A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia

Highlights

• AML is hypersensitive to the knockdown of TAF12, a subunit of TFIID and SAGA complexes

• Normal tissues can persist in a TAF12-deficient state

• A TAF12/TAF4 histone-fold heterodimer binds to the activation domain of MYB

• Peptide-based squelching of TAF12/MYB leads to potent anti-leukemia effects

Summary

Targeting of general coactivators is an emerging strategy to interfere with oncogenic transcription factors (TFs). However, coactivator perturbations often lead to pleiotropic effects by influencing numerous TFs. Here we identify TAF12, a subunit of TFIID and SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a TF with established roles in leukemogenesis. Ectopic expression of the TAF4 histone-fold fragment can efficiently squelch TAF12 in cells, suppress MYB, and regress AML in mice. Our study reveals a strategy for potent MYB inhibition in AML and highlights how an oncogenic TF can be selectively neutralized by targeting a general coactivator complex.