Introduction:
Studies examining the epigenomic profile of patients with blood-related cancers have found changes in how DNA and its modifications are handled. This includes modifications like cytosine methylation and its oxidized forms and alterations in how certain proteins associated with DNA, called histones, are modified. Simultaneously, genetic studies in patients with blood cancers have rapidly identified gene mutations responsible for these modifications. While these mutations are essential for assessing the risk of certain blood cancers, researchers are still figuring out how these abnormal changes in the genetic material contribute to the development of blood cancers.
What Are the Hematological Malignancies in Epigenetics?
Epigenetic Regulation in Hematological Malignancies:
-
DNA wraps around histone proteins to form nucleosomes.
-
Epigenetic marks on DNA and histones are added by "writers" like DNMT3A, TET2, EZH1/2, and histone acetylases.
-
Marks can be removed by "erasers" such as Lysine-Specific Demethylases (LSD) and histone deacetylases (HDAC).
-
Special "reader" domains, like plant homeodomain (PHD) finger proteins, recognize these marks, recruiting regulators to DNA and histones.
Epigenetic Dysregulation in Hematological Malignancies:
-
Mutations or complex formations disturb the normal epigenetic program.
-
MLL gene translocations, common in leukemias, create abnormal MLL-fusion proteins like SEC and DOT1L complexes.
-
DOT1L complex misdirects H3K79 methylation, sustaining expression of pro-leukemic genes.
-
SEC complex phosphorylates RNA polymerase II, promoting the activation of crucial oncogenes.
Metabolic Dysregulation in Hematological Malignancies:
-
IDH1/2 mutations lead to 2-hydroxyglutarate (2HG) production, disrupting normal gene regulation.
-
2HG inhibits the hydroxylation of 5-mC by TET2, contributing to the disease.
Therapeutic Targets for Hematological Malignancies:
- FDA-approved drugs include DNMT3A inhibitors for AML and MDS and HDAC inhibitors for T cell lymphoma and multiple myeloma.
-
Investigational drugs at various stages of development target different aspects of epigenetic and genetic dysregulation.
What Is the Role of Epigenetic Alterations in Hematological Malignancies in Cancer?
Epigenetic chaos in cancer involves widespread loss of DNA methylation, causing genetic instability and muting crucial genes. Extensive studies show that DNA methylation decreases across gene-poor regions as tumors become more invasive. This global hypomethylation promotes cancer by destabilizing chromosomes, reactivating disruptive elements, and erasing genetic imprints.
Key tumor-suppressor genes like Rb, VHL, p16INK4a, BRCA1, and hMLH1 are inactivated through excessive methylation. Each cancer type possesses a unique methylation pattern, forming a distinct "hypermethylome." In acute myelogenous leukemia (AML), abnormal methylation disrupts the function of vital genes like C/EBPα. In some cancers, epigenetic regulators can be directly mutated, creating a positive feedback loop favoring cancer cell growth. While such mutations are rare in solid tumors, they are more common in hematologic cancers, providing valuable insights into cancer's epigenetic dysregulation.
What Is the Role of Polycomb Group Proteins in Hematological Cancers?
- Introduction to Polycomb Group Proteins (PcG): PcG proteins regulate genes involved in cell fate decisions. Two key complexes, PRC1 and PRC2, control gene activity through histone modifications.
-
PRC2 and the Significance of EZH2: PRC2 core components include EZH1/2, EED, and SUZ12. EZH2 is a key methyltransferase linked to aberrant repression of tumor suppressor genes. Mutations in EZH2, particularly Y641 mutations, enhance its activity and contribute to lymphomas.
-
EZH2 in Myeloid Malignancies: Loss-of-function mutations of EZH2 are prevalent in myeloid malignancies. These mutations indicate a poorer overall survival in conditions like CMML, MDS, and primary myelofibrosis. The exact biological consequences of inactivating EZH2 mutations in blood cell development are not fully understood.
-
ASXL1 Mutations and their Impact: ASXL1 mutations are associated with myeloid malignancies. Inactivating ASXL1 mutations leads to a global decrease in H3K27 methylation and upregulation of specific genes. ASXL1 interacts with EZH2, emphasizing its role in gene regulation and epigenetic control.
-
Other PcG Proteins in Hematopoiesis: Members of PRC1, including cbx family and BMI-1, also influence blood cell development. Cbx family members, such as cbx7 and cbx8, mediate the balance between cell self-renewal and differentiation. BMI-1, a subunit of PRC1, is crucial for stem cell self-renewal, but increased expression is linked to poor survival in certain blood cancers.
What Are the Epigenetic Therapies in Hematological Cancers?
Epigenome's Role in Hematological Malignancies: Enzymes that manage the epigenome, crucial for normal blood development, are often disrupted in blood cancers. This disruption makes them a target for treatment. Epigenetic drugs emerge as vital tools for managing blood cancers, alone or combined with existing chemotherapies.
DNMT Inhibitors: Azacitidine and Decitabine disrupt DNA methylation in cancer cells. These drugs, approved by the FDA, work by incorporating DNA during cell replication, gaining approval for treating myelodysplastic syndromes (MDS). Azacitidine has shown effectiveness in improving overall survival and delaying the progression to acute myeloid leukemia (AML). Modified versions of these drugs, like SGI-110, are in clinical trials. The key is finding the right dosage for maximum effectiveness; lower doses have shown better outcomes.
Azacitidine's Impact on MDS Treatment: CALGB trials demonstrated azacitidine's efficacy in MDS, leading to FDA approval. AZA-001 trial revealed prolonged overall survival in higher-risk MDS with azacitidine compared to conventional care.
Decitabine Role in MDS Treatment: Decitabine or 5-AZA-CdR, approved by the FDA, showed clinical effectiveness in MDS treatment. Ongoing research explores different schedules for enhanced therapeutic benefits.
New Epigenetic Drugs - SGI-110: Modified analogs like SGI-110, resistant to cytidine deaminase activity, show promise in treating AML and MDS. Clinical trials are underway, with positive results indicating potential AML and MDS treatment advancements.
IDH Inhibitors: Mutant IDH2 is targeted by inhibitors like AG-6780 and AG-221, showing promise in AML and T-cell lymphoma. Clinical trials are underway to explore their potential further.
HDAC Inhibitors: Increased HDAC activity in blood cancers makes HDAC inhibitors crucial. Vorinostat and Panobinostat, among others, alter gene expression, inducing cell cycle arrest and apoptosis.
BET Inhibitors: BET inhibitors like I-BET762 and JQ1 disrupt chromatin complexes, downregulating crucial oncogenes. Early clinical trials, such as those with OTX015, show promising antitumor activity in acute leukemia and other blood cancers.
Conclusion:
Researchers have found that certain genes controlling how the genetic material functions, known as epigenetic modifiers, often have mutations in people with blood-related cancers. While we have a list of these alterations and are starting to understand their possible connections to the patients' conditions, there's much to figure out. For example, we have yet to thoroughly explore the detailed effects of these mutations on the body. Studies using mice might help to understand how these gene changes impact blood formation. By combining genetic studies with analyses of how genes are turned on or off and how they function, researchers hope to discover new ways to treat these disorders.
