Mixed Lineage Leukemia Gene Rearrangements - Epigenetic Diseases Require Epigenetic Treatments

Abstract SCI-8

Reaching optimal treatment results in MLL-rearranged Acute Lymphoblastic Leukemia (ALL) remains one of the major challenges in pediatric oncology. This aggressive type of ALL is initiated by chromosomal translocations involving the MLL gene, fusing the N-terminal portion of the MLL gene to the C-terminal region of one of its many translocation partner genes. Such MLL rearrangements generate fusion proteins that possess pronounced transforming capacity and typically arise in utero. Hence, MLL-rearranged ALL is usually diagnosed in infants at or shortly after birth. The survival chances for these young patients still ranges from 20–40%, while the long-term survival rates for childhood ALL in general easily exceeds 80%.

MLL-rearranged ALL samples display unique and ample deregulated gene expression profiles that are clearly distinguishable from profiles found in other ALL subtypes. Inappropriate gene activation seems to be largely driven by abnormal histone modifications established by the MLL fusion protein itself. In contrast, we recently showed that substantial amounts of gene inactivation in MLL-rearranged infant ALL can be explained by aberrant promoter hypermethylation. The expression of numerous of these epigenetically silenced genes can be restored by demethylating agents and results in severe induction of leukemic cell death. Moreover, the degree of genome-wide promoter methylation appeared to be of prognostic significance with patients displaying more heavily methylated genomes being at extreme high-risk of disease relapse.

In additional studies focusing on genome-wide promoter methylation we found that MLL-rearranged infant ALL is characterized by the activation of a particular set of proto-oncogenes as a result of abnormal promoter hypomethylation. Strikingly, the activation of several of these genes had already been associated with activating histone marks induced by the MLL fusion protein. Together these findings demonstrate the sound interplay between histone modifications and downstream DNA methylation. In search of therapeutic strategies to target these epigenetically activated proto-oncogenes, we found that HDAC inhibitors represent particularly suitable compounds. Exposing MLL-rearranged infant ALL cells to HDAC inhibitors effectively induced leukemic cell death, while at similar concentrations normal bone marrow samples were practically unharmed. Interestingly, these cytotoxic responses were accompanied by the rapid down-regulation of multiple of the proto-oncogenes, but more importantly, was preceded by the degradation of the oncogenic MLL fusion product.

Collectively, these observations clearly demonstrate that MLL-rearranged ALL represents an epigenetic malignancy that should be treated accordingly using epigenetic drugs like demethylating agents and HDAC inhibitors. With these pre-clinical studies showing great potential of these drugs in vitro, these compounds should now be tested in vivo in mouse models to pave the way for future clinical trials.