Structural and functional analysis of the DOT1L–AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis

Zhou, Bo; Su, Qin; Xu, Jing; Harding, Rachel; Tempel, W.; Nayak, Vinod; Li, Yanjun; Loppnau, P.; Dou, Yali; Min, Jinrong

doi:10.1101/gad.311639.118

Cited by 19 publications

(27 citation statements)

References 37 publications

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“…1B). Our findings are consistent with the newly reported results that CC1, CC2, and CC3 can individually interact with the OM-LZ domain of AF10, and they bind with the dissociate constants of 0.1 μM, 0.6 μM, and 27.1 μM, respectively (24).…”

Section: Af10-interacting Domains Of Dot1lsupporting

confidence: 93%

“…This AF10 binding region in DOT1L is distinct from that of another MLL1 fusion partner, AF9, which bears no similarity in binding mode despite also showing a weak interaction with the CC3 domain of DOT1L (25). Among CC1 to CC3 of DOT1L, it was found that CC1 has the highest affinity toward AF10 OM-LZ , ∼6and 270-fold higher than that of CC2 and CC3, respectively (24). Finally, a crystal structure of a chimeric complex of human AF10 OM-LZ and zebrafish DOT1L CC2 was solved, providing an understanding of the intermolecular interaction between AF10 and DOT1L, but leaving a number of questions, such as whether CC1 and CC3 interact with AF10 in a similar way and what is the role of CC0 in AF10 binding, unanswered.…”

Section: Significancementioning

confidence: 90%

“…1A). A recent work demonstrated that the CC1-CC3 domains of human DOT1L are involved in AF10 binding (24). This AF10 binding region in DOT1L is distinct from that of another MLL1 fusion partner, AF9, which bears no similarity in binding mode despite also showing a weak interaction with the CC3 domain of DOT1L (25).…”

Section: Significancementioning

confidence: 99%

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A higher-order configuration of the heterodimeric DOT1L–AF10 coiled-coil domains potentiates their leukemogenenic activity

Song

Yang

Wang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Chromosomal translocations of MLL1 (Mixed Lineage Leukemia 1) yield oncogenic chimeric proteins containing the N-terminal portion of MLL1 fused with distinct partners. The MLL1–AF10 fusion causes leukemia through recruiting the H3K79 histone methyltransferase DOT1L via AF10’s octapeptide and leucine zipper (OM-LZ) motifs. Yet, the precise interaction sites in DOT1L, detailed interaction modes between AF10 and DOT1L, and the functional configuration of MLL1–AF10 in leukeomogenesis remain unknown. Through a combined approach of structural and functional analyses, we found that the LZ domain of AF10 interacts with the coiled-coil domains of DOT1L through a conserved binding mode and discovered that the C-terminal end of the LZ domain and the OM domain of AF10 mediate the formation of a DOT1L–AF10 octamer via tetramerization of the binary complex. We reveal that the oligomerization ability of the DOT1L–AF10 complex is essential for MLL1–AF10’s leukemogenic function. These findings provide insights into the molecular basis of pathogenesis by MLL1 rearrangements.

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Section: Af10-interacting Domains Of Dot1lsupporting

confidence: 93%

Section: Significancementioning

confidence: 90%

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A higher-order configuration of the heterodimeric DOT1L–AF10 coiled-coil domains potentiates their leukemogenenic activity

Song

Yang

Wang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…overexpression, such as KMT2A rearrangement (15), FLT-ITD (15), MLL gene abnormality (16)(17)(18)(19). HOXA9, HOXA7, HOXA11 were associated with adverse prognosis in AML (20,21).…”

mentioning

confidence: 97%

Overexpression of HOXA10 is associated with unfavorable prognosis of acute myeloid leukemia

Guo

Zhang

et al. 2020

Preprint

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Background HOXA family genes were crucial transcription factors involving cell proliferation and apoptosis. While few studies have focused on HOXA10 in AML. We aimed to investigate the prognostic significance of HOXA10. Methods We downloaded datasets from GEO and BeatAML database, to compare HOXA expression level between AML patients and controls. Kaplan-Meier curves were used to estimate the impact of HOXA10 expression on AML survival. The differentially expressed genes, miRNAs, lncRNAs and methylated regions between HOXA10-high and -low groups were obtained using R (version 3.6.0). Accordingly, the gene set enrichment analysis (GSEA) was accomplished using MSigDB database. Moreover, the regulatory TFs/microRNAs/lncRNAs of HOXA10 were identified. A LASSO-Cox model fitted OS to clinical and HOXA10-associated genetic variables by glmnet package. Results HOXA10 was overexpressed in AML patients than that in controls. The HOXA10-high group is significantly associated with shorter OS and DFS. A total of 1219 DEGs, 131 DEmiRs, 282 DElncRs were identified to be associated with HOXA10. GSEA revealed that 12 suppressed and 3 activated pathways in HOXA10-high group. Furthermore, the integrated regulatory network targeting HOXA10 was established. The LASSO-Cox model fitted OS to AML-survival risk scores, which included age, race, molecular risk, expression of IKZF2/LINC00649/LINC00839/FENDRR and has-miR-424-5p. The time dependent ROC indicated a satisfying AUC (1-year AUC 0.839, 3-year AUC 0.871 and 5-year AUC 0.813). Conclusions Our study identified HOXA10 overexpression as an adverse prognostic factor for AML. The LASSO-COX regression analysis revealed novel prediction model of OS with superior diagnostic utility.

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“…These complexes have different functions in leukaemogenesis. MLL-AF10 transforms haematopoietic progenitors via the DOT1L interaction domain, while MLL-ENL/AF9 does so through the ANC1 homology domain, which is responsible for its association with both AF4 and DOT1L [101].…”

Section: Mll Translocationmentioning

confidence: 99%

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

2019

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Methylation of histone 3 at lysine 79 (H3K79) is one of the principal mechanisms involved in gene expression. The histone methyltransferase DOT1L, which mono-, di-and trimethylates H3K79 using S-adenosyl-L-methionine as a co-factor, is involved in cell development, cell cycle progression, and DNA damage repair. However, changes in normal expression levels of this enzyme are found in prostate, breast, and ovarian cancer. High levels of H3K79me are also detected in acute myeloid leukaemia patients bearing MLL rearrangements (MLL-r). MLL translocations are found in approximately 80% of paediatric patients, leading to poor prognosis. DOT1L is recruited on DNA and induces hyperexpression of HOXA9 and MEIS1. Based on these findings, selective drugs have been developed to induce apoptosis in MLL-r leukaemia cells by specifically inhibiting DOT1L. The most potent DOT1L inhibitor pinometostat has been investigated in Phase I clinical trials for treatment of paediatric and adult patients with MLL-driven leukaemia, showing promising results. ARTICLE HISTORY

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Structural and functional analysis of the DOT1L–AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis

Cited by 19 publications

References 37 publications

A higher-order configuration of the heterodimeric DOT1L–AF10 coiled-coil domains potentiates their leukemogenenic activity

A higher-order configuration of the heterodimeric DOT1L–AF10 coiled-coil domains potentiates their leukemogenenic activity

Overexpression of HOXA10 is associated with unfavorable prognosis of acute myeloid leukemia

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment

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