Publications by authors named "Maria E Figueroa"

73 Publications

Transcriptional silencing of ALDH2 confers a dependency on Fanconi anemia proteins in acute myeloid leukemia.

Cancer Discov 2021 Apr 23. Epub 2021 Apr 23.

Cold Spring Harbor Laboratory

Hundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitination machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T and FANCL as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and Aldehyde Dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxicity of endogenous aldehydes. We show that DNA hypermethylation and silencing of ALDH2 occur in a recurrent manner in human AML, which is sufficient to confer FA pathway dependency. Our study suggests that targeting of the ubiquitination reaction catalyzed by FA proteins can eliminate ALDH2-deficient AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-20-1542DOI Listing
April 2021

Combination of azacitidine and enasidenib enhances leukemic cell differentiation and cooperatively hypomethylates DNA.

Exp Hematol 2021 Jun 29;98:47-52.e6. Epub 2021 Mar 29.

Bristol Myers Squibb, Princeton, NJ.

Azacitidine and enasidenib are two therapies available for treatment of acute myelogenous leukemia (AML), and the mechanisms of action of these drugs involve alteration of aberrant DNA methylation. We hypothesized that a combination of these agents could have interactive effects on DNA methylation and enhance differentiation in mIDH2 cells. Combination treatment enhanced cellular differentiation in TF-1 cells overexpressing IDJ2R140Q through increased hemoglobinization and increased hemoglobin γ RNA expression compared with the effects of single agents. Furthermore, in primary AML samples (IDH2R140Q or R172K), combination treatment reduced CD34+ cells and increased CD15+ cells to a greater extent than attained with single agents. To explore the mechanism of enhanced differentiation with combination treatment, the TF-1 epigenome was analyzed by profiling 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) DNA methylation changes. Enasidenib treatment alone increased 5hmC, consistent with reactivation of ten-eleven-translocation (TET) enzyme activity. Compared with treatment with azacitidine alone, combination treatment reduced 5mC levels at greater numbers of sites and these loci were significantly enriched in regions with increased 5hMC (25.8% vs. 7.4%). Results are consistent with a model in which enasidenib-mediated reactivation of ten-eleven-translocation enzymes cooperates with azacitidine-mediated inhibition of DNA methyltransferase enzymes, leading to greater reductions in DNA methylation and enhanced erythroid differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exphem.2021.03.003DOI Listing
June 2021

TNFAIP3 Plays a Role in Aging of the Hematopoietic System.

Front Immunol 2020 3;11:536442. Epub 2020 Nov 3.

Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.

Hematopoietic stem and progenitor cells (HSPC) experience a functional decline in response to chronic inflammation or aging. Haploinsufficiency of A20, or TNFAIP3, an innate immune regulator, is associated with a variety of autoimmune, inflammatory, and hematologic malignancies. Based on a prior analysis of epigenomic and transcriptomic changes during normal human aging, we find that the expression of A20 is significantly reduced in aged HSPC as compared to young HSPC. Here, we show that the partial reduction of A20 expression in young HSPC results in characteristic features of aging. Specifically, heterozygous deletion of A20 in hematopoietic cells resulted in expansion of the HSPC pool, reduced HSPC fitness, and myeloid-biased hematopoiesis. These findings suggest that altered expression of A20 in HSPC contributes to an aging-like phenotype, and that there may be a common underlying mechanism for diminished HSPC function between inflammatory states and aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.536442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670064PMC
April 2021

5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers.

Clin Epigenetics 2020 11 17;12(1):175. Epub 2020 Nov 17.

Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Ave., Ann Arbor, MI, 48109-2218, USA.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied.

Results: We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(-) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(-) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(-) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(-) oral cavity cell lines.

Conclusion: Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancer-related processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-020-00965-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672859PMC
November 2020

Human hematopoiesis: aging and leukemogenic risk.

Curr Opin Hematol 2021 Jan;28(1):57-63

Department of Human Genetics.

Purpose Of Review: Our understanding of the effects of aging on human hematopoiesis has advanced significantly in recent years, yet the full ramifications of these findings are not fully understood. This review summarizes these findings and discusses their implication as they relate to malignant hematopoiesis.

Recent Findings: With human aging there is an impaired immune response, loss of hematopoietic stem cell (HSC) function, increase in clonal hematopoiesis, and higher frequency of myeloid malignancies. Although murine models have implicated abnormalities in DNA damage repair, autophagy, metabolism, and epigenetics, studies in primary human specimens are more limited. The development of age-related clonal hematopoiesis and the risk associated with this is one of the major findings in the field of recent years. This is accompanied by changes in bone marrow stem and progenitor composition, changes in the epigenetic program of stem cells and an inflammatory milieu in the bone marrow. The precise consequences of these changes for the development of age-related malignancies are still unclear.

Summary: Advances in the field have begun to reveal the mechanisms driving human HSC loss of function with age. It will be critical to delineate between normal and malignant aging in order to better prevent age-associated myeloid malignancies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MOH.0000000000000622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737681PMC
January 2021

Cancer-specific CTCF binding facilitates oncogenic transcriptional dysregulation.

Genome Biol 2020 09 15;21(1):247. Epub 2020 Sep 15.

Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, USA.

Background: The three-dimensional genome organization is critical for gene regulation and can malfunction in diseases like cancer. As a key regulator of genome organization, CCCTC-binding factor (CTCF) has been characterized as a DNA-binding protein with important functions in maintaining the topological structure of chromatin and inducing DNA looping. Among the prolific binding sites in the genome, several events with altered CTCF occupancy have been reported as associated with effects in physiology or disease. However, hitherto there is no comprehensive survey of genome-wide CTCF binding patterns across different human cancers.

Results: To dissect functions of CTCF binding, we systematically analyze over 700 CTCF ChIP-seq profiles across human tissues and cancers and identify cancer-specific CTCF binding patterns in six cancer types. We show that cancer-specific lost and gained CTCF binding events are associated with altered chromatin interactions, partially with DNA methylation changes, and rarely with sequence mutations. While lost bindings primarily occur near gene promoters, most gained CTCF binding events exhibit enhancer activities and are induced by oncogenic transcription factors. We validate these findings in T cell acute lymphoblastic leukemia cell lines and patient samples and show that oncogenic NOTCH1 induces specific CTCF binding and they cooperatively activate expression of target genes, indicating transcriptional condensation phenomena.

Conclusions: Specific CTCF binding events occur in human cancers. Cancer-specific CTCF binding can be induced by other transcription factors to regulate oncogenic gene expression. Our results substantiate CTCF binding alteration as a functional epigenomic signature of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-020-02152-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493976PMC
September 2020

Risk of disease progression in low-risk MDS is linked to distinct epigenetic subtypes.

Leukemia 2019 11 22;33(11):2753-2757. Epub 2019 Jul 22.

Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-019-0518-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842085PMC
November 2019

levels in human hematopoietic progenitors are regulated by aging and dictate erythroid-myeloid balance.

Haematologica 2020 04 6;105(4):905-913. Epub 2019 Jun 6.

Department of Pathology, University of Virginia School of Medicine, Charlottesville, USA

Healthy bone marrow progenitors yield a co-ordinated balance of hematopoietic lineages. This balance shifts with aging toward enhanced granulopoiesis with diminished erythropoiesis and lymphopoiesis, changes which likely contribute to the development of bone marrow disorders in the elderly. In this study, RUNX3 was identified as a hematopoietic stem and progenitor cell factor whose levels decline with aging in humans and mice. This decline is exaggerated in hematopoietic stem and progenitor cells from subjects diagnosed with unexplained anemia of the elderly. Hematopoietic stem cells from elderly unexplained anemia patients had diminished erythroid but unaffected granulocytic colony forming potential. Knockdown studies revealed human hematopoietic stem and progenitor cells to be strongly influenced by RUNX3 levels, with modest deficiencies abrogating erythroid differentiation at multiple steps while retaining capacity for granulopoiesis. Transcriptome profiling indicated control by RUNX3 of key erythroid transcription factors, including and These findings thus implicate RUNX3 as a participant in hematopoietic stem and progenitor cell aging, and a key determinant of erythroid-myeloid lineage balance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.208918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109730PMC
April 2020

Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia.

Cancer Discov 2019 08 13;9(8):1080-1101. Epub 2019 May 13.

Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida.

Aging is associated with functional decline of hematopoietic stem cells (HSC) as well as an increased risk of myeloid malignancies. We performed an integrative characterization of epigenomic and transcriptomic changes, including single-cell RNA sequencing, during normal human aging. LineageCD34CD38 cells [HSC-enriched (HSCe)] undergo age-associated epigenetic reprogramming consisting of redistribution of DNA methylation and reductions in H3K27ac, H3K4me1, and H3K4me3. This reprogramming of aged HSCe globally targets developmental and cancer pathways that are comparably altered in acute myeloid leukemia (AML) of all ages, encompassing loss of 4,646 active enhancers, 3,091 bivalent promoters, and deregulation of several epigenetic modifiers and key hematopoietic transcription factors, such as KLF6, BCL6, and RUNX3. Notably, downregulation of KLF6 results in impaired differentiation, increased colony-forming potential, and changes in expression that recapitulate aging and leukemia signatures. Thus, age-associated epigenetic reprogramming may form a predisposing condition for the development of age-related AML. SIGNIFICANCE: AML, which is more frequent in the elderly, is characterized by epigenetic deregulation. We demonstrate that epigenetic reprogramming of human HSCs occurs with age, affecting cancer and developmental pathways. Downregulation of genes epigenetically altered with age leads to impairment in differentiation and partially recapitulates aging phenotypes..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-18-1474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080409PMC
August 2019

Multilayer intraclonal heterogeneity in chronic myelomonocytic leukemia.

Haematologica 2020 01 2;105(1):112-123. Epub 2019 May 2.

INSERM U1170, Gustave Roussy Cancer Center, Villejuif, France

The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood. This question is addressed in chronic myelomonocytic leukemia, a myeloid neoplasm in which clinical diversity contrasts with limited genetic heterogeneity. To generate induced pluripotent stem cell clones, we reprogrammed CD34 cells collected from a patient with a chronic myelomonocytic leukemia in which whole exome sequencing of peripheral blood monocyte DNA had identified 12 gene mutations, including a mutation in and two heterozygous mutations in in the founding clone and a secondary (G12D) mutation. CD34 cells from an age-matched healthy donor were also reprogrammed. We captured a part of the genetic heterogeneity observed in the patient, i.e. we analyzed five clones with two genetic backgrounds, without and with the (G12D) mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient's disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior of hematopoietic cells derived from induced pluripotent stem cell clones with similar genetic background, correlating with limited epigenetic changes. These analyses suggest that, beyond the coding mutations, several levels of intraclonal heterogeneity may participate in the yet unexplained clinical heterogeneity of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.208488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939510PMC
January 2020

A distinct epigenetic program underlies the 1;7 translocation in myelodysplastic syndromes.

Leukemia 2019 10 28;33(10):2481-2494. Epub 2019 Mar 28.

Department of Medicine, Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, Italy.

The unbalanced translocation dic(1;7)(q10;p10) in myelodysplastic syndromes (MDS) is originated by centromeric juxtaposition resulting into 1q trisomy and 7q monosomy. More than half of cases arise after chemo/radio-therapy. To date, given the absence of genes within the centromeric regions, no specific molecular events have been identified in this cytogenetic subgroup. We performed the first comprehensive genetic and epigenetic analysis of MDS with dic(1;7)(q10;p10) compared to normal controls and therapy-related myeloid neoplasms (t-MNs). RNA-seq showed a unique downregulated signature in dic(1;7) cases, affecting more than 80% of differentially expressed genes. As revealed by pathway and gene ontology analyses, downregulation of ATP-binding cassette (ABC) transporters and lipid-related genes and upregulation of p53 signaling were the most relevant biological features of dic(1;7). Epigenetic supervised analysis revealed hypermethylation at intronic enhancers in the dicentric subgroup, in which low expression levels of enhancer putative target genes accounted for around 35% of the downregulated signature. Enrichment of Krüppel-like transcription factor binding sites emerged at enhancers. Furthermore, a specific hypermethylated pattern on 1q was found to underlie the hypo-expression of more than 50% of 1q-deregulated genes, despite trisomy. In summary, dic(1;7) in MDS establishes a specific transcriptional program driven by a unique epigenomic signature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-019-0433-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340798PMC
October 2019

IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response.

Sci Transl Med 2019 02;11(479)

Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30322, USA.

Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1) are younger at diagnosis and live longer. mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 ) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1 mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1, and inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1 in the context of TP53 and ATRX loss. We discovered that IDH1 expression in the genetic context of and gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the ataxia-telangiectasia-mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors' radiosensitivity. Translation of these findings to patients with IDH1 glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aaq1427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400220PMC
February 2019

TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis.

Cancer Discov 2018 12 1;8(12):1632-1653. Epub 2018 Oct 1.

INSERM U1170, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

somatic mutations occur in ∼10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in -mutant DLBCLs. Accordingly, mutation in patients yields a -mutant gene-expression signature, and mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies somatic mutation. These results advocate for sequencing in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors...
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-18-0657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279514PMC
December 2018

Polycomb complexes associate with enhancers and promote oncogenic transcriptional programs in cancer through multiple mechanisms.

Nat Commun 2018 08 23;9(1):3377. Epub 2018 Aug 23.

Sylvester Comprehensive Cancer Center, Biomedical Research Building, 1501 NW 10th Avenue, Miami, FL, 33136, USA.

Polycomb repressive complex 1 (PRC1) plays essential roles in cell fate decisions and development. However, its role in cancer is less well understood. Here, we show that RNF2, encoding RING1B, and canonical PRC1 (cPRC1) genes are overexpressed in breast cancer. We find that cPRC1 complexes functionally associate with ERα and its pioneer factor FOXA1 in ER+ breast cancer cells, and with BRD4 in triple-negative breast cancer cells (TNBC). While cPRC1 still exerts its repressive function, it is also recruited to oncogenic active enhancers. RING1B regulates enhancer activity and gene transcription not only by promoting the expression of oncogenes but also by regulating chromatin accessibility. Functionally, RING1B plays a divergent role in ER+ and TNBC metastasis. Finally, we show that concomitant recruitment of RING1B to active enhancers occurs across multiple cancers, highlighting an under-explored function of cPRC1 in regulating oncogenic transcriptional programs in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-05728-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107513PMC
August 2018

Oncogenic N-Ras and Tet2 haploinsufficiency collaborate to dysregulate hematopoietic stem and progenitor cells.

Blood Adv 2018 06;2(11):1259-1271

Department of Internal Medicine and.

Concurrent genetic lesions exist in a majority of patients with hematologic malignancies. Among these, somatic mutations that activate oncogenes and inactivate the epigenetic modifier ten-eleven translocation 2 () frequently co-occur in human chronic myelomonocytic leukemias (CMMLs) and acute myeloid leukemias, suggesting a cooperativity in malignant transformation. To test this, we applied a conditional murine model that endogenously expressed oncogenic and monoallelic loss of and explored the collaborative role specifically within hematopoietic stem and progenitor cells (HSPCs) at disease initiation. We demonstrate that the 2 mutations collaborated to accelerate a transplantable CMML-like disease in vivo, with an overall shortened survival and increased disease penetrance compared with single mutants. At preleukemic stage, N-Ras and Tet2 haploinsufficiency together induced balanced hematopoietic stem cell (HSC) proliferation and enhanced competitiveness. / HSCs displayed increased self-renewal in primary and secondary transplantations, with significantly higher reconstitution than single mutants. Strikingly, the 2 mutations together conferred long-term reconstitution and self-renewal potential to multipotent progenitors, a pool of cells that usually have limited self-renewal compared with HSCs. Moreover, HSPCs from / mice displayed increased cytokine sensitivity in response to thrombopoietin. Therefore, our studies establish a novel tractable CMML model and provide insights into how dysregulated signaling pathways and epigenetic modifiers collaborate to modulate HSPC function and promote leukemogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2018017400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998937PMC
June 2018

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression.

Cell 2017 Sep 17;170(6):1079-1095.e20. Epub 2017 Aug 17.

Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura & Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA. Electronic address:

Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2 and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer. PAPERCLIP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2017.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755977PMC
September 2017

Epigenetic Identity in AML Depends on Disruption of Nonpromoter Regulatory Elements and Is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers.

Cancer Discov 2017 08 13;7(8):868-883. Epub 2017 Apr 13.

Department of Human Genetics and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.

We performed cytosine methylation sequencing on genetically diverse patients with acute myeloid leukemia (AML) and found leukemic DNA methylation patterning is primarily driven by nonpromoter regulatory elements and CpG shores. Enhancers displayed stronger differential methylation than promoters, consisting predominantly of hypomethylation. AMLs with dominant hypermethylation featured greater epigenetic disruption of promoters, whereas those with dominant hypomethylation displayed greater disruption of distal and intronic regions. Mutations in and had opposing and mutually exclusive effects on the epigenome. Notably, co-occurrence of both mutations resulted in epigenetic antagonism, with most CpGs affected by either mutation alone no longer affected in double-mutant AMLs. Importantly, this epigenetic antagonism precedes malignant transformation and can be observed in preleukemic LSK cells from or single-mutant and / double-mutant mice. Notably, double-mutant AMLs manifested upregulation of a RAS signaling signature and displayed unique sensitivity to MEK inhibition as compared with AMLs with either single mutation. AML is biologically heterogeneous with subtypes characterized by specific genetic and epigenetic abnormalities. Comprehensive DNA methylation profiling revealed that differential methylation of nonpromoter regulatory elements is a driver of epigenetic identity, that gene mutations can be context-dependent, and that co-occurrence of mutations in epigenetic modifiers can result in epigenetic antagonism. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-16-1032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540802PMC
August 2017

The multidimensional nature of HIV stigma: evidence from Mozambique.

Afr J AIDS Res 2017 Mar;16(1):11-18

b Johns Hopkins Center for Communications Programs , Baltimore , Maryland , USA.

HIV stigma continues to be a major challenge to addressing HIV/AIDS in various countries in sub-Saharan Africa, including Mozambique. This paper explores the multidimensional nature of HIV stigma through the thematic analysis of five qualitative studies conducted in high HIV prevalence provinces in Mozambique between 2009 and 2012. These studies included 23 interviews with people living with HIV (PLHIV) (10 women and 13 men); 6 focus groups with 32 peer educators (24 women and 8 men) working for community-based organisations (CBOs) providing services to PLHIV; 17 focus groups with community members (72 men and 70 women); 6 interviews (4 women and 2 men) with people who had family members living with HIV/AIDS; 24 focus groups (12 with men and 12 with women) and 6 interviews with couples. Our findings indicate that HIV stigma is a barrier to HIV testing and counselling, status disclosure, partner notification, and antiretroviral therapy (ART) access and adherence, and that moral stigma seems to be more common than physical stigma. Additionally, the findings highlight that HIV stigma is a dynamic social process that is conceptualised as being tied to personal responsibility. To effectively diminish HIV stigma in Mozambique, future interventions should address moral stigma and re-conceptualise HIV as a chronic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2989/16085906.2016.1264983DOI Listing
March 2017

Autophagy maintains the metabolism and function of young and old stem cells.

Nature 2017 03 1;543(7644):205-210. Epub 2017 Mar 1.

Department of Medicine, Hem/Onc Division, The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA.

With age, haematopoietic stem cells lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting haematopoietic stem cells from metabolic stress. Here we show that loss of autophagy in haematopoietic stem cells causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs haematopoietic stem-cell self-renewal activity and regenerative potential. Strikingly, most haematopoietic stem cells in aged mice share these altered metabolic and functional features. However, approximately one-third of aged haematopoietic stem cells exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young haematopoietic stem cells. Our results demonstrate that autophagy actively suppresses haematopoietic stem-cell metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old haematopoietic stem cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature21388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344718PMC
March 2017

A clinical measure of DNA methylation predicts outcome in de novo acute myeloid leukemia.

JCI Insight 2016 Jun;1(9)

Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Variable response to chemotherapy in acute myeloid leukemia (AML) represents a major treatment challenge. Clinical and genetic features incompletely predict outcome. The value of clinical epigenetic assays for risk classification has not been extensively explored. We assess the prognostic implications of a clinical assay for multilocus DNA methylation on adult patients with de novo AML.

Methods: We performed multilocus DNA methylation assessment using xMELP on samples and calculated a methylation statistic (M-score) for 166 patients from UPENN with de novo AML who received induction chemotherapy. The association of M-score with complete remission (CR) and overall survival (OS) was evaluated. The optimal M-score cut-point for identifying groups with differing survival was used to define a binary M-score classifier. This classifier was validated in an independent cohort of 383 patients from the Eastern Cooperative Oncology Group Trial 1900 (E1900; NCT00049517).

Results: A higher mean M-score was associated with death and failure to achieve CR. Multivariable analysis confirmed that a higher M-score was associated with death ( = 0.011) and failure to achieve CR ( = 0.034). Median survival was 26.6 months versus 10.6 months for low and high M-score groups. The ability of the M-score to perform as a classifier was confirmed in patients ≤ 60 years with intermediate cytogenetics and patients who achieved CR, as well as in the E1900 validation cohort.

Conclusion: The M-score represents a valid binary prognostic classifier for patients with de novo AML. The xMELP assay and associated M-score can be used for prognosis and should be further investigated for clinical decision making in AML patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.87323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951094PMC
June 2016

Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia.

Haematologica 2016 06;101(6):672-9

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

Wilms tumor 1 (WT1) has long been implicated in acute myeloid leukemia. It has been described to be both overexpressed and mutated in different forms of acute myeloid leukemia, and overexpression has been reported to play a prognostic role in this disease. However, the precise mechanism through which WT1 may play a role in leukemogenesis has remained elusive. In recent years, new evidence has emerged that points towards a novel role of WT1 mutations in the deregulation of epigenetic programs in leukemic cells through its interaction with TET proteins. Herein we review the current status of the field and its therapeutic and prognostic implications in acute myeloid leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2015.141796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013955PMC
June 2016

DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia.

Cancer Discov 2016 05 25;6(5):501-15. Epub 2016 Mar 25.

Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Unlabelled: Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3(ITD)/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3(ITD) myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation.

Significance: DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3(ITD)-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501-15. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-16-0008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861898PMC
May 2016

Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation.

Haematologica 2015 Aug 18;100(8):1064-75. Epub 2015 Jun 18.

Department of Laboratory Medicine, University of California, San Francisco, CA, USA

Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality implicated in this pathology, but the mechanisms by which this chimeric fusion protein initiates disease are incompletely understood. Identifying PML/RARA targets in vivo is critical for comprehending the road to pathogenesis. Utilizing a novel sorting strategy, we isolated highly purified promyelocyte populations from normal and young preleukemic animals, carried out microarray and methylation profiling analyses, and compared the results from the two groups of animals. Surprisingly, in the absence of secondary lesions, PML/RARA had an overall limited impact on both the transcriptome and methylome. Of interest, we did identify down-regulation of secondary and tertiary granule genes as the first step engaging the myeloid maturation block. Although initially not sufficient to arrest terminal granulopoiesis in vivo, such alterations set the stage for the later, complete differentiation block seen in leukemia. Further, gene set enrichment analysis revealed that PML/RARA promyelocytes exhibit a subtle increase in expression of cell cycle genes, and we show that this leads to both increased proliferation of these cells and expansion of the promyelocyte compartment. Importantly, this proliferation signature was absent from the poorly leukemogenic p50/RARA fusion model, implying a critical role for PML in the altered cell-cycle kinetics and ability to initiate leukemia. Thus, our findings challenge the predominant model in the field and we propose that PML/RARA initiates leukemia by subtly shifting cell fate decisions within the promyelocyte compartment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2014.123018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004423PMC
August 2015

Dissecting the role of aberrant DNA methylation in human leukaemia.

Nat Commun 2015 May 22;6:7091. Epub 2015 May 22.

1] Harvard Medical School, Boston, Massachusetts 02115, USA [2] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA [3] Cancer Science Institute, National University of Singapore, Singapore 66123, Singapore.

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the genetic translocation t(9;22)(q34;q11.2) encoding for the BCR-ABL fusion oncogene. However, many molecular mechanisms of the disease progression still remain poorly understood. A growing body of evidence suggests that the epigenetic abnormalities are involved in tyrosine kinase resistance in CML, leading to leukaemic clone escape and disease propagation. Here we show that, by applying cellular reprogramming to primary CML cells, aberrant DNA methylation contributes to the disease evolution. Importantly, using a BCR-ABL inducible murine model, we demonstrate that a single oncogenic lesion triggers DNA methylation changes, which in turn act as a precipitating event in leukaemia progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms8091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443494PMC
May 2015

Cytosine modifications in myeloid malignancies.

Pharmacol Ther 2015 Aug 5;152:42-53. Epub 2015 May 5.

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, United States.

Aberrant DNA methylation is a hallmark of many cancers, including the myeloid malignancies acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The discovery of TET-mediated demethylation of 5-methylcytosine (5mC) and technological advancements in next-generation sequencing have permitted the examination of other cytosine modifications, namely 5-hydroxymethylcytosine (5hmC), in these myeloid malignancies on a genome-wide scale. Due to the prominence of mutations in epigenetic modifiers that can influence cytosine modifications in these disorders, including IDH1/2, TET2, and DNMT3A, many recent studies have evaluated the relative levels, distribution, and functional consequences of cytosine modifications in leukemic cells. Furthermore, several therapies are being used to treat AML and MDS that target various proteins within the cytosine modification pathway in an effort to revert the abnormal epigenetic patterns that contribute to the diseases. In this review, we provide an overview of cytosine modifications and selected technologies currently used to distinguish and analyze these epigenetic marks in the genome. Then, we discuss the role of mutant enzymes, including DNMT3A, TET2, IDH1/2, and the transcription factor, WT1, in disrupting normal patterns of 5mC and 5hmC in AML and MDS. Finally, we describe several therapies, both standard, front-line treatments and new drugs in clinical trials, aimed at inhibiting the proteins that ultimately lead to aberrant cytosine modifications in these diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2015.05.002DOI Listing
August 2015

Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia.

J Clin Invest 2015 May 30;125(5):1857-72. Epub 2015 Mar 30.

Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in genes encoding epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable, with few means to predict which patients will benefit. Here, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients who were responsive or resistant to decitabine (DAC) in order to develop a molecular means of predicting response at diagnosis. While somatic mutations did not differentiate responders from nonresponders, we identified 167 differentially methylated regions (DMRs) of DNA at baseline that distinguished responders from nonresponders using next-generation sequencing. These DMRs were primarily localized to nonpromoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. Transcriptional analysis revealed differences in gene expression at diagnosis between responders and nonresponders. In responders, the upregulated genes included those that are associated with the cell cycle, potentially contributing to effective DAC incorporation. Treatment with CXCL4 and CXCL7, which were overexpressed in nonresponders, blocked DAC effects in isolated normal CD34+ and primary CMML cells, suggesting that their upregulation contributes to primary DAC resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI78752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611703PMC
May 2015

Enhanced reduced representation bisulfite sequencing for assessment of DNA methylation at base pair resolution.

J Vis Exp 2015 Feb 24(96):e52246. Epub 2015 Feb 24.

Department of Medicine, Weill Cornell Medical College.

DNA methylation pattern mapping is heavily studied in normal and diseased tissues. A variety of methods have been established to interrogate the cytosine methylation patterns in cells. Reduced representation of whole genome bisulfite sequencing was developed to detect quantitative base pair resolution cytosine methylation patterns at GC-rich genomic loci. This is accomplished by combining the use of a restriction enzyme followed by bisulfite conversion. Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) increases the biologically relevant genomic loci covered and has been used to profile cytosine methylation in DNA from human, mouse and other organisms. ERRBS initiates with restriction enzyme digestion of DNA to generate low molecular weight fragments for use in library preparation. These fragments are subjected to standard library construction for next generation sequencing. Bisulfite conversion of unmethylated cytosines prior to the final amplification step allows for quantitative base resolution of cytosine methylation levels in covered genomic loci. The protocol can be completed within four days. Despite low complexity in the first three bases sequenced, ERRBS libraries yield high quality data when using a designated sequencing control lane. Mapping and bioinformatics analysis is then performed and yields data that can be easily integrated with a variety of genome-wide platforms. ERRBS can utilize small input material quantities making it feasible to process human clinical samples and applicable in a range of research applications. The video produced demonstrates critical steps of the ERRBS protocol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3791/52246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354670PMC
February 2015

Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program.

J Clin Invest 2015 Mar 9;125(3):1286-98. Epub 2015 Feb 9.

Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI78440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362230PMC
March 2015

Plasticity of DNA methylation in a nerve injury model of pain.

Epigenetics 2015 ;10(3):200-12

a Departments of Anesthesiology; Oncology; and Biostatistics and Bioinformatics; Mayo Clinic , Rochester , MN USA.

The response of the peripheral nervous system (PNS) to injury may go together with alterations in epigenetics, a conjecture that has not been subjected to a comprehensive, genome-wide test. Using reduced representation bisulfite sequencing, we report widespread remodeling of DNA methylation in the rat dorsal root ganglion (DRG) occurring within 24 h of peripheral nerve ligation, a neuropathy model of allodynia. Significant (P < 10(-4)) cytosine hyper- and hypo-methylation was found at thousands of CpG sites. Remodeling occurred outside of CpG islands. Changes affected genes with known roles in the PNS, yet methylome remodeling also involved genes that were not linked to neuroplasticity by prior evidence. Consistent with emerging models relying on genome-wide methylation and RNA-seq analysis of promoter regions and gene bodies, variation of methylation was not tightly linked with variation of gene expression. Furthermore, approximately 44% of the dynamically changed CpGs were located outside of genes. We compared their positions with the intergenic, tissue-specific differentially methylated CpGs (tDMCs) of an independent experimental set consisting of liver, spleen, L4 control DRG, and muscle. Dynamic changes affected those intergenic CpGs that were different between tissues (P < 10(-15)) and almost never the invariant portion of the methylome (those CpGs that were identical across all tissues). Our findings-obtained in mixed tissue-show that peripheral nerve injury leads to methylome remodeling in the DRG. Future studies may address which of the cell types found in the DRG, such as specific groups of neurons or non-neuronal cells are affected by which aspect of the observed methylome remodeling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15592294.2015.1006493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622653PMC
October 2015

DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia.

Cell Rep 2014 Dec 4;9(5):1841-1855. Epub 2014 Dec 4.

Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA; The Feil Family Brain and Mind Research Institute, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address:

Somatic mutations in IDH1/IDH2 and TET2 result in impaired TET2-mediated conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). The observation that WT1 inactivating mutations anticorrelate with TET2/IDH1/IDH2 mutations in acute myeloid leukemia (AML) led us to hypothesize that WT1 mutations may impact TET2 function. WT1 mutant AML patients have reduced 5hmC levels similar to TET2/IDH1/IDH2 mutant AML. These mutations are characterized by convergent, site-specific alterations in DNA hydroxymethylation, which drive differential gene expression more than alterations in DNA promoter methylation. WT1 overexpression increases global levels of 5hmC, and WT1 silencing reduced 5hmC levels. WT1 physically interacts with TET2 and TET3, and WT1 loss of function results in a similar hematopoietic differentiation phenotype as observed with TET2 deficiency. These data provide a role for WT1 in regulating DNA hydroxymethylation and suggest that TET2 IDH1/IDH2 and WT1 mutations define an AML subtype defined by dysregulated DNA hydroxymethylation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2014.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267494PMC
December 2014