The DNA methylation landscape of hematological malignancies: an update

Abstract

The rapid advances in high-throughput sequencing technologies have made it more evident that epigenetic modifications orchestrate a plethora of complex biological processes. During the last decade, we have gained significant knowledge about a wide range of epigenetic changes that crucially contribute to some of the most aggressive forms of leukemia, lymphoma, and myelodysplastic syndromes. DNA methylation is a key epigenetic player in the abnormal initiation, development, and progression of these malignancies, often acting in synergy with other epigenetic alterations. It also contributes to the acquisition of drug resistance. In this review, we summarize the role of DNA methylation in hematological malignancies described in the current literature. We discuss in detail the dual role of DNA methylation in normal and aberrant hematopoiesis, as well as the involvement of this type of epigenetic change in other aspects of the disease. Finally, we present a comprehensive overview of the main clinical implications, including a discussion of the therapeutic strategies that regulate or reverse aberrant DNA methylation patterns in hematological malignancies, including their combination with (chemo)immunotherapy.

Keywords: cancer; epigenetics; hematology; leukemia; lymphoma; methylation.

Fig. 1

DNA methylation and hematopoietic development. (A) Schematic of the ‘classical’ view of hematopoiesis, where starting from a HSC, the whole blood cell population is formed in every subsequent step (binary bifurcation points). Epigenetics plays an important role in regulating both the myeloid and lymphoid lineages. Genes with key roles in HSC self‐renewal and pluripotency (termed stemness genes in the picture) are preferentially expressed at early stages of the process. On the contrary, as the different lineages are selected, the respective lineage‐specific genes are expressed accordingly. (B) In hematological malignancies, the epigenetic patterns present under homeostatic control become aberrant and the cells may suffer malignant transformations in every stage of the process. We illustrate schematically the main consequences of key effector methylation enzymes' malfunction and their impact in self‐renewal, lineage bias, and differentiation, along with some examples of the resulting up‐ or downregulated target genes.

Fig. 2

Cellular regulation of DNA methylation. DNA methylation influences neoplastic cell's metabolism and vice versa. (A) Glycolysis is regulated by, among others, the HIF1 pathway. A crucial TSG of this pathway, VHL, has been shown to be epigenetically silenced in hematological malignancies. See text for more details. (B) SAM is the substrate needed by DNMTs in order to methylate the DNA, and it is one of the limiting aspects that favors DNMT impairment in tumors. SAM is then converted to SAH, which usually accumulates and acts as an inhibitor of the process in the normal product‐negative regulation of the enzyme function. See text for more details. (C) Although the tumor cell prefers to transform glucose into lactate to rapidly obtain ATP, intermediate metabolites and redox power, TCA cycle intermediates play an important role in methylation as several of them act upon TET demethylases. TET enzymes use α‐KG as a substrate to actively demethylate DNA, and, as SAM, it is rather limited in the tumor cell. α‐KG can be transformed into 2‐HG by mutated forms of IDH1 or IDH2, which acts as a competitor of α‐KG and impairs TET function. SDH and FH might be silenced in hematological malignancies, which originates an accumulation of succinate and fumarate, which together with 2‐HG act as TET inhibitors in the cell. (D) Due to the increase in nutrient uptake, hypoxic conditions, redox stress, and environment acidification, the tumor cell creates an environment, which enhances tumor survival while it dampens immune cell activation, that is, favoring macrophage M2 polarization or Treg phenotype. 3PG, 3‐phosphoglycerate; G6P, glucose‐6‐phosphate; α‐KG, α‐ketoglutarate.

Fig. 3

Impaired regulatory elements in leukemia and lymphoma. Different miRNA/lncRNA colors (left) match the corresponding up/downregulated genes (right). Methylation of miRNA/lncRNAs promoters in the figure has all negative impact in the disease, except for the lncRNA MEG3, which has been shown to suppress leukemogenesis (see text). miRNAs might be both TSG and oncogenes, as specified in the text. miRNA genes marked with (*) are also found hypermethylated both in lymphoma and in leukemia (A) miRNAs genes are small noncoding RNA fragments that usually interact with the target mRNA and repress its translation. In leukemia and lymphoma, several miRNAs' promoter regions have been described to be hypermethylated, which allows the target genes to be expressed. (B) lncRNA are long RNA fragments that by interacting with their target can interfere in several stages of target expression and function. In the figure, we show how hypermethylation of the promoter region of different genes allows that several members of MLL fusion gene family to be translated contributing to leukemia progression. (C) Superenhancers are DNA elements, which by loop formation allow an increase in the production of its targets. In leukemia, enhancers of TSGs are hypermethylated, whereas oncogene's enhancers are found to be hypomethylated. E, enhancer; Me, 5‐methyl cytosine; RISC, RNA‐induced silencing complex.

Fig. 4

Mechanism of action of TET inhibitors. (A) Direct inhibition. A novel compound discovered by Chua et al. [121], Bobcat 339 emerged from a selection of different TET enzyme inhibitors as the most successful on inhibiting the enzyme function by binding its Cl residue on the pocket reserved for Me. The drug blocks both TET1 and TET2 enzymes and does not interact with other methylation enzymes such as DNMTs. (B) Indirect inhibition. JAK/STAT pathway is involved in TET1 transcription, and STAT inhibitor UC‐514321 seems to stop aberrant TET1 function found in AML according to Jiang et al. [122]. (C) Indirect inhibition. SP1 appears to be a transcription factor involved in TET1 transcription, and as in the case of UC‐514321, blocking TET1 transcription and translation in AML gives promising results avoiding the spread of the malignancy.