Epigenetics Directing Therapy in Acute Lymphocytic Leukemia: Emerging Roles and New Therapies

In the last 15 years, our understanding of the contribution of epigenetic mechanisms to ALL leukemogenesis has increased exponentially. Epigenetic alterations are particularly interesting from a therapeutic standpoint, as they are potentially reversible and amenable to pharmacologic modulation. Indeed, inhibitors of DNA methylation, histone deactylation and histone methylation all have entered clinical trials, and early results for several of these agents are encouraging. Incorporating epigenetic modulation into ALL therapy may therefore hold great promise in improving tolerability and outcomes. Specifically, this session will address:

- Patterns of aberrant DNA methylation and clinical trials combining "demethylating" agents with standard chemotherapy for relapsed ALL.DNA methylation patterns have been shown to correlate with outcome. Basic studies failed to conclusively link the regulation of specific genes or pathways to aberrant DNA methylation, and upfront methylation patterns poorly predict response to demethylating agents. Nevertheless, several clinical trials combining demethylating agents and chemotherapy in relapsed ALL are ongoing, with encouraging early results. These included responses of patients treated with decitabine and HyperCVAD who had previously failed to respond HyperCVAD alone.

- Patterns of aberrant histone acetylation, the biology of histone acetyl transferases (HATs) and histone deacetylases (HDACS) in ALL, and clinical trials modulating histone acetylation. Histone acetylation patterns and a high frequency of deletions of the HAT CBP at relapse suggest that aberrant histone acetylation contributes to relapse and resistance. HDAC inhibitors show efficacy on ALL cells in preclinical studies, and clinical trials are ongoing.

- The role of the histone acetylation "reader" protein Brd4 in ALL. In addition to "writers" (HAT) and "erasers" (HDACs), readers of histone acetylation may play a role in leukemia. Inhibition of Brd4 showed activity in several lymphoblastic leukemia models, and two Brd4 inhibitors are currently in clinical trials for relapsed/refractory hematologic malignancies including ALL.

- Patterns of aberrant histone methylation, biology and therapeutic possibilities. Aberrant histone methylation is also emerging as a contributor to leukemogenesis, and may offer opportunities for therapeutic intervention. Loss of function mutations of the H3K27 histone methyltransferase EZH2 or other members of its complex (SUZ12, EED) are often found in early T-cell precursor ALL (ETP), and loss of EED or EZH2 contributes to aberrant T-cell development and leukemic transformation in mouse models. Gain of function of the H3K36 histone methyltransferase NSD2 have recently been described in pre-B ALL, raising the obvious question whether these leukemias depend on H3K36 hypermethylation, and NSD2 inhibition would have a therapeutic effect. Finally, aberrant recruitment of the histone methyltransferase DOT1L is observed in MLL-rearranged ALL, and an inhibitor of DOT1L is in clinical trials for MLL-rearranged malignancies, including ALL.

Basic and translational studies support a critical role for epigenetic mechanisms in ALL leukemogenesis, drug resistance and relapse. Early results from clinical trials demonstrate that pharmacologic modulation of epigenetic modifiers can produce clinically meaningful responses. The next few years will likely see an increased number of compounds that modulate epigenetics enter clinical trials. Current assignment of patients to studies/compounds is crude, based on tumor type and status (i.e. "relapsed hematologic malignancy") or cytogenetics (i.e. MLL-rearrangement), rather than epigenetic profiling or an understanding of the biology that drives an individual patient's leukemia. As our diagnostic and therapeutic tools improve, epigenetic modulation may become an important component of ALL therapy.