The Leukemia-Driving Fusion Protein TCF3–HLF Is Regulated by EP300

The chimeric transcription factor TCF3–HLF characterizes a subtype of acute lymphoblastic leukemia (ALL) that is highly recalcitrant to treatment. In a study of this cancer-driving fusion protein, Huang, Mouttet, Warnatz, and colleagues first verified that TCF3–HLF is required for disease maintenance in an ALL cell line, a finding they confirmed in two patient-derived xenograft (PDX) mouse models of ALL. Further experiments in an ALL cell line implied that the presence of TCF3–HLF may interfere with transcriptional programs that ordinarily drive lymphoid differentiation and may also increase MYC RNA and MYC protein levels, promoting a stem-like state. In the ALL cells, TCF3–HLF predominantly occupied active enhancers, particularly superenhancers, and notably appeared to target a superenhancer cluster ∼2 Mb downstream of MYC. Chromosome-conformation capture coupled with qPCR in the ALL cell line and the PDX models revealed that TCF3–HLF was required for spatial interactions between the MYC promoter and a pair of superenhancers occupied by the fusion protein. TCF3–HLF colocalized with the proto-oncoprotein ERG on chromatin in ALL cells, including at the previously noted MYC superenhancer, and loss of TCF3–HLF abolished ERG binding at all tested loci, whereas loss of ERG only moderately interfered with TCF3–HLF binding at the same sites, hinting that TCF3–HLF may act as a pioneer transcription factor in this context. Interactome profiling of TCF3–HLF in ALL cells uncovered interactions between the fusion protein and several other transcription factors; of note, there was evidence for interactions between TCF3–HLF and the histone acetyltransferase EP300 as well as some proteins implicated in leukemias and other cancers. In the PDX models, treatment with the EP300 inhibitor A-485 substantially reduced TCF3–HLF RNA levels, decreased the expression of genes activated by TCF3–HLF, and stalled leukemogenesis. Together, these results provide a detailed characterization of TCF3–HLF⁺ ALL and identify EP300 as a potentially targetable vulnerability in this fatal subtype of leukemia.

Huang Y, Mouttet B, Warnatz HJ, Risch T, Rietmann F, Frommelt F, et al. The leukemogenic TCF3-HLF complex rewires enhancers driving cellular identity and self-renewal conferring EP300 vulnerability. Cancer Cell 2019;36:630–44.e9.

• ©2020 American Association for Cancer Research.