One of the greatest challenges in effectively treating hematologic disorders is the diversity of molecular abnormalities that underlie a disease. However, many common threads are emerging, including alterations in proteins that function through epigenetic mechanisms. For example, in AML with the 3q21;q26 cytogenetic abnormality (which has a particularly poor prognosis), a segment of a chromosome is inverted, placing a DNA sequence that normally activates its neighboring gene in close proximity to a cancer-causing proto-oncogene. This elevates expression of the proto-oncogene, disrupting the epigenetic mechanism controlling cell proliferation and therefore driving leukemogenesis. Similar mechanisms have been noted in other hematologic disorders, including leukemias, lymphomas, multiple myeloma, and MDS.
Since alterations in epigenetic mechanisms commonly mediate hematologic malignancies, epigenetic regulators represent a rich pipeline of potential targets that could be transformative for the treatment of blood cancers. Potential epigenetic targets include proteins that control histone methylation and acetylation, which can regulate genes that control proliferation; proteins that read histone marks and orchestrate changes in gene expression that cause malignancy; and DNA methyltransferases. For instance, the state of the epigenome determines the accessibility of DNA to the transcriptome machinery, thus allowing DNA to execute its functions. Further, fundamental mechanistic studies will continue to lead to the discovery of promising new targets.
Additional research will lay the groundwork in the context of precision medicine, elucidating potentially critical determinants of responsiveness to therapeutic regimens.
|1.1 ||Targeting and reversing malignant histone modifications. Enzymes that catalyze addition and removal of post-translational modifications to histone tails are recurrently mutated in a variety of blood cancers. Many researchers have shown that the abnormal distribution of the histone marks resulting from mutation of these enzymes can activate or silence expression of critical genes involved in malignant transformation. Finding ways to reverse these pathogenic histone marks, either through inhibiting the writers and erasers of the specific mark or by direct epigenetic reprogramming, could have a beneficial effect in restoring normal gene expression programs and alleviating the disease.|
|1.2||Identifying small molecules that target epigenetic modifiers in hematopoietic malignancies. Genetic mutations that produce gain-of-function or neomorphic proteins (such as IDH1/2 mutations, EZH2Y641F) are common in leukemias and lymphomas. The mutant proteins go on to corrupt the epigenome resulting in oncogenic gene expression signatures. Development of small molecules that specifically inhibit the mutant protein, but not the wild-type (these mutations are typically heterozygous meaning the wild-type protein is still expressed from the non-mutated allele), could prove beneficial for many patients.|
|1.3|| Developing tools and technologies for locus-specific epigenetic reprogramming. Current epigenetic therapies (e.g., hypomethylating agents) cause global changes to the epigenome, but the disease is likely driven by specific, local epigenetic dysregulation at several critical loci. The development of tools such as modified CRISPR/Cas9 systems to target and correct aberrant DNA methylation patterns at specific disease-causing genes while leaving the rest of the normal epigenetic marks in the cell intact (for translational purposes), warrants further investigation.|