Chromatin is a macromolecular complex predominantly comprising DNA, histone proteins and RNA. The methylation of chromatin components is highly conserved as it helps coordinate the regulation of gene expression, DNA repair and DNA replication. Dynamic changes in chromatin methylation are essential for cell-fate determination and development. Consequently, inherited or acquired mutations in the major factors that regulate the methylation of DNA, RNA and/or histones are commonly observed in developmental disorders, ageing and cancer. This has provided the impetus for the clinical development of epigenetic therapies aimed at resetting the methylation imbalance observed in these disorders. In this Review, we discuss the cellular functions of chromatin methylation and focus on how this fundamental biological process is corrupted in cancer. We discuss methylation-based cancer therapies and provide a perspective on the emerging data from early-phase clinical trial therapies that target regulators of DNA and histone methylation. We also highlight promising therapeutic strategies, including monitoring chromatin methylation for diagnostic purposes and combination epigenetic therapy strategies that may improve immune surveillance in cancer and increase the efficacy of conventional and targeted anticancer drugs.

/pdf/the-roles-of-dna-rna-and-histone-methylation-in-ageing-and-1ixnnx1f5k.pdf

The roles of DNA, RNA and histone methylation in ageing and cancer.

Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and clinical heterogeneity. Advances in genomic technologies have increasingly shown the complexity and heterogeneity of genetic and epigenetic alterations in AML. Among the genetic alterations occurring in AML, frequent are the genetic alterations at the level of various genes involved in the epigenetic control of the DNA methylome and histone methylome. In fact, genes involved in DNA demethylation (such as DNMT3A, TET2, IDH1, and IDH2) or histone methylation and demethylation (EZH2, MLL, DOT1L) are frequently mutated in primary and secondary AML. Furthermore, some histone demethylases, such as LSD1, are frequently overexpressed in AML. These observations have strongly supported a major role of dysregulated epigenetic regulatory processes in leukemia onset and development. This conclusion was further supported by the observation that mutations in genes encoding epigenetic modifiers, such as DMT3A, ASXL1, TET2, IDH1, and IDH2, are usually acquired early and are present in the founding leukemic clone. These observations have contributed to development of the idea that targeting epigenetic abnormalities could represent a potentially promising strategy for the development of innovative treatments of AML. In this review, we analyze those proteins and their inhibitors that have already reached the first stages of clinical trials in AML, namely the histone methyltransferase DOT1L, the demethylase LSD1, and the MLL-interacting protein menin.

/pdf/targeting-histone-methyltransferase-and-demethylase-in-acute-z34n14636r.pdf

Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy.

DNA Hydroxymethylation Profiling Reveals That WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia

Epigenetic allele diversity is linked to inferior prognosis in acute myeloid leukemia (AML). However, the source of epiallele heterogeneity in AML is unknown. Herein we analyzed epiallele diversity in a genetically and clinically annotated AML cohort. Notably, AML driver mutations linked to transcription factors and favorable outcome are associated with epigenetic destabilization in a defined set of susceptible loci. In contrast AML subtypes linked to inferior prognosis manifest greater abundance and highly stochastic epiallele patterning. We report an epiallele outcome classifier supporting the link between epigenetic diversity and treatment failure. Mouse models with TET2 or IDH2 mutations show that epiallele diversity is especially strongly induced by IDH mutations, precedes transformation to AML, and is enhanced by cooperation between somatic mutations. Furthermore, epiallele complexity was partially reversed by epigenetic therapies in AML driven by TET2/IDH2, suggesting that epigenetic therapy might function in part by reducing population complexity and fitness of AMLs.

/pdf/somatic-mutations-drive-specific-but-reversible-epigenetic-2acea0za3g.pdf

Somatic Mutations Drive Specific, but Reversible, Epigenetic Heterogeneity States in AML

Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and transcriptional states in leukemic cells. Here, we develop an experimental model system using in vitro lineage tracing coupled with exome, transcriptome and in vivo functional readouts to assess the AML population dynamics and associated molecular determinants underpinning chemoresistance development. We find that combining standard chemotherapeutic regimens with low doses of DNA methyltransferase inhibitors (DNMTi, hypomethylating drugs) prevents chemoresistant relapses. Mechanistically, DNMTi suppresses the outgrowth of a pre-determined set of chemoresistant AML clones with stemness properties, instead favoring the expansion of rarer and unfit chemosensitive clones. Importantly, we confirm the capacity of DNMTi combination to suppress stemness-dependent chemoresistance development in xenotransplantation models and primary AML patient samples. Together, these results support the potential of DNMTi combination treatment to circumvent the development of chemorefractory AML relapses.

/pdf/lineage-tracing-of-acute-myeloid-leukemia-reveals-the-impact-2ga1zki0v8.pdf

Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

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; {"type":"clinical-trial","attrs":{"text":"NCT00049517","term_id":"NCT00049517"}}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 (P = 0.011) and failure to achieve CR (P = 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.

/pdf/a-clinical-measure-of-dna-methylation-predicts-outcome-in-de-530s64wfjw.pdf

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

To the Editor: A number of recent studies have documented the frequency and prognostic importance of recurrent mutations in acute myeloid leukemia (AML) [1,2]. However, other studies have demonstrated that AML risk classification using genetic and clinical data incompletely predicts outcome after induction chemotherapy, and additional prognostic tools are still needed for accurate risk stratification [3]. We have developed both a clinical assay to assess multi-locus DNA methylation (xMELP), and a companion random forest classification system (M-score) for AML patient prognosis [4,5]. We recently demonstrated that M-score predicts outcomes in a cohort of 166 adult patients with AML treated at the University of Pennsylvania (UPENN), and in an independent cohort of 383 patients treated within the Eastern Cooperative Oncology Group (ECOG) E1900 AML study [6]. These results suggest that the rapid and technically straightforward evaluation of DNA methylation by M-score analysis could be a valuable prognostic test for AML patients at diagnosis. We now validate xMELP and M-score in an independent cohort of patients with AML treated at the University of Texas MD Anderson Cancer Center (UTMDACC), and include an analysis of patients with acute promyelocytic leukemia (APL) and secondary AML who have not been previously studied. Genomic DNA was isolated from diagnostic blood or marrow samples collected at UTMDACC from 149 consecutive AML patients (2001–2013) who consented to donation of a sample to the UTMDACC Leukemia Tissue Bank, had adequate DNA quality, and

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.24597

Validation of a clinical assay of multi‐locus DNA methylation for prognosis of newly diagnosed AML

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

Validation of a clinical assay of multi‐locus DNA methylation for prognosis of newly diagnosed AML