Alterations of the CxxC domain preclude oncogenic activation of mixed-lineage leukemia 2

Bach, Christian; Mueller, Dorothée; Buhl, Sebastian; García-Cuéllar, María-Paz; Slany, Robert K.

doi:10.1038/onc.2008.443

Cited by 75 publications

(69 citation statements)

References 30 publications

(38 reference statements)

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“…37,38 Although the carboxyl-flanking region of the MLL CXXC domain (the "post-CxxC" moiety of MLL, which is rich in basic aa) is not required for binding to CpG sites, 37 it also contributes to MLL-associated myeloid transformation. 37,43 We found that the MLL deletion construct lacking the CXXC carboxyflanking region (MLL 1-1194, Figure 3B) could downregulate Figure 3B), suggesting that the CXXC flanking region may play a synergistic role with the core CXXC motif in RUNX1 downregulation either through stabilization of the structure or through a protein-protein interaction. Recently, the polymerase-associated factor complex (PAFc) has been found to interact with the CXXC-RD2 region in MLL.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal

Zhao

Chen

Yan

et al. 2014

Blood

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Key Points• MLL oncoproteins downregulate RUNX1/CBFb by the CXXC domain and flanking region as a critical step in the development of MLL-related leukemias.RUNX1/CBFb (core binding factor [CBF]) is a heterodimeric transcription factor complex that is frequently involved in chromosomal translocations, point mutations, or deletions in acute leukemia. The mixed lineage leukemia (MLL) gene is also frequently involved in chromosomal translocations or partial tandem duplication in acute leukemia. The MLL protein interacts with RUNX1 and prevents RUNX1 from ubiquitin-mediated degradation. RUNX1/CBFb recruits MLL to regulate downstream target genes. However, the functional consequence of MLL fusions on RUNX1/CBFb activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFb protein expression via the MLL CXXC domain and flanking regions. We confirmed this finding in Mll-Af9 knock-in mice and human M4/M5 acute myeloid leukemia (AML) cell lines, with or without MLL translocations, showing that MLL translocations cause a hypomorph phenotype of RUNX1/CBFb. Overexpression of RUNX1 inhibits the development of AML in Mll-Af9 knock-in mice; conversely, further reducing Runx1/Cbfb levels accelerates MLL-AF9-mediated AML in bone marrow transplantation assays. These data reveal a newly defined negative regulation of RUNX1/CBFb by MLL fusion proteins and suggest that targeting RUNX1/CBFb levels may be a potential therapy for MLLs.

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Section: Discussionmentioning

confidence: 99%

Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal

Zhao

Chen

Yan

et al. 2014

Blood

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“…Mll1 and Mll2 mouse knockouts also demonstrate that these two closely related genes are not redundant (Yu et al 1995;Lubitz et al 2007). Further evidence of nonredundancy between these two proteins is that Mll2 cannot substitute for Mll1 in mouse models of leukemogenesis (Bach et al 2009). …”

Section: Differences Between Compass and Compass-like Complexesmentioning

confidence: 99%

The super elongation complex (SEC) and MLL in development and disease

Smith¹,

Lin²,

Shilatifard³

2011

Genes Dev.

304

329

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Transcriptional regulation at the level of elongation is vital for the control of gene expression and metazoan development. The mixed lineage leukemia (MLL) protein and its Drosophila homolog, Trithorax, which exist within COMPASS (complex of proteins associated with Set1)-like complexes, are master regulators of development. They are required for proper homeotic gene expression, in part through methylation of histone H3 on Lys 4. In humans, the MLL gene is involved in a large number of chromosomal translocations that create chimeric proteins, fusing the N terminus of MLL to several proteins that share little sequence similarity. Several frequent translocation partners of MLL were found recently to coexist in a super elongation complex (SEC) that includes known transcription elongation factors such as eleven-nineteen lysine-rich leukemia (ELL) and P-TEFb. Importantly, the SEC is required for HOX gene expression in leukemic cells, suggesting that chromosomal translocations involving MLL could lead to the overexpression of HOX and other genes through the involvement of the SEC. Here, we review the normal developmental roles of MLL and the SEC, and how MLL fusion proteins can mediate leukemogenesis.

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“…domain seems to be a major determinant of subnuclear localization and target gene selection. 51 In addition, the CxxC region also has been shown to recruit repressive factors like histone deacetylases and polycomb group proteins. 52 This interaction appeared to be regulated by conformational changes elicited by the prolyl-isomerase cyclophilin 33 (Cyp33) that interacts further carboxy-terminal with the plant homeodomain (PHD) of MLL N .…”

Section: Normal Mll -A Histone Methyltransferase Necessary For Efficimentioning

confidence: 99%

The molecular biology of mixed lineage leukemia

Slany¹

2009

Haematologica

284

280

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Mixed lineage leukemia is a very aggressive blood cancer that predominantly occurs in pediatric patients. In contrast to other types of childhood acute leukemias, mixed lineage leukemia presents with a dismal prognosis and despite the availability of advanced treatment methods cure rates have stagnated over the last years. Mixed lineage leukemia is characterized by the presence of MLL fusion proteins that are the result of chromosomal translocations affecting the MLL gene at 11q23. These events juxtapose the amino-terminus of the histone methyltransferase MLL with a variety of different fusion partners that destroy normal histone methyltransferase function of MLL and replace it by heterologous functions contributed by the fusion partner. The resulting chimeras are transcriptional regulators that take control of targets normally controlled by MLL with the clustered HOX homeobox genes as prominent examples. Recent studies suggested that MLL fusion partners activate transcription by two different mechanisms. Some of these proteins are themselves chromatin modifiers that introduce histone acetylation whereas other fusion partners can recruit histone methyltransferases.In particular, histone H3 specific methylation at lysine 79 catalyzed by DOT1L has been recognized as a hallmark of chromatin activated by MLL fusion proteins. Interestingly, several frequent MLL fusion partners seem to coordinate DOT1L activity with a protein complex that stimulates the elongation phase of transcription by phosphorylating the carboxy-terminal repeat domain of RNA polymerase II. The discovery of these novel enzymatic activities that are essentially involved in MLL fusion protein function presents potential new targets for a rational drug development.

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Alterations of the CxxC domain preclude oncogenic activation of mixed-lineage leukemia 2

Cited by 75 publications

References 30 publications

Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal

Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal

The super elongation complex (SEC) and MLL in development and disease

The molecular biology of mixed lineage leukemia

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