Structural highlights
Disease
[AF10_HUMAN] Precursor T-cell acute lymphoblastic leukemia. A chromosomal aberration involving MLLT10 is associated with acute leukemias. Translocation t(10;11)(p12;q23) with KMT2A/MLL1. The result is a rogue activator protein. A chromosomal aberration involving MLLT10 is associated with diffuse histiocytic lymphomas. Translocation t(10;11)(p13;q14) with PICALM.
Function
[AF10_HUMAN] Probably involved in transcriptional regulation. In vitro or as fusion protein with KMT2A/MLL1 has transactivation activity. Binds to cruciform DNA.[1]
Publication Abstract from PubMed
The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A (HOXA) gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10(OM-LZ) and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation. We further show that zinc stabilizes the DOT1L-AF10 complex and may be involved in the regulation of the HOXA gene expression. Our studies may also pave the way for the rational design of therapeutic drugs against MLL-rearranged leukemia.
Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis.,Zhang H, Zhou B, Qin S, Xu J, Harding R, Tempel W, Nayak V, Li Y, Loppnau P, Dou Y, Min J Genes Dev. 2018 Mar 1;32(5-6):341-346. doi: 10.1101/gad.311639.118. Epub 2018 Mar, 21. PMID:29563185[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Forissier S, Razanajaona D, Ay AS, Martel S, Bartholin L, Rimokh R. AF10-dependent transcription is enhanced by its interaction with FLRG. Biol Cell. 2007 Oct;99(10):563-71. PMID:17868029
- ↑ Zhang H, Zhou B, Qin S, Xu J, Harding R, Tempel W, Nayak V, Li Y, Loppnau P, Dou Y, Min J. Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis. Genes Dev. 2018 Mar 1;32(5-6):341-346. doi: 10.1101/gad.311639.118. Epub 2018 Mar, 21. PMID:29563185 doi:http://dx.doi.org/10.1101/gad.311639.118
