Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways

Yokoyama, Akihiko; Ficara, Francesca; Murphy, Mark; Meisel, Christian; Naresh, Alpana; Kitabayashi, Issay; Cleary, Michael L.

doi:10.1242/jcs.080523

Cited by 32 publications

(59 citation statements)

References 72 publications

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“…16 The first and fourth PHD fingers function together with the phenylalanine/tyrosine-rich (FYRN) domain to mediate the intramolecular interaction between MLL N and MLL C . 47 In our experiments, inclusion of the bromodomain is sufficient to mediate the interaction with ASB2, whereas the addition of PHD4 enhances binding (Figure 3). Several bromodomains have been demonstrated to mediate protein-protein interaction through recognizing acetylated lysines.…”

Section: Discussionmentioning

confidence: 55%

ECSASB2 mediates MLL degradation during hematopoietic differentiation

Wang

Muntean

Hess

2012

Blood

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IntroductionThe histone H3 lysine 4 (H3K4) methyltransferase mixed lineage leukemia (MLL) is necessary for the maintenance of HOX patterning and essential for normal hematopoiesis. Full-length MLL is a 3968 amino acid multi-domain protein, which is proteolytically cleaved into a 320 kDa N-terminal fragment (MLL N ) and a 180 kDa C-terminal fragment (MLL C ) that noncovalently associate to form a stable complex. 1 MLL N contains several DNA-binding domains including 3 AT-hooks and a CxxC domain, as well as a poorly understood PHD/Bromodomain (PHD/Bromo) region that contains 4 plant homeodomain fingers (PHD1-4), and a bromodomain between PHD3 and PHD4. MLL C contains a transactivation domain and a SET domain with intrinsic H3K4 methyltransferase activity ( Figure 1A). MLL positively regulates target gene expression through methylation of H3K4, an epigenetic mark closely associated with transcriptional activation. Genome-wide analysis has identified a large number of genes that are regulated by MLL, including homeobox (HOX) genes and their cofactors, such as MEIS1. 2 HOX genes are a group of transcription factors that specify segment identity and cell fate during development, and play essential roles during hematopoiesis. 3 MLL is responsible for maintaining expression of HOX and MEIS1 through H3K4 methylation in hematopoietic stem cells and progenitors, which is required for stem cell self-renewal and progenitor expansion. 2,4,5 Mll-null mice are defective in maintaining Hox gene expression resulting in embryonic lethality by E10.5, whereas reexpression of Hox genes in Mll-deficient progenitors rescues hematopoietic colony formation. 6,7 HOX expression decreases concurrent with hematopoietic differentiation. This is crucial for normal hematopoiesis, as constitutive activation of HOX genes is associated with leukemia and other malignancies. 3 In fact, HOXA9 was identified as the most highly correlated gene for poor prognosis in acute myeloid leukemia (AML). 8 Chromosomal translocations involving MLL are one of the most common genetic alterations in human leukemia, accounting for up to 80% of infant leukemia and approximately 5%-10% of adult leukemia overall. 9,10 Most of the leukemogenic MLL fusion proteins contain the N-terminus of MLL fused in frame to the C-terminus of a translocation partner, generally a transcription activator or a dimerizing protein, thus forming a chimeric protein with abnormal transactivation ability. 10 Both in vitro and in vivo studies have demonstrated that these MLL fusion proteins induce leukemogenesis mainly through constitutive activation of HOXA9 and MEIS1. [11][12][13] Notably, translocations of MLL invariably occur within the breakpoint cluster region (BCR), which leads to the deletion or disruption of the PHD/Bromo region. 14 Further, insertion of PHD/Bromo into MLL-AF9 and MLL-ENL fusion proteins abolishes their transformation ability, suggesting that this region may be important for the regulation of MLL. 15,16 Recent studies discovered that reciprocal MLL fusion proteins conta...

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Section: Discussionmentioning

confidence: 55%

ECSASB2 mediates MLL degradation during hematopoietic differentiation

Wang

Muntean

Hess

2012

Blood

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“…A knockin allele lacking the SET domain of the Mll gene resulted in reduced Hoxc8 expression and a decreased amount of mono-methylated histone H3 lysine 4 modification at the Hoxc8 locus in embryos [37]. However, this mouse line was viable after birth, unlike other Mll-deficient mouse lines [16,17,29]. No differences in Hoxa9 expression and repopulating potential were observed in the cells of the LSK fraction (containing HSCs and MPPs) from SET domain-deficient mice compared to the wild-type animals [38].…”

Section: Introductionmentioning

confidence: 94%

“…Posterior Hoxa genes facilitate the expansion of immature hematopoietic progenitors [28], suggesting that MLL drives the proliferation of immature hematopoietic cells by upregulating posterior Hoxa genes. Studies of Mll-knockout mice have confirmed its requirement in the hematopoietic lineage of both adult and fetal hematopoietic systems [17,24,29,30]. Mll-deficient embryos produce a smaller population of hematopoietic stem cells (HSCs), MPPs, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) in the fetal liver than in the control [29].…”

Section: Introductionmentioning

confidence: 99%

“…Studies of Mll-knockout mice have confirmed its requirement in the hematopoietic lineage of both adult and fetal hematopoietic systems [17,24,29,30]. Mll-deficient embryos produce a smaller population of hematopoietic stem cells (HSCs), MPPs, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) in the fetal liver than in the control [29]. MLL function appears to be most critical for hematopoietic progenitors that are actively expanding.…”

Section: Introductionmentioning

confidence: 99%

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Molecular mechanisms of MLL-associated leukemia

Yokoyama

2015

Int J Hematol

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genes [1][2][3]. To date, more than 70 MLL fusion genes have been reported [4]. Leukemia associated with MLL gene alterations (hereafter referred to as MLL-associated leukemia) accounts for ~5-10 % of total acute leukemia cases and is a major cause of infant acute lymphoblastic leukemia [5]. Clinical outcomes of MLL-associated leukemia are often unfavorable; therefore, the development of better therapeutic strategies is needed.Significant progress in understanding MLL-associated leukemia has been achieved in the past two decades. The coding sequence of the MLL gene was established in the early 1990s [1,2]. The first mouse model of MLL-associated leukemia using retroviral gene transduction or knockin strategies was generated in the late 1990s [6,7], and several other sophisticated disease models using murine cells [8][9][10][11][12] and human cells [13,14] that mimic the human disease have been developed. Recent technological advances in genetics, such as DNA microarray and short hairpin RNA library screening have enabled identification of a number of novel pathways that play critical roles in the development of MLL-associated leukemia, and these are reviewed in detail elsewhere [15]. In this review, I focus on the mechanistic aspects of MLL fusion-dependent leukemic transformation. MLL activates transcription of cellular memory genesMLL is structurally similar to the Drosophila trithorax protein, as both have an evolutionarily conserved SET domain (Fig. 1a) [1, 2]. Knockout of Mll results in a loss of the expression of several posterior homeobox (Hox) genes [16,17], similar to the consequences of the genetic ablation of trithorax in Drosophila [18,19]. Hox genes are Abstract Gene rearrangements of the mixed lineage leukemia (MLL) gene cause aggressive leukemia. The fusion of MLL and its partner genes generates various MLL fusion genes, and their gene products trigger aberrant self-renewal of hematopoietic progenitors leading to leukemia. Since the identification of the MLL gene two decades ago, a substantial amount of information has been obtained regarding the mechanisms by which MLL mutations cause leukemia. Wild-type MLL maintains the expression of Homeobox (HOX) genes during development. MLL activates the expression of posterior HOX-A genes in the hematopoietic lineage to stimulate the expansion of immature progenitors. MLL fusion proteins constitutively activate the HOX genes, causing aberrant self-renewal. The modes of transcriptional activation vary depending on the fusion partners and can be categorized into at least four groups. Here I review the recent progress in research related to the molecular mechanisms of MLL fusion-dependent leukemogenesis.

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“…H3K4 trimethylation (H3K4me3) catalyzed by MLL activates transcription, leading to orchestrated upregulation of key developmental genes, such as Hox genes (23,24,26,27). Notably, the activity of MLL is modulated by posttranslational modifications, such as phosphorylation, ubiquitination, and proteolysis (20,21,28,29). MLL undergoes site-specific proteolytic cleavage by taspase-1 (encoded by TASP1), which gives rise to a mature 500-kDa MLL N320/C180 heterodimer (28).…”

Section: Introductionmentioning

confidence: 99%