Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: A critical regulatory circuit lost in leukemogenic MLL fusions

ArticleinGenes & Development 21(19):2385-98 · November 2007with15 Reads
DOI: 10.1101/gad.1574507 · Source: PubMed
Abstract
Human chromosome 11q23 translocations disrupting MLL result in poor prognostic leukemias. It fuses the common MLL N-terminal approximately 1400 amino acids in-frame with >60 different partners without shared characteristics. In addition to the well-characterized activity of MLL in maintaining Hox gene expression, our recent studies established an MLL-E2F axis in orchestrating core cell cycle gene expression including Cyclins. Here, we demonstrate a biphasic expression of MLL conferred by defined windows of degradation mediated by specialized cell cycle E3 ligases. Specifically, SCF(Skp2) and APC(Cdc20) mark MLL for degradation at S phase and late M phase, respectively. Abolished peak expression of MLL incurs corresponding defects in G1/S transition and M-phase progression. Conversely, overexpression of MLL blocks S-phase progression. Remarkably, MLL degradation initiates at its N-terminal approximately 1400 amino acids, and tested prevalent MLL fusions are resistant to degradation. Thus, impaired degradation of MLL fusions likely constitutes the universal mechanism underlying all MLL leukemias. Our data conclude an essential post-translational regulation of MLL by the cell cycle ubiquitin/proteasome system (UPS) assures the temporal necessity of MLL in coordinating cell cycle progression.
    • "HOXA9 and its transcriptional co-factor MEIS1 are the most critical downstream targets deregulated by KMT2A fusion proteins, as their co-expression is sufficient to transform cells and induce acute myeloid leukemia [24]. Additionally, KMT2A-fusion proteins exhibit resistance to degradation by the ubiquitin-proteasome system, which may contribute to their leukemogenic potential [19]. The functional consequences of KMT2A translocations in mature B-NHL, including the two DLBCL presented T Gindin et al. "
    [Show abstract] [Hide abstract] ABSTRACT: Translocations of the histone-lysine N-methyltransferase 2A (KMT2A) gene, formerly known as myeloid lymphoid leukemia/mixed-lineage leukemia gene, are commonly associated with high-risk de novo or therapy-associated B-cell and T-cell lymphoblastic leukemias and myeloid neoplasms. Rare B-cell non-Hodgkin lymphomas harboring KMT2A translocations have been reported, but information regarding the clinical behavior of such cases is limited. Here, we describe two extranodal diffuse large B-cell lymphomas (DLBCLs): a primary thyroid DLBCL and a large cell transformation of a splenic marginal zone lymphoma, which displayed complex karyotypes and translocations involving chromosome 11q23 targeting the KMT2A gene. The pathological and clinical characteristics of these cases are discussed in the context of previously reported lymphomas associated with different types of KMT2A genetic aberrations. In contrast to the poor clinical outcomes of patients with acute leukemias and myeloid neoplasms associated with KMT2A translocations, patients with B-cell non-Hodgkin lymphomas, exhibiting similar translocations, appear to respond well to immunochemotherapy. Our findings add to the growing list of histone methyltransferase genes deregulated in DLBCL and highlight the diversity of mechanisms, altering the function of epigenetic modifier genes in lymphomas.
    Full-text · Article · Aug 2014
    • "Previous studies including ours have indicated that MLL participates in the progression of S phase (22–24,26,30). MLL complexes with Host cell factor-1 (HCF-1) to interact with E2F1 and activate S-phase genes (23). "
    [Show abstract] [Hide abstract] ABSTRACT: MLL, the trithorax ortholog, is a well-characterized histone 3 lysine 4 methyltransferase that is crucial for proper regulation of the Hox genes during embryonic development. Chromosomal translocations, disrupting the Mll gene, lead to aggressive leukemia with poor prognosis. However, the functions of MLL in cellular processes like cell-cycle regulation are not well studied. Here we show that the MLL has a regulatory role during multiple phases of the cell cycle. RNAi-mediated knockdown reveals that MLL regulates S-phase progression and, proper segregation and cytokinesis during M phase. Using deletions and mutations, we narrow the cell-cycle regulatory role to the C subunit of MLL. Our analysis reveals that the transactivation domain and not the SET domain is important for the S-phase function of MLL. Surprisingly, disruption of MLL–WRAD interaction is sufficient to disrupt proper mitotic progression. These mitotic functions of WRAD are independent of SET domain of MLL and, therefore, define a new role of WRAD in subset of MLL functions. Finally, we address the overlapping and unique roles of the different SET family members in the cell cycle.
    Full-text · Article · May 2014
    • "Plasmid Constructs FLAG-tagged fragments consisting of MLL amino acids 1–400, 400–750, 1–750, 750–1,400, 1,400–2,664, and 1–1,400 derived from wild-type MLL were inserted into eukaryotic expression vectors pCI-neo (Promega) for transient transfection assays. FLAG-tagged MLL fusion genes, including MLL-AF4 and MLL-AF9, MLL-ENL and MLL-ELL, in eukaryotic expression vector were described previously (Liu et al., 2007). MLL-AF4 and MLL-AF9 were also inserted into pMSCV-puro vector (Clontech) for retrovirus production. "
    [Show abstract] [Hide abstract] ABSTRACT: Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by caspase-8 and upregulation of p27, respectively. Furthermore, proteasome inhibition conferred preliminary benefit to patients with MLL-AF4 leukemia. Hence, feasible strategies to treat cancer-type and oncogene-specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions.
    Article · Apr 2014
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