Featured Research

from universities, journals, and other organizations

Fruit fly studies help scientists swat aggressive relapsing leukemia

Date:
December 16, 2013
Source:
Cincinnati Children's Hospital Medical Center
Summary:
Using genetic information initially uncovered in fruit fly studies, scientists have developed a unique therapeutic strategy that stops an aggressive and deadly form of leukemia in laboratory models of the disease. Researchers say their findings provide strong evidence for developing clinical therapies that block what are called microRNAs to help treat acute myelogenous leukemia.

Using genetic information initially uncovered in fruit fly studies, scientists have developed a unique therapeutic strategy that stops an aggressive and deadly form of leukemia in laboratory models of the disease.

Related Articles


Reporting their results Dec. 16 in the Journal of Clinical Investigation, researchers say their findings provide strong evidence for developing clinical therapies that block what are called microRNAs to help treat acute myelogenous leukemia (AML). The study was led by scientists at Cincinnati Children's Hospital Medical Center and included a multi-institutional team of researchers.

"Using ancient and evolutionarily conserved molecular pathways, we demonstrate for the first time in mice transplanted with human AML the therapeutic potential of targeting microRNAs to significantly improve current therapies," said H. Leighton Grimes, PhD, senior investigator and a researcher in the divisions of Immunobiology and Experimental Hematology/Cancer Biology at Cincinnati Children's. "This work provides a proof of principle that moves forward the concept of RNA therapies capable of blocking microRNAs that trigger relapsed AML."

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.

Grimes and his research colleagues are aiming for a new therapeutic approach that could augment existing treatments. An important goal is helping increase the number of patients with aggressive and relapsed AML who are eligible for a bone marrow transplant. At present, bone marrow transplant is the only curative therapy for relapsed AML, but many patients do not respond well enough to chemotherapy to have the procedure.

In mouse models of AML and in relapsed human AML, scientists and clinicians are concerned about so-called leukemia-initiating cells. These initiating cells are a subset of human AML cells capable of taking hold after being transplanted into mouse models of the disease. Similarly, it is suspected that a subset of human AML cells in patients can reinitiate disease if chemotherapy does not eliminate all of the leukemic cells. When this occurs, these cancer stem cells are thought to be responsible for relapse in people with AML.

In their study, the authors tested a particularly aggressive, high-relapse form of AML driven by what are called homeobox or Hox genes. Cancer proteins fueled by HOX genes (in particular one called HoxA9, which can be traced back to Drosophila fruit flies) result in an AML subtype with very poor prognosis for people.

The researchers initially studied genes and related molecular pathways that decide the fate of cells forming in the posterior half of fruit fly embryos. They focused on molecules called transcription factors that activate genes -- specifically two fruit fly transcription factors that are related to those found in mammals: HoxA9 (which activates genes) and Gfi1 (a transcriptional repressor). By competing against each other to control gene expression, the transcription factors determine the fate of the cells.

The scientists then extended this concept to uncover a similar fight between HoxA9 and Gfi1 in controlling the transformation of mammalian blood cells by leukemia-causing proteins. It was known prior to this study that HoxA9 plays an important role in transforming cells to become leukemic, but Grimes and his colleagues discovered that Gfi1 is able to cancel this effect. The researchers believe Gfi1 does this by repressing key target genes that HoxA9 must activate to continue the leukemia process.

Specifically, Gfi1 competes with HoxA9 over control of two microRNAs -- miR-21 and miR-196b. MicroRNAs are small strands of genetic code that fine tune the production of proteins from messenger RNA (mRNA), which convey genetic information from DNA to cells. In the case of miR-21 and miR-196b, the scientists found these microRNAs fuel the production of leukemia initiating cells that can trigger a relapse of aggressive AML in mice.

To therapeutically translate the effect of Gfi1 repressing microRNAs targeted by HoxA9, the scientists blocked miR-21 and -196b -- and their production of leukemia initiating cells -- by using short synthetic strands of RNA called antagomirs. The structure of antagomirs allows them to block the function of specific microRNAs inside a living organism, like a mouse.

Grimes and his colleagues tested the antagomirs in several different experiments involving AML cells and in mouse models of AML. The experiments showed the antagomirs stopped the growth of leukemia cells. This included a typically fatal form of multi-lineage leukemia caused by an abnormal rearrangement of chromosomes (called chromosomal translocations) involving the human chromosome band 11q23. Researchers report antagomir therapy eliminated these leukemia cells.

In one test, the scientists treated humanized mouse models (transplanted with human 11q23-translocation leukemia) with a combination of antagomirs that block miR-21 and miR-196b and chemotherapy. Mice treated with either chemotherapy alone or chemotherapy with control antagomir therapy died on average in about 62 days. Mice treated with chemotherapy and miR-21 and miR-196b-specific antagomirs saw their survival extend significantly to an average of about 80 days.

The researchers emphasized that significant additional study is required before extending their findings to the treatment of human leukemia patients.


Story Source:

The above story is based on materials provided by Cincinnati Children's Hospital Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Chinavenmeni S. Velu, Aditya Chaubey, James D. Phelan, Shane R. Horman, Mark Wunderlich, Monica L. Guzman, Anil G. Jegga, Nancy J. Zeleznik-Le, Jianjun Chen, James C. Mulloy, Jose A. Cancelas, Craig T. Jordan, Bruce J. Aronow, Guido Marcucci, Balkrishen Bhat, Brian Gebelein, H. Leighton Grimes. Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity. Journal of Clinical Investigation, 2013; DOI: 10.1172/JCI66005

Cite This Page:

Cincinnati Children's Hospital Medical Center. "Fruit fly studies help scientists swat aggressive relapsing leukemia." ScienceDaily. ScienceDaily, 16 December 2013. <www.sciencedaily.com/releases/2013/12/131216142533.htm>.
Cincinnati Children's Hospital Medical Center. (2013, December 16). Fruit fly studies help scientists swat aggressive relapsing leukemia. ScienceDaily. Retrieved December 18, 2014 from www.sciencedaily.com/releases/2013/12/131216142533.htm
Cincinnati Children's Hospital Medical Center. "Fruit fly studies help scientists swat aggressive relapsing leukemia." ScienceDaily. www.sciencedaily.com/releases/2013/12/131216142533.htm (accessed December 18, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Thursday, December 18, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Kids Die While Under Protective Services

Kids Die While Under Protective Services

AP (Dec. 18, 2014) As part of a six-month investigation of child maltreatment deaths, the AP found that hundreds of deaths from horrific abuse and neglect could have been prevented. AP's Haven Daley reports. (Dec. 18) Video provided by AP
Powered by NewsLook.com
UN: Up to One Million Facing Hunger in Ebola-Hit Countries

UN: Up to One Million Facing Hunger in Ebola-Hit Countries

AFP (Dec. 17, 2014) Border closures, quarantines and crop losses in West African nations battling the Ebola virus could lead to as many as one million people going hungry, UN food agencies said on Wednesday. Duration: 00:52 Video provided by AFP
Powered by NewsLook.com
When You Lose Weight, This Is Where The Fat Goes

When You Lose Weight, This Is Where The Fat Goes

Newsy (Dec. 17, 2014) Can fat disappear into thin air? New research finds that during weight loss, over 80 percent of a person's fat molecules escape through the lungs. Video provided by Newsy
Powered by NewsLook.com
Why Your Boss Should Let You Sleep In

Why Your Boss Should Let You Sleep In

Newsy (Dec. 17, 2014) According to research out of the University of Pennsylvania, waking up for work is the biggest factor that causes Americans to lose sleep. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins