Click here to close now.


Agile Computing Authors: Pat Romanski, Brian Daleiden, Philippe Abdoulaye, Dana Gardner, Elizabeth White

News Feed Item

Study Involving Twin Sisters Provides Clues for Battling Aggressive Cancers

CINCINNATI, Feb. 9, 2014 /PRNewswire-USNewswire/ -- Analyzing the genomes of twin 3-year-old sisters – one healthy and one with aggressive leukemia – led an international team of researchers to identify a novel molecular target that could become a way to treat recurring and deadly malignancies.


Scientists in China and the United States report their findings online Feb. 9 in Nature Genetics. The study points to a molecular pathway involving a gene called SETD2, which can mutate in blood cells during a critical step as DNA is being transcribed and replicated.

The findings stem from the uniquely rare opportunity to compare the whole genomes of the monozygotic twin sisters (which means they came from a single egg). This led to a series of follow up experiments in human samples from leukemia patients and mouse models of human disease. Those tests verified and extended initial findings researchers gleaned from the twin sisters' blood samples, according to Gang Huang, PhD, co-corresponding author and a researcher in the divisions of Pathology and Experimental Hematology and Cancer Biology at Cincinnati Children's Hospital Medical Center.

"We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events," Huang said. "This provided a strong basis for comparison and analysis. We identified a gene mutation involving SETD2 that contributes to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells."

The twin sisters' genomes were compared at the laboratory of co-corresponding author Qian-fei Wang, PhD, Beijing Institute of Genomics, Chinese Academy of Sciences in Beijing, China. The sick sister had a particularly acute and aggressive form of the acute myeloid leukemia (AML) known as MLL, or multi-lineage leukemia.

Acute and aggressive leukemia like MLL develops and progresses rapidly in patients, requiring prompt treatment with chemotherapy, radiation or bone marrow transplant. These treatments can be risky or only partially effective. About 70 percent of people with AML respond initially to standard chemotherapy. Unfortunately, five-year survival rates vary between 15-70 percent, depending on the subtype of AML.

The researchers – including co-corresponding author Tao Cheng, MD, Chinese Academy of Medical Sciences & Peking Union Medical College in Tianjin, China – are searching for improved and more targeted treatment strategies. The authors show in their current study that the onset of aggressive and acute leukemia is fueled by a spiraling cascade of multiple gene mutations and what are called chromosomal translocations – essentially incorrect alignments of DNA and genetic information during cell replication.

In comparing the blood cells of both twin sisters, these researchers identified a chromosomal translocation generated what is known as the MLL-NRIP3 fusion leukemia gene. When they activated the MLL-NRIP3 gene in laboratory mouse models, the animals developed the same type of leukemia, but it took a long period of time for them to do so. Researchers said this suggested that there had to be additional cooperative epigenetic and molecular events in play to induce full-blown leukemia.

The authors went on to demonstrate that activation of the MLL-NRIP3 fusion leukemia gene cooperated with the molecular cascade (including mutations in SETD2) to cause the multi-lineage form of acute myeloid leukemia (AML). The scientists' initial clue came by looking for additional genomic alterations in the leukemic blood cells of the sick twin sister. They discovered activation of the MLL-NRIP3 fusion leukemia started the molecular cascade that led to bi-allelic (two mutations) in the gene SETD2 – a tumor suppressor and enzyme that regulates a specific histone modification protein called H3K36me3.

During a process called transcriptional elongation, SETD2 and H3K36me3 normally mark the zone for accurate gene transcription along the DNA. In the case of the sick twin sister, the gene mutations and molecular cascade disrupted the H3K36me3 mark, leading to abnormal transcription and the multi-lineage form of acute leukemia.

Researchers then analyzed blood samples from 241 people who had different forms acute leukemia. SETD2 mutations were found in samples from 6.2 percent of those patients. Patients with SETD2 mutations also had a leukemia associated with major chromosomal translocations and disruption of the H3K36me3 mark.  

In follow up tests on cell cultures of pre-leukemic cells and mouse models, researchers saw the same progression of gene mutations and related molecular events fuel the growth of leukemic cells. Researchers also noticed mutation of SETD2 activated two genes (MTOR and JAK-STAT) that known contributors to cancer and leukemia. The scientists decided to test two existing targeted molecular inhibitors of MTOR on pre-leukemic cells that are generated by SETD2 gene mutations.

That treatment resulted in a marked decrease in cell growth, indicating that SETD2 mutations activate numerous molecular pathways to generate leukemia. Huang said the tests also demonstrate that there are multiple opportunities to find new molecular targets for developing more effective drugs – in particular those that would target the MLL fusion-SETD2-H3K36me3 pathway for treating acute and aggressive multi-lineage leukemia.

Researchers are following up their current study by identifying additional pathways activated by mutations of SETD2. They also are looking possible new molecular targets and therapeutic strategies for block disruptions in the MLL fusions-SETD2-H3K36me3 pathway.

Other collaborating institutions include: the Institute of Hematology and Blood Diseases Hospital at the Chinese Academy of Medical Sciences and Peking Union Medical College; the University of Science & Technology, Wuhan, Hubei, China; Changhai Hospital, Second Military Medical University, Shanghai, China; the University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital of Chicago Research Center, Chicago. Co-first authors are: Xiaofan Zhu, Fuhong He, Huimin Zeng, Shaoping Ling and Aili Chen.

Funding support came from: the China Ministry of Science and Technology (2011CB964801, 2012CB966600, 2010DFB30270); the Chinese Academy of Sciences; the National Natural Science Foundation of China (81090411, 81000220, 81130074, 30825017) Tianjin Municipal Science & Technology Commission (09ZCZDSF03800).

About Cincinnati Children's:
Cincinnati Children's Hospital Medical Center ranks third in the nation among all Honor Roll hospitals in U.S. News and World Report's 2013 Best Children's Hospitals ranking. It is ranked #1 for cancer and in the top 10 for nine of 10 pediatric specialties. Cincinnati Children's, a non-profit organization, is one of the top three recipients of pediatric research grants from the National Institutes of Health, and a research and teaching affiliate of the University of Cincinnati College of Medicine. The medical center is internationally recognized for improving child health and transforming delivery of care through fully integrated, globally recognized research, education and innovation. Additional information can be found at Connect on the Cincinnati Children's blog, via Facebook and on Twitter.

SOURCE Cincinnati Children's Hospital Medical Center

More Stories By PR Newswire

Copyright © 2007 PR Newswire. All rights reserved. Republication or redistribution of PRNewswire content is expressly prohibited without the prior written consent of PRNewswire. PRNewswire shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon.

@ThingsExpo Stories
There are over 120 breakout sessions in all, with Keynotes, General Sessions, and Power Panels adding to three days of incredibly rich presentations and content. Join @ThingsExpo conference chair Roger Strukhoff (@IoT2040), June 7-9, 2016 in New York City, for three days of intense 'Internet of Things' discussion and focus, including Big Data's indespensable role in IoT, Smart Grids and Industrial Internet of Things, Wearables and Consumer IoT, as well as (new) IoT's use in Vertical Markets.
Today air travel is a minefield of delays, hassles and customer disappointment. Airlines struggle to revitalize the experience. GE and M2Mi will demonstrate practical examples of how IoT solutions are helping airlines bring back personalization, reduce trip time and improve reliability. In their session at @ThingsExpo, Shyam Varan Nath, Principal Architect with GE, and Dr. Sarah Cooper, M2Mi’s VP Business Development and Engineering, explored the IoT cloud-based platform technologies driving this change including privacy controls, data transparency and integration of real time context with p...
The Internet of Things (IoT) is growing rapidly by extending current technologies, products and networks. By 2020, Cisco estimates there will be 50 billion connected devices. Gartner has forecast revenues of over $300 billion, just to IoT suppliers. Now is the time to figure out how you’ll make money – not just create innovative products. With hundreds of new products and companies jumping into the IoT fray every month, there’s no shortage of innovation. Despite this, McKinsey/VisionMobile data shows "less than 10 percent of IoT developers are making enough to support a reasonably sized team....
We all know that data growth is exploding and storage budgets are shrinking. Instead of showing you charts on about how much data there is, in his General Session at 17th Cloud Expo, Scott Cleland, Senior Director of Product Marketing at HGST, showed how to capture all of your data in one place. After you have your data under control, you can then analyze it in one place, saving time and resources.
Just over a week ago I received a long and loud sustained applause for a presentation I delivered at this year’s Cloud Expo in Santa Clara. I was extremely pleased with the turnout and had some very good conversations with many of the attendees. Over the next few days I had many more meaningful conversations and was not only happy with the results but also learned a few new things. Here is everything I learned in those three days distilled into three short points.
As organizations realize the scope of the Internet of Things, gaining key insights from Big Data, through the use of advanced analytics, becomes crucial. However, IoT also creates the need for petabyte scale storage of data from millions of devices. A new type of Storage is required which seamlessly integrates robust data analytics with massive scale. These storage systems will act as “smart systems” provide in-place analytics that speed discovery and enable businesses to quickly derive meaningful and actionable insights. In his session at @ThingsExpo, Paul Turner, Chief Marketing Officer at...
DevOps is about increasing efficiency, but nothing is more inefficient than building the same application twice. However, this is a routine occurrence with enterprise applications that need both a rich desktop web interface and strong mobile support. With recent technological advances from Isomorphic Software and others, rich desktop and tuned mobile experiences can now be created with a single codebase – without compromising functionality, performance or usability. In his session at DevOps Summit, Charles Kendrick, CTO and Chief Architect at Isomorphic Software, demonstrated examples of com...
In his General Session at 17th Cloud Expo, Bruce Swann, Senior Product Marketing Manager for Adobe Campaign, explored the key ingredients of cross-channel marketing in a digital world. Learn how the Adobe Marketing Cloud can help marketers embrace opportunities for personalized, relevant and real-time customer engagement across offline (direct mail, point of sale, call center) and digital (email, website, SMS, mobile apps, social networks, connected objects).
Two weeks ago (November 3-5), I attended the Cloud Expo Silicon Valley as a speaker, where I presented on the security and privacy due diligence requirements for cloud solutions. Cloud security is a topical issue for every CIO, CISO, and technology buyer. Decision-makers are always looking for insights on how to mitigate the security risks of implementing and using cloud solutions. Based on the presentation topics covered at the conference, as well as the general discussions heard between sessions, I wanted to share some of my observations on emerging trends. As cyber security serves as a fou...
The Internet of Everything is re-shaping technology trends–moving away from “request/response” architecture to an “always-on” Streaming Web where data is in constant motion and secure, reliable communication is an absolute necessity. As more and more THINGS go online, the challenges that developers will need to address will only increase exponentially. In his session at @ThingsExpo, Todd Greene, Founder & CEO of PubNub, exploreed the current state of IoT connectivity and review key trends and technology requirements that will drive the Internet of Things from hype to reality.
Continuous processes around the development and deployment of applications are both impacted by -- and a benefit to -- the Internet of Things trend. To help better understand the relationship between DevOps and a plethora of new end-devices and data please welcome Gary Gruver, consultant, author and a former IT executive who has led many large-scale IT transformation projects, and John Jeremiah, Technology Evangelist at Hewlett Packard Enterprise (HPE), on Twitter at @j_jeremiah. The discussion is moderated by me, Dana Gardner, Principal Analyst at Interarbor Solutions.
Too often with compelling new technologies market participants become overly enamored with that attractiveness of the technology and neglect underlying business drivers. This tendency, what some call the “newest shiny object syndrome” is understandable given that virtually all of us are heavily engaged in technology. But it is also mistaken. Without concrete business cases driving its deployment, IoT, like many other technologies before it, will fade into obscurity.
The Internet of Things is clearly many things: data collection and analytics, wearables, Smart Grids and Smart Cities, the Industrial Internet, and more. Cool platforms like Arduino, Raspberry Pi, Intel's Galileo and Edison, and a diverse world of sensors are making the IoT a great toy box for developers in all these areas. In this Power Panel at @ThingsExpo, moderated by Conference Chair Roger Strukhoff, panelists discussed what things are the most important, which will have the most profound effect on the world, and what should we expect to see over the next couple of years.
With all the incredible momentum behind the Internet of Things (IoT) industry, it is easy to forget that not a single CEO wakes up and wonders if “my IoT is broken.” What they wonder is if they are making the right decisions to do all they can to increase revenue, decrease costs, and improve customer experience – effectively the same challenges they have always had in growing their business. The exciting thing about the IoT industry is now these decisions can be better, faster, and smarter. Now all corporate assets – people, objects, and spaces – can share information about themselves and thei...
PubNub has announced the release of BLOCKS, a set of customizable microservices that give developers a simple way to add code and deploy features for realtime apps.PubNub BLOCKS executes business logic directly on the data streaming through PubNub’s network without splitting it off to an intermediary server controlled by the customer. This revolutionary approach streamlines app development, reduces endpoint-to-endpoint latency, and allows apps to better leverage the enormous scalability of PubNub’s Data Stream Network.
I recently attended and was a speaker at the 4th International Internet of @ThingsExpo at the Santa Clara Convention Center. I also had the opportunity to attend this event last year and I wrote a blog from that show talking about how the “Enterprise Impact of IoT” was a key theme of last year’s show. I was curious to see if the same theme would still resonate 365 days later and what, if any, changes I would see in the content presented.
Apps and devices shouldn't stop working when there's limited or no network connectivity. Learn how to bring data stored in a cloud database to the edge of the network (and back again) whenever an Internet connection is available. In his session at 17th Cloud Expo, Ben Perlmutter, a Sales Engineer with IBM Cloudant, demonstrated techniques for replicating cloud databases with devices in order to build offline-first mobile or Internet of Things (IoT) apps that can provide a better, faster user experience, both offline and online. The focus of this talk was on IBM Cloudant, Apache CouchDB, and ...
Microservices are a very exciting architectural approach that many organizations are looking to as a way to accelerate innovation. Microservices promise to allow teams to move away from monolithic "ball of mud" systems, but the reality is that, in the vast majority of organizations, different projects and technologies will continue to be developed at different speeds. How to handle the dependencies between these disparate systems with different iteration cycles? Consider the "canoncial problem" in this scenario: microservice A (releases daily) depends on a couple of additions to backend B (re...
Discussions of cloud computing have evolved in recent years from a focus on specific types of cloud, to a world of hybrid cloud, and to a world dominated by the APIs that make today's multi-cloud environments and hybrid clouds possible. In this Power Panel at 17th Cloud Expo, moderated by Conference Chair Roger Strukhoff, panelists addressed the importance of customers being able to use the specific technologies they need, through environments and ecosystems that expose their APIs to make true change and transformation possible.
Container technology is shaping the future of DevOps and it’s also changing the way organizations think about application development. With the rise of mobile applications in the enterprise, businesses are abandoning year-long development cycles and embracing technologies that enable rapid development and continuous deployment of apps. In his session at DevOps Summit, Kurt Collins, Developer Evangelist at, examined how Docker has evolved into a highly effective tool for application delivery by allowing increasingly popular Mobile Backend-as-a-Service (mBaaS) platforms to quickly crea...