A new epigenetic cancer

Researchers have discovered a new category of cancer caused by chromatin recognition gone awry. An aberrant protein that binds to activated DNA-winding proteins drives up gene expression leading to unchecked cell growth, according to a linkurl:study;http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature08036.html published online yesterday (May 10) in __Nature__.

By | May 11, 2009

Researchers have discovered a new category of cancer caused by chromatin recognition gone awry. An aberrant protein that binds to activated DNA-winding proteins drives up gene expression leading to unchecked cell growth, according to a linkurl:study;http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature08036.html published online yesterday (May 10) in __Nature__.
Chromatin wound on histone proteins
Image: Eric Smith, DFCI
Several forms of the blood cancer linkurl:acute myeloid leukemia;http://www.cancer.org/docroot/CRI/content/CRI_2_4_1x_What_Is_Acute_Myeloid_Leukemia.asp (AML) are marked by a chromosomal crossover, or translocation, between the genes that code for two protein fragments: a short, common protein motif known as the linkurl:plant homeodomain (PHD) finger,;http://en.wikipedia.org/wiki/PHD_finger which is involved in chromatin recognition and gene regulation, and a large protein responsible for trafficking RNA into and out of the nucleus, called linkurl:nucleoporin-98;http://atlasgeneticsoncology.org/Genes/NUP98.html (NUP98). How these translocations bring about cancer, however, was largely a mystery. "We now have a much better sense for why those translocations would be messing up the cell and promoting cancer," linkurl:Or Gozami,;http://www.stanford.edu/group/gozani/ a molecular cancer biologist at Stanford University who was not involved in the study, told __The Scientist__. The newfound mechanism is probably a common conduit leading to many pathologies, he added. "This is something that's beyond AML." linkurl:David Allis,;http://www.rockefeller.edu/labheads/allis/allis-lab.php a chromatin biochemist at the Rockefeller University in New York City, and his postdoc Gang (Greg) Wang used mouse bone marrow cells to study the NUP98-PHD finger fusion -- the "funky hybrid protein," as Allis called it. Allis and Wang showed that the PHD domain in the protein fusion acted like "chromatin Velcro," binding to and docking on a "landing pad" formed by a particular triple methylated histone protein, H3K4me3. The PHD finger then served as a "protective cap" to block enzymes that normally remove methyl groups from the histone protein in order to dampen gene expression. In this way, the rogue NUP98-PHD fusion "somehow sets up an epigenetic signature which pretty much correlates with on-ness," Allis said.
Mouse cells with leukemia
Image: Greg Wang
Allis and Wang performed microarray analyses, real time PCRs, and chromatin immunoprecipitation assays, and showed that capping the histone with the PHD finger led to substantial and prolonged upregulation of critical developmental genes, including several HOX genes. This epigenetic "on state" is typical of leukemia cancer stem cells. The researchers also injected mice with bone marrow cells -- either containing or lacking the PHD domain bound to the NUP98 protein -- and found that those with the hybrid fusion died of leukemia within a few months whereas all the control animals without the PHD domain survived for at least a year. Thus, Allis and Wang concluded that the misguided PHD sticks its finger in the wrong place and drives cancer progression through its effect on histone modifications. "Our cell and animal cancer models clearly demonstrated that the PHD finger harbored in leukemic fusion proteins is indeed a 'reader' of histone mark H3K4me3, and is essential in driving the normal blood progenitor cells into the cancerous ones," Wang told __The Scientist__ in an email. Since there are some 200 different PHD fingers in the human genome, with many linked to a wide range of diseases, Wang proposed that similar cellular "misreadings" of histone modifications might underlie other unstudied pathologies. Since we know what goes wrong in diseases with harried histones, we can try and fix it, noted Gozani. "We have a target to go after now," he said. Still, the explanation that the PHD finger is modifying only a select few key developmental genes is probably overly simplistic, he added. "I'm positive it's more complicated than that. It's part of what's going on, but I'm sure that there are other regions of the human genome that are probably also being misregulated and therefore contributing to this cancer."
__Correction (May 11): A previous version of the story incorrectly stated that a chromosomal translocation occurred between two protein fragments. In fact, the translocation happened between the genes that code for these proteins.__ The Scientist__ regrets the error.__
**__Related stories:__***linkurl:Demystifying histone demethylases;http://www.the-scientist.com/article/display/54229/
[February 2008]*linkurl:Support for histone code?;http://www.the-scientist.com/blog/display/23474/
[22nd May 2006]*linkurl:Researchers focus on histone code;http://www.the-scientist.com/article/display/12599/
[17th September 2001]


Avatar of: anonymous poster

anonymous poster

Posts: 8

May 11, 2009

The findings by Allis and Wang are extraordinary, as they provide a clear explanation of an epigenetic process that leads to several forms of AML. The news article could benefit from one modification. The second paragraph should read:\n\n"...Several forms of the blood cancer acute myeloid leukemia (AML) are marked by a chromosomal crossover, or translocation, between two DNA SEGMENTS IN NONHOMOLOGOUS CHROMOSOMES THAT CODE FOR TWO protein fragments:..." \n\nThis edit is relevant because translocation happens at the DNA level; the proteins coded by genes don't "translocate".

May 11, 2009

The findingds and the logic butressing looks both-promising & challenging. It goes beyond drawing a neat flow diagram for pathogenesis of AML.\nIt is crucial that the results are ascertained in different labs;and later on with at least 3 more suspected "rouges" to put across a cogent theory necessary for experimental challenges. Tumor biology had long ago prposed co-carcinogen inhibitor escape as the mechanism for trigger to Cancers. 3 decades later, it is heartening to read something that may open a new vista\nDrSapatnekar\nDean,\nClinical Research Education & Management Academy, India
Avatar of: anonymous poster

anonymous poster

Posts: 1

May 11, 2009

This is fascinating work, but you mislead the reader by saying it is an "epigenetic cancer"..the fundamental basis is a genetic translocation which causes epigenetic dysregulation. "Epigenetic cancer" implies that its root cause is epigenetic, and that is not the case.
Avatar of: anonymous poster

anonymous poster

Posts: 26

May 11, 2009

An epigenetic cancer would be heritable from cell to cell without any DNA (genetic) alteration. The cancer described here is genetic. A genetic mutation (a translocation) creates a mutant protein that abberantly activates some genes. Granted, it does so by altering chomatin structure. But, in general, genes are activated by altering chromatin structure - that what enhancer elements, and to some extent, promoters are for...\n\nSo, a more appropriate title might be "Cancer caused by mutations affecting histone demethylation".\n\nA more intersting study would be to determine what sort of mutation or brain damage led to the insanity of the post (below) about palm reading.\n\nBaxter Zappa
Avatar of: anonymous poster

anonymous poster

Posts: 18

May 12, 2009

The following commentary is way off base and should be deleted from this post:\n\nisland at the end of life line of palm print indicating earlier cancer\nby sankaravelayudhan nandakuamr\n\nIt does not advance The Scientist article in any manner. This is the second time this nonsensical and distracting commentary has been used.

May 12, 2009

The comment suggesting astro-etiologyshows only delusions of grandeur by the commentator.Please use your editorial prerogative to delete such nonsence. Otherwise soon we will have black magic therapies for cure of epigenetic cancers from the Commentator who cannot spell "Lifeline"!


Posts: 10

May 12, 2009

Several respondents question whether the phenomenon observed by Wang et al. is epigenetic. My evidence suggests that not only can it be epigenetic, but, more important, an underlying phenomenon dubbed autovirulence also can explain the aberrant molecular functions. This precisely was a reason for inventing the preliophic moleculator and its associated preliophic processes - to elucidate aberrant molecular functions in contrast to electrophoresis used in elucidating aberrant molecular structures.\n\nA succinct explanation of my views is cited in an article by Chris Fisher in The Behavioral Medicine Report (see bmedreport.com/archives/1411). Autovirulence was first discussed in 1983 and 1984 (see Smith, RW. Annals of the New York Academy of Sciences 1984; 437:576-607).
Avatar of: Alison McCook

Alison McCook

Posts: 68

May 12, 2009

Thanks readers-\n\nIndeed, one of the posted comments was quite irrelevant to the story, and the email address was a fake. So it's been rejected. Thanks for the heads up.\n\nAlison McCook\nDeputy Editor

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