The Histone Methyltransferase Activity of MLL1 Is Dispensable for Hematopoiesis and Leukemogenesis

Mishra, Bibhu Prasad; Zaffuto, Kristin M.; Artinger, Erika L.; Org, Tõnis; Mikkola, Hanna; Cheng, Chao; Djabali, Malek; Ernst, Patricia

doi:10.1016/j.celrep.2014.04.015

Cited by 115 publications

(107 citation statements)

References 46 publications

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“…As well as a role in redox regulation, ROS might also function to alter the epigenetic landscape, which plays a particularly pertinent role in regulating stem cell fate (Challen et al, 2012;Mishra et al, 2014;Rimmelé et al, 2014;Singh et al, 2013;Trowbridge et al, 2009;. Many metabolic intermediates are necessary substrates for the post-translational modifications of histones that together establish the epigenetic landscape of stem cells.…”

Section: Box 1 Tools For Ros Detection and Their Limitationsmentioning

confidence: 99%

Stem cells and the impact of ROS signaling

2014

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An appropriate balance between self-renewal and differentiation is crucial for stem cell function during both early development and tissue homeostasis throughout life. Recent evidence from both pluripotent embryonic and adult stem cell studies suggests that this balance is partly regulated by reactive oxygen species (ROS), which, in synchrony with metabolism, mediate the cellular redox state. In this Primer, we summarize what ROS are and how they are generated in the cell, as well as their downstream molecular targets. We then review recent findings that provide molecular insights into how ROS signaling can influence stem cell homeostasis and lineage commitment, and discuss the implications of this for reprogramming and stem cell ageing. We conclude that ROS signaling is an emerging key regulator of multiple stem cell populations.

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Section: Box 1 Tools For Ros Detection and Their Limitationsmentioning

confidence: 99%

Stem cells and the impact of ROS signaling

2014

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“…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]. These results suggest that the transcriptional activation of cellular memory genes is mostly independent of the HMT activity mediated by the SET domain.…”

Section: Introductionmentioning

confidence: 57%

“…MENIN has two stretches of positively charged amino acids in its carboxyl region that bind DNA in a sequence-independent manner [66]. Moreover, several lines of evidence suggest that wild-type MLL, but not its HMT activity, is required for the targeting of MLL fusion proteins [38,49,67]. These additional interactions/factors likely contribute to proper targeting of MLL fusion proteins.…”

Section: Mechanisms Of Target Recognition By Mll Fusion Proteinsmentioning

confidence: 99%

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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“…Insertion of a stop codon after either exon 3 or 12 leading to loss of MLL1 results in early embryonic death and severe hematopoietic abnormalities (Yu et al 1995;Yagi et al 1998). Surprisingly, mice with genetic deletion of only the MLL1 SET domain are born fertile and only show modest skeletal abnormalities and no gross hematopoietic defects (Terranova et al 2006;Mishra et al 2014). Moreover, loss of MLL1 does not result in global changes of H3K4 methylation, suggesting MLL1 is not the major H3K4 methyltransferase in most cells (Wang et al 2009).…”

Section: Structure Of the Mll/kmt2 Familymentioning

confidence: 99%

Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia

Krivtsov

Hoshii

Armstrong

2017

Cold Spring Harb Perspect Med

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Recent studies have shown the importance of chromatin-modifying complexes in the maintenance of developmental gene expression and human disease. The mixed lineage leukemia gene (MLL1) encodes a chromatin-modifying protein and was discovered as a result of the cloning of translocations involved in human leukemias. MLL1 is a histone lysine 4 (H3K4) methyltransferase that supports transcription of genes that are important for normal development including homeotic (Hox) genes. MLL1 rearrangements result in expression of fusion proteins without H3K4 methylation activity but may gain the ability to recruit other chromatin-associated complexes such as the H3K79 methyltransferase DOT1L and the super elongation complex. Therefore, chromosomal translocations involving MLL1 appear to directly perturb the regulation of multiple chromatin-associated complexes to allow inappropriate expression of developmentally regulated genes and thus drive leukemia development. IDENTIFICATION AND STRUCTURE OF MLL FUSIONS

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The Histone Methyltransferase Activity of MLL1 Is Dispensable for Hematopoiesis and Leukemogenesis

Cited by 115 publications

References 46 publications

Stem cells and the impact of ROS signaling

Stem cells and the impact of ROS signaling

Molecular mechanisms of MLL-associated leukemia

Mixed-Lineage Leukemia Fusions and Chromatin in Leukemia

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