Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10–positive leukemias

Lin, Yi Hui; Kakadia, Purvi M.; Chen, Ying; Li, Ya Qiang; Deshpande, Aniruddha J.; Buske, Christian; Zhang, Kangling; Zhang, Yi; Xu, Guo Liang; Bohlander, Stefan K.

doi:10.1182/blood-2009-03-209395

Cited by 57 publications

(70 citation statements)

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“…To investigate the possible link between H3K23 hyperpropionylation and CALM-AF10 fusion, CALM-AF10 and its OM-LZ deletion mutant were induced to express in T-REx-293 stable cell lines with tetracycline. Consistent with our previous report (6), global hypomethylation of H3K79 was detected upon induction of CALM-AF10 but not the OM-LZ deletion mutant (data not shown). However, the H3K23 propionylation level did not change significantly in response to the induced expression of the CALM-AF10 proteins in the stable cell lines, and neither did the acetylation level (Fig.…”

Section: Down-regulation Of Af10 or Ectopic Expression Of Calm-af10 Fsupporting

confidence: 81%

“…However, no change in H3K23 propionylation was observed in U937 cells upon ectopic expression of the wild-type AF10 protein or the mutant AF10 protein with a deletion of the hDOT1L-binding domain OM-LZ (Fig. 3A), which is crucial for AF10-mediated restoration of H3K79 in U937T cells (6). This result suggests that hyperpropionylation in U937 cells is not caused by down-regulation of AF10.…”

Section: Down-regulation Of Af10 or Ectopic Expression Of Calm-af10 Fmentioning

confidence: 58%

“…The U937 cell line is characterized by the presence of a t(10;11)(p13;q14) chromosome translocation leading to the fusion of the CALM (clathrin assembly lymphoid myeloid leukemia) gene with the putative transcription factor gene AF10 (14). The CALM-AF10 fusion protein causes global hypomethylation at H3K79 due to the functional perturbation of the responsible histone methyltransferase hDOT1L by the fusion (6). Ectopic expression of CALM-AF10 in T-REx-293 cells results in H3K79 hypomethylation (6) but has no effect on Lys 23 propionylation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the Lys 23 acetylation levels were similar in the different cell lines. The global H3K79 -2me hypomethylation is a characteristic of U937 cells, in which the CALM-AF10 fusion protein affects the association of the H3K79 methyltransferase hDOT1L with chromatin as described in our previous report (6).…”

Section: Identification Of Histone H3 Lysine 23 Propionylation In Thementioning

confidence: 99%

“…(H3K79) hypermethylation and the activation of oncogenic HOX genes are prominent causes for leukemia with chromosome translocation involving the AF10 gene (4,5), whereas global hypomethylation at H3K79 sites has been proposed to cause genome instability in AF10-related leukemia cancers (6). Alteration in histone modification patterns serves as a hallmark of cancer that provides clues for cancer diagnosis and treatment (7).…”

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Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells

Liu

Lin

Darwanto

et al. 2009

Journal of Biological Chemistry

114

135

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Propionylation has been identified recently as a new type of protein post-translational modification. Bacterial propionylCoA synthetase and human histone H4 are propionylated at specific lysine residues that have been known previously to be acetylated. However, other proteins subject to this modification remain to be identified, and the modifying enzymes involved need to be characterized. In this work, we report the discovery of histone H3 propionylation in mammalian cells. Propionylation at H3 lysine Lys 23 was detected in the leukemia cell line U937 by mass spectrometry and Western analysis using a specific antibody. In this cell line, the propionylated form of Lys 23 accounted for 7%, a level at least 6-fold higher than in other leukemia cell lines (HL-60 and THP-1) or non-leukemia cell lines (HeLa and IMR-90). The propionylation level in U937 cells decreased remarkably during monocytic differentiation, indicating that this modification is dynamically regulated. Moreover, in vitro assays demonstrated that histone acetyltransferase p300 can catalyze H3 Lys 23 propionylation, whereas histone deacetylase Sir2 can remove this modification in the presence of NAD ؉ .These results suggest that histone propionylation might be generated by the same set of enzymes as for histone acetylation and that selection of donor molecules (propionyl-CoA versus acetylCoA) may determine the difference of modifications. Because like acetyl-CoA, propionyl-CoA is an important intermediate in biosynthesis and energy production, histone H3 Lys 23 propionylation may provide a novel epigenetic regulatory mark for cell metabolism.Eukaryotic histones are rich in multiple post-translational modifications, the combinatory array of which is the basis for epigenetic regulation of gene expression (1). Appropriate histone modifications are required for normal cell growth and differentiation, whereas aberrant histone modifications contribute to tumor formation such as malignant hematopoiesis (2). For example, genome-wide alterations of histone modification patterns are found in prostate cancer and are predictive of clinical outcomes (3); histone H3 Lys 79 (H3K79) hypermethylation and the activation of oncogenic HOX genes are prominent causes for leukemia with chromosome translocation involving the AF10 gene (4, 5), whereas global hypomethylation at H3K79 sites has been proposed to cause genome instability in AF10-related leukemia cancers (6). Alteration in histone modification patterns serves as a hallmark of cancer that provides clues for cancer diagnosis and treatment (7).Lysine propionylation has recently been identified as a new type of post-translational modification. It was first discovered in human histone H4 enriched for acetylation using anti-acetyl H4 antibodies (9). The propionyl-CoA synthetase of Salmonella enterica was also found to be propionylated at lysine 592, which inactivates the enzyme activity in vivo (8). In vitro experiments showed that histone acetyltransferase p300 and CREBbinding protein (CBP) can propionylate histone H4,...

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Section: Down-regulation Of Af10 or Ectopic Expression Of Calm-af10 Fsupporting

confidence: 81%

Section: Down-regulation Of Af10 or Ectopic Expression Of Calm-af10 Fmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Histone H3 Lysine 23 Propionylation In Thementioning

confidence: 99%

mentioning

confidence: 99%

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Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells

Liu

Lin

Darwanto

et al. 2009

Journal of Biological Chemistry

114

135

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MLL Leukemia and Future Treatment Strategies

Marschalek

2015

Archiv der Pharmazie

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Chromosomal rearrangements of the MLL gene are associated with high-risk infant, pediatric, adult, and therapy-induced acute leukemias. So far, about 80 different direct MLL fusions and about 120 reciprocal MLL fusions have been characterized at the molecular level. The common theme in these leukemia-associated genetic rearrangements is the genetic disruption of the MLL gene. This leads to MLL-X fusion proteins that still bind to nuclear factors (e.g., MEN1, LEDGF), which in turn allow them to target promoters and cause ectopic gene transcription. In addition, the most frequent MLL fusions (MLL-AF4, MLL-AF9, MLL-AF10, and MLL-ENL) are all recruiting the wild-type AF4 multiprotein complex that contains the target proteins P-TEFb, BRD4, and DOT1L. Vice versa, reciprocal X-MLL fusions exhibit a PHD domain (H3K4me3 reader domain), sequester the histone acetyltransferases CREBBP and MOF1 and bear a histone methyltransferase domain at their very C-terminus (SET domain). Except for AF4-MLL, the functional consequences deriving from reciprocal fusion proteins are not very well understood. However, based on our knowledge about the above-mentioned MLL fusions, it is reasonable to inhibit their oncogenic activity in a targeted fashion. Recent efforts in developing such inhibitors and their mode of action will be critically discussed.

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Genetic instability in inherited and sporadic leukemias

Popp

Bohlander

2010

Genes Chromosomes & Cancer

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Genetic instability due to increased DNA damage and altered DNA repair is of central significance in the initiation and progression of inherited and sporadic human leukemias. Although very rare, some inherited DNA repair insufficiency syndromes (e.g., Fanconi anemia, Bloom's syndrome) have added substantially to our understanding of crucial mechanisms of leukemogenesis in recent years. Conversely, sporadic leukemias account for the main proportion of leukemias and here DNA damaging reactive oxygen species (ROS) play a central role. Although the exact mechanisms of increased ROS production remain largely unknown and no single pathway has been detected thus far, some oncogenic proteins (e.g., the activated tyrosine kinases BCR-ABL1 and FLT3-ITD) seem to play a key role in driving genetic instability by increased ROS generation which influences the disease course (e.g., blast crisis in chronic myeloid leukemia or relapse in FLT3-ITD positive acute myeloid leukemia). Of course other mechanisms, which promote genetic instability in leukemia also exist. A newly emerging mechanism is the genome-wide alteration of epigenetic marks (e.g., hypomethylation of histone H3K79), which promotes chromosomal instability. Taken together genetic instability plays a critical role both in inherited and sporadic leukemias and emerges as a common theme in both inherited and sporadic leukemias. Beyond its theoretical impact, the analysis of genetic instability may lead the way to the development of innovative therapy strategies.

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Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10–positive leukemias

Cited by 57 publications

References 50 publications

Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells

Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells

MLL Leukemia and Future Treatment Strategies

Genetic instability in inherited and sporadic leukemias

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