney revealed that expression domains of egr1, gata2, and id1 overlapped with that of abcg2a, a marker for zSPs. These results suggest that the overlapping genes identified in this study are regulated in HSCs and play important roles in their functions.

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