6cko › Citations

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 32 341-346 (2018)
Cited: 12 times
EuropePMC logo PMID: 29563185

Abstract

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 AF10OM-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.

Reviews - 6cko mentioned but not cited (1)

  1. Activation and regulation of H2B-Ubiquitin-dependent histone methyltransferases. Worden EJ, Wolberger C. Curr. Opin. Struct. Biol. 59 98-106 (2019)

Articles - 6cko mentioned but not cited (2)

  1. A higher-order configuration of the heterodimeric DOT1L-AF10 coiled-coil domains potentiates their leukemogenenic activity. Song X, Yang L, Wang M, Gu Y, Ye B, Fan Z, Xu RM, Yang N. Proc. Natl. Acad. Sci. U.S.A. 116 19917-19923 (2019)
  2. M-Ionic: prediction of metal-ion-binding sites from sequence using residue embeddings. Shenoy A, Kalakoti Y, Sundar D, Elofsson A. Bioinformatics 40 btad782 (2024)


Reviews citing this publication (4)

  1. The language of chromatin modification in human cancers. Zhao S, Allis CD, Wang GG. Nat Rev Cancer 21 413-430 (2021)
  2. A Box of Chemistry to Inhibit the MEN1 Tumor Suppressor Gene Promoting Leukemia. Ozyerli-Goknar E, Nizamuddin S, Timmers HTM. ChemMedChem 16 1391-1402 (2021)
  3. The Role of HOX Transcription Factors in Cancer Predisposition and Progression. Li B, Huang Q, Wei GH. Cancers (Basel) 11 (2019)
  4. Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation. Perner F, Armstrong SA. Cells 9 (2020)

Articles citing this publication (5)

  1. Identification of DOT1L inhibitors by structure-based virtual screening adapted from a nucleoside-focused library. Gibbons GS, Chakraborty A, Grigsby SM, Umeano AC, Liao C, Moukha-Chafiq O, Pathak V, Mathew B, Lee YT, Dou Y, Schürer SC, Reynolds RC, Snowden TS, Nikolovska-Coleska Z. Eur J Med Chem 189 112023 (2020)
  2. DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment. Sarno F, Nebbioso A, Altucci L. Epigenetics 15 439-453 (2020)
  3. Overexpression of HOXA10 is associated with unfavorable prognosis of acute myeloid leukemia. Guo C, Ju QQ, Zhang CX, Gong M, Li ZL, Gao YY. BMC Cancer 20 586 (2020)
  4. High-resolution characterization of gene function using single-cell CRISPR tiling screen. Yang L, Chan AKN, Miyashita K, Delaney CD, Wang X, Li H, Pokharel SP, Li S, Li M, Xu X, Lu W, Liu Q, Mattson N, Chen KY, Wang J, Yuan YC, Horne D, Rosen ST, Soto-Feliciano Y, Feng Z, Hoshii T, Xiao G, Müschen M, Chen J, Armstrong SA, Chen CW. Nat Commun 12 4063 (2021)
  5. The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations. Klein BJ, Deshpande A, Cox KL, Xuan F, Zandian M, Barbosa K, Khanal S, Tong Q, Zhang Y, Zhang P, Sinha A, Bohlander SK, Shi X, Wen H, Poirier MG, Deshpande AJ, Kutateladze TG. Nat Commun 12 4130 (2021)


Quick links