Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis

Mohan, Man; Lin, Chengqi; Guest, Erin; Shilatifard, Ali

doi:10.1038/nrc2915

Cited by 160 publications

(191 citation statements)

References 90 publications

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“…MLL has around 100 different partners, and the functions of some of them have been identified (30,52). MLL itself is a large multifunctional protein (homolog of Drosophila trithorax) with many functions related to chromatin structure; many of MLL's partners are members of chromatin-modifying complexes including ENL, AF9, AF4, and AF10, which interact with DOT1L, and ELL, AF4/FMR2 family member 1 (AFF1), and AFF4, which interact with positive transcription elongation factor b (P-TEFb) (37,(53)(54)(55)(56). Thus, a fusion protein consisting of MLL and one of the members of the complexes would be much more effective in promoting regulation of critical targets and enhancing cell proliferation than the two proteins produced independently in the cell and meeting at a critical location by chance.…”

Section: Discussionmentioning

confidence: 99%

TET1 plays an essential oncogenic role in MLL -rearranged leukemia

Huang¹,

Jiang²,

Li³

et al. 2013

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

200

198

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The ten-eleven translocation 1 (TET1) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent downregulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL-rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL-rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 (Hoxa9)/myeloid ecotropic viral integration 1 (Meis1)/pre-B-cell leukemia homeobox 3 (Pbx3) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/ Pbx3 signaling axis in MLL-rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.

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Section: Discussionmentioning

confidence: 99%

TET1 plays an essential oncogenic role in MLL -rearranged leukemia

Huang¹,

Jiang²,

Li³

et al. 2013

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

200

198

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“…MLL gene is altered by rearrangements in leukemias and contributes to leukemogenesis [7][8][9]. Because such rearrangements have not been found in solid cancers and MLL gene expression is not limited to hematopoietic system, we hypothesized that MLL gene could be altered by other mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the earlier reports that MLL proteins are critically involved in chromatin modification and are implicated in the pathogenesis of human diseases [1][2][3][4][5][6][7][8][9], we attempted to determine whether somatic frameshift mutation of MLL genes is present in GC and CRC tissues that are the most common cancers in gastrointestinal tract. We found frameshift mutations of MLL, MLL2, MLL3 and MLL5 genes in both GC and CRC.…”

Section: Discussionmentioning

confidence: 99%

“…MLL is essential for proper maintenance of HOX gene expression during hematopoiesis and embryonic development [4][5][6]. The MLL gene is frequently involved in chromosomal translocations associated with acute leukemias [2,[7][8][9]. Although nomenclature of the MLL gene came from its function in hematopoiesis and its alterations in leukemias, it is ubiquitously expressed in most tissues [10].…”

Section: Mixed Lineage Leukemia (Mll) Genes Include Mll Mll2 Mll3 mentioning

confidence: 99%

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Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability

Je¹,

Yoo²,

LEE³

2012

neo

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MLL genes encode histone methyltransferases that are required for proper expression of a variety of genes. The pathologic implications of MLL genes have been studied not only in leukemias, but also in some solid cancers. We found in a public database that MLL, MLL2, MLL3, MLL4 and MLL5 genes had mononucleotide repeats that might be mutated in cancers with microsatellite instability (MSI). Frameshift mutations in a repeat of MLL3 have been found in colorectal cancers (CRC), but there is no frameshift mutation data of the other genes. In this study, we analyzed these repeats in 32 gastric cancers (GC) with high MSI (MSI-H), 59 GC with low MSI (MSI-L)/stable MSI (MSS), 40 CRC with MSI-H and 59 CRC with MSI-L/MSS by single-strand conformation polymorphism and DNA sequencing. We also analyzed MLL3 expression in GC and CRC tissues using immunohistochemistry. We found MLL, MLL2, MLL3 and MLL5 frameshift mutations in two (one GC and one CRC), three (one GC and two CRC), 17 (14 GC and three CRC) and six (four GC and two CRC) cancers, respectively. They were detected exclusively in MSI-H cancers, but not in MSI-L/MSS cancers. All of the cancers with MLL3 mutations showed loss of MLL3 expression, and their values were significantly lower than in those without MLL3 mutation (50.9%). Of note, the GC with MSI-H had significantly higher incidences in both MLL mutations and MLL3 expression loss than the CRC with MSI-H. Our data indicate that frameshift mutations of MLL genes and loss of expression of MLL3 protein are common in GC and CRC with MSI-H.

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“…58,60,61 In addition, the misexpression of HOX genes in leukemia could result from the stabilized recruitment of SEC, giving rise to the unregulated release of RNA Pol II. 62 Two additional P-TEFb-containing complexes have been identified, SEC-L2 and SEC-L3 63 whose subunit composition genes via effects on factors other than NELF, such as DSIF, and/or without a significant effect on NELF occupancy as determined by ChIP. 2 Accumulating evidence supports a model wherein paused RNA Pol II is not a stable repressed state, but rather a highly dynamic state, whose effective duration can be regulated in response to signals and changing cellular environments.…”

Section: Sp3 Promotes Occupancy Of the Nelf Complexmentioning

confidence: 99%

Enforcing the pause: Transcription factor Sp3 limits productive elongation by RNA polymerase II

Valín

Gill²

2013

Cell Cycle

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Abbreviations: CDK, cyclin-dependent kinase; CTD, C-terminal domain of the RNA polymerase II; DSIF, DRB sensitivity-inducing factor; H3K4me3, histone H3 trimethylated at lysine 4; H3K36me3, histone H3 trimethylated at lysine 36; H3S10, histone H3 serine 10; NELF, negative elongation factor complex; P-TEFb, positive transcription elongation factor b; PP, protein phosphatase; p21 CIP1 , cyclin-dependent kinase inhibitor 1A; RNA Pol II, RNA polymerase II; SUMO, small ubiquitin-related modifier T he transition of paused RNA polymerase II into productive elongation is a highly dynamic process that serves to fine-tune gene expression in response to changing cellular environments. We have recently reported that the transcription factor Sp3 inhibits the transition of paused RNA Pol II to productive elongation at the promoter of the cyclin-dependent kinase inhibitor p21 CIP1 and other Sp3-repressed genes. Our studies support the view that Sp3 has three modes of action: activation, SUMO-Sp3-mediated heterochromatin silencing and SUMOindependent inhibition of elongation. At the p21 CIP1 promoter, binding of the positive elongation factor P-TEFb kinase was not affected by Sp3. In contrast, Sp3 promoted binding of the protein phosphatase PP1 to the p21 CIP1 promoter, suggesting that Sp3-dependent regulation of the local balance between kinase and phosphatase activities may contribute to gene expression. Our findings show that the transition of paused RNA Pol II to productive elongation is an important step regulated by both promoter-specific activators and repressors to finely modulate mRNA expression levels.

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Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis

Cited by 160 publications

References 90 publications

TET1 plays an essential oncogenic role in MLL -rearranged leukemia

TET1 plays an essential oncogenic role in MLL -rearranged leukemia

Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability

Enforcing the pause: Transcription factor Sp3 limits productive elongation by RNA polymerase II

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