Epigenetics is pivotal in the pathogenesis of acute myeloid leukemia (AML), a disease marked by uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells¹. Epigenetic modifications, such as DNA methylation, histone modifications, and RNA modifications, regulate gene expression without altering the DNA sequence. Various proteins, including writers, erasers, and readers, regulate these modifications, which add, remove, and interpret these marks accordingly. Dysregulation of these epigenetic mechanisms contributes to leukemogenesis and disease progression. Our Epigenetics in AML pathway poster highlights key elements of the multifaceted epigenetic alterations involved in this aggressive blood malignancy.

DNA methylation is defined by adding a methyl group to the cytosine base in DNA, typically at CpG dinucleotides, and is generally linked with gene repression. In AML, aberrant DNA methylation patterns are typical and contribute to the silencing of tumor suppressor genes and activating oncogenes. Key enzymes involved in this process include DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes². For example, mutations in DNMT3A lead to altered DNA methylation patterns, contributing to leukemogenesis. Moreover, TET2 mutations impair DNA demethylation, resulting in the hypermethylation of tumor suppressor genes. These mutations are present in a significant proportion of AML patients and are associated with poor prognosis³.

Key epigenetic enzymes can be categorized as readers, writers, and erasers. Readers are proteins that recognize and bind to specific epigenetic marks, influencing gene expression⁴. The bromodomain and extraterminal (BET) family of proteins, including BRD4, are critical epigenetic readers. BRD4 binds to acetylated histones and recruits transcriptional machinery to promote the expression of oncogenes such as MYC⁵. Inhibitors targeting BET proteins, such as JQ1, have shown promise in preclinical models of AML by disrupting these interactions and reducing the expression of oncogenic transcriptional programs.

Writers are enzymes that add chemical groups to DNA, histones, or RNA, with DNMTs and histone methyltransferases being vital players in epigenetic modifications. DNMT3A adds methyl groups to DNA; its mutations are frequently found in AML⁶. Another critical writer enzyme is EZH2. This protein is a histone methyltransferase that adds methyl groups to histones, repressing tumor suppressor genes. Dysregulation of these writers causes abnormal gene expression that promotes leukemogenesis. Lastly, epigenetic erasers are proteins that remove chemical groups from DNA, histones, or RNA. In AML, primary erasers include the TET family of enzymes and histone deacetylases (HDACs). TET2 enzymes remove methyl groups from DNA, and mutations in TET2 disrupt this process. Simultaneously, HDACs remove acetyl groups from histones, resulting in chromatin condensation and gene repression. HDAC inhibitors also have shown promise in preclinical AML models by reversing abnormal histone deacetylation and reactivating tumor suppressor genes⁷.

In addition, numerous transcription factors are often mutated or dysregulated in AML, participating in leukemogenesis. Mutations in the transcription factor CEBPA, for instance, disrupt normal myeloid differentiation and promote leukemic transformation⁸. Similarly, the fusion protein RUNX1-ETO, resulting from the t(8;21) translocation, acts as an aberrant transcription factor that represses differentiation and promotes self-renewal of leukemic cells⁹.

RNA-binding proteins (RBPs) are essential for post-transcriptional regulation of gene expression. In AML, dysregulation of RBPs can promote disease progression. For instance, RBM5 is crucial for AML cell survival by regulating oncogenic proteins like HOXA9. Targeting RBPs poses a promising therapeutic approach in AML, as they are imperative for sustaining leukemic traits¹⁰.

Epigenetic dysregulation is a hallmark of AML, contributing to its initiation and progression. Understanding the roles of DNA methylation, key epigenetic enzymes, transcription factors, and binding proteins in AML provides insights into the molecular mechanisms driving leukemogenesis. This knowledge paves the way for new therapeutic interventions, enabling the development of targeted therapies that can reverse abnormal epigenetic changes and enhance outcomes for AML patients. Discover the vital role of epigenetics in cancer by exploring our comprehensive Epigenetics pathways in cancer poster here.

To help you study epigenetic mechanisms in AML, the poster covers all key established and promising epigenetics targets in acute myeloid leukemia, including:

• Histone modifications, such as H2AR3, H3K4, H3K36, H3K27, H3K9, H3R8, H3K79, H4R3
• Histone methylation/demethylation enzymes, including EZH2, KMT2A, SETD2, G9A (EHMT2), PRMT1, PRMT5, and DOT1L
• DNA methylation enzymes, such as DNMT3A, TET1/2/3, IDH1, IDH2
• Transcription factors, such as HOXA9, PU1, CEBPA, and RUNX1
• RNA binding proteins, including RBM39, IGF2BP1, Musashi 2, hnRNP K, NCL, WT1
• RNA methyltransferase METTL3
• Epigenetic reader BRD4

Once you’ve downloaded the poster, click on the highlighted epigenetic targets to access the range of corresponding products.

References

1. Plass, C., Oakes, C., Blum, W. & Marcucci, G. Epigenetics in acute myeloid leukemia.  Semin. Oncol.   35, 378–387 (2008).

2. Yang, X., Wong, M. P. M. & Ng, R. K. Aberrant DNA Methylation in Acute Myeloid Leukemia and Its Clinical Implications.  Int. J. Mol. Sci.   20, 4576 (2019).

3. Park, D. J. et al. Characteristics of DNMT3A mutations in acute myeloid leukemia.  Blood Res.   55, 17–26 (2020).

4. Biswas, S. & Rao, C. M. Epigenetic tools (The Writers, The Readers, and The Erasers) and their implications in cancer therapy.  Eur. J. Pharmacol.   837, 8–24 (2018).

5. Roe, J. S. & Vakoc, C. R. The Essential Transcriptional Function of BRD4 in Acute Myeloid Leukemia.  Cold Spring Harb. Symp. Quant. Biol.   81, 61–66 (2016).

6. Chaudry, S. F. & Chevassut, T. J. Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute Myeloid Leukaemia and Clonal Haematopoiesis.  Biomed. Res. Int.   2017, 5473197 (2017).

7. Huang, F. et al. HDAC4 inhibition disrupts TET2 function in high-risk MDS and AML.  Aging (Albany NY)   12, 16759–16774 (2020).

8. Su, L., Shi, Y. Y., Liu, Z. Y. & Gao, S. J. Acute Myeloid Leukemia With CEBPA Mutations: Current Progress and Future Directions.  Front. Oncol.   12, 806137 (2022).

9. Ptasinska, A. et al. RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBPα- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction.  Cell Rep.   28, 3022–3031.e7 (2019).

10. Zhang, M. et al. RNA-binding protein RBM5 plays an essential role in acute myeloid leukemia by activating the oncogenic protein HOXA9.  Genome Biol.   25, 16 (2024).