One of the greatest challenges in effectively treating hematologic disorders is the diversity of molecular abnormalities that underlie a disease. However, a number of common threads are emerging, including alterations in proteins that function through epigenetic mechanisms. For example, in acute myeloid leukemia (AML) with a 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 provoking leukemogenesis. Similar mechanisms have been noted in other hematologic disorders, including leukemias, lymphomas, multiple myeloma, and myelodysplastic syndrome (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 is a critical determinant of the accessibility of the DNA itself to execute its functions. Further, fundamental mechanistic studies will continue to lead to the discovery of promising new targets that have not yet been categorized.
Additional research will lay the groundwork in the context of precision medicine, elucidating potentially critical determinants of responsiveness to therapeutic regimens.
|1.1||Dedicated research focusing on emerging targets is needed to identify their role in the development of hematologic disorders and design potential targeted treatments to counter their effects. Promising targets include DOT1L, EZH2, NSD1 and NSD2, bromodomain and isocitrate dehydrogenase-2 (IDH2) inhibitors, and histone demethylases and deacetylases.|
|1.2||Understanding the impact of currently used epigenetic therapies (e.g., hypomethylating agents) on pre-leukemic cells harboring mutations in epigenetic regulators may lead to early intervention approaches and new agents.|
|1.3||Research in this area relies on technologies that decipher protein function at the whole genome level and requires sophisticated analytical approaches to contend with exceptionally large datasets. Thus it will be critical to establish and nurture highly advanced computational and biostatistical expertise among new investigators in the hematology community.|