Tissue- and tumor-type-specific expression of internal-promoter-driven YEATS-domain-devoid isoforms of MLLT1 and MLLT3.

As integral parts of the transcription super elongation complex, the ENL and AF9 proteins are two master regulators of gene expression involved in the development and homeostasis of various tissues. They are encoded by MLLT1 and MLLT3, two genes that frequently undergo oncogenic mutations or chromosomal translocations in cancers. In addition, we discovered an internal promoter driving the production of a YEATS (named after the five proteins first shown to contain this domain: Yaf9, ENL, AF9, Taf14, and Sas5)-domain-devoid AF9 isoform massively expressed in healthy hematopoietic stem cells (HSCs), as well as in the blasts of patients with extremely poor-prognosis acute myeloid leukemia (AML). Here, we show that such internal promoter is also active in a subset of digestive tissues, including the small intestine, colon and stomach. We also reveal the existence of a similar internal promoter in the MLLT1 locus that is inactive in the hematopoietic lineage and AML but functional in other healthy tissues, including the pituitary gland, brain, thyroid, uterus and lung. Furthermore, the YEATS-domain-devoid MLLT1 isoform may exhibit tumor-type-specific biomarker values, whereas full-length MLLT1 does not. It is highly expressed in the gonadotroph subtype of pituitary tumors, and its expression in non-small cell lung cancer inversely correlates with the epidermal growth factor mutation and a transcriptomic signature associated with a good prognosis. Thus, both MLLT1 and MLLT3 have tissue- and tumor-type-specific internal promoters driving expression of similar YEATS domain-devoid isoforms. This suggests that the functions of both MLLT1 and MLLT3 in tissue homeostasis and cancers, as well as their potentials as biomarkers should be re-evaluated taking into account expression of these YEATS-domain-devoid ENL and AF9 transcription factors.