Abstract

Gene rearrangements of the human MLL gene (also known as KMT2A) generate multiple fusion oncoproteins which cause leukemia with poor prognosis. MLL is an epigenetic regulator that reads and writes epigenetic information and has an evolutionarily conserved role maintaining expression of Homeotic (HOX) genes during embryonic development. Most MLL gene rearrangements found in leukemia generate a constitutively active version of the wild-type protein, which causes overexpression of HOX and other genes and leukemic transformation of normal hematopoietic progenitors. Elucidating the molecular mechanisms underlying how MLL activates gene expression and how gene rearrangements affect this gene-regulating activity provided therapeutic opportunities to block fusion oncoprotein-specific activities. One uniform molecular dependency of MLL fusion oncoproteins is its interaction with the chromatin-binding partner MENIN that is essential to maintain leukemic transformation. MENIN inhibitors that interfere with the MLL-MENIN interaction have been developed and are now entering clinical practice. Also, the MLL complex physically interacts with several histone acetyl transferases (HATs), including MOZ/MORF, HBO1, and EP300/CREBBP to effect MLL-MENIN-dependent gene activation. Aberrant recruitment of these HATs and other transcriptional effector complexes are key differences between MLL and MLL fusion oncoproteins. In this review, we first summarize our current understanding of wild-type MLL function and aberrant function of its oncogenic variants. We then discuss in detail how chromosomal translocations generate constitutive active forms of MLL and categorize them into five major classes. We touch on the collaborative gene activation by MLL and specific interacting HATs. Lastly, we discuss how these mechanistic insights have led to the development of the first-in-class MENIN inhibitors and discuss efforts to anticipate and treat both genetic and non-genetic mechanisms of resistance.