Featured Research

from universities, journals, and other organizations

Scientists reveal mechanism behind 'oncogene addiction' in acute leukemia

Date:
August 1, 2011
Source:
Cold Spring Harbor Laboratory
Summary:
Scientists have laid bare the mechanism behind oncogene addiction, in mice suffering from a form of leukemia that mimics acute myelogenous leukemia (AML) in humans. The team was able to target "addiction" pathways in the model mice, resulting in rapid and complete eradication of the cancer, which is usually fatal and resistant to conventional chemotherapy.

A team of scientists at Cold Spring Harbor Laboratory (CSHL) has laid bare the mechanism behind a phenomenon called oncogene addiction in mice suffering from a form of leukemia that mimics acute myelogenous leukemia (AML) in humans. Significantly, the team was able to mobilize their newly gained understanding to target "addiction" pathways in the model mice, resulting in rapid and complete eradication of the cancer, which is usually fatal and resistant to conventional chemotherapy.

Oncogene addiction refers to the curious phenomenon that cancer cells, despite harboring many genetic alterations, can remain dependent on the continuing expression of a single aberrant, cancer-promoting gene -- an oncogene. In this case, the gene in question, called MLL, has long been implicated in human cancers of the blood. In AML, as a result of a genetic anomaly, the protein expressed by the MLL gene fuses with another protein, to form a fusion oncoprotein called MLL-AF9. It is this protein to which AML cancer cells are "addicted."

"The crucial questions are what MLL-AF9 enables cancer cells to do, and how we might intervene to suppress these effects -- in other words, how to use our knowledge of the mechanism behind the cancer cell's addiction for developing highly specific anti-cancer therapies.," says CSHL Adjunct Professor and HHMI Investigator Scott W. Lowe, who directed the research, which is reported in a paper that appears August 1 in the journal Genes & Development. "Until now, we've not been able to answer these questions in living animals."

The team's research demonstrated that MLL-AF9 enforces a cellular program that enables blood cells to keep renewing themselves, rather than progressing through the usual stages of cellular life, and eventually dying. While this property of aberrant self-renewal has been a known characteristic of leukemia cells for many years, Lowe and his CSHL colleagues were able to decipher the underlying genetic program in unprecedented detail. The central player orchestrating these cancer-specific self-renewal programs was found to be Myb, a protein known to regulate normal blood cell production that previously also has been implicated in certain subtypes of leukemia.

"MLL-AF9 apparently 'hijacks' Myb to enforce a program of aberrant self-renewal," explains Amy Rappaport, who was a co-first author on the paper, with Johannes Zuber. The team also included Christopher Vakoc, a CSHL Fellow, among others. "The consequences of inhibiting Myb in established leukemia were striking," says Zuber. "Following Myb suppression, mouse leukemia cells invariably lost their aberrant self-renewal ability, resumed their normal cell fate, maturing into white blood cells, and eventually got eliminated." As a consequence, mice harboring this aggressive and chemotherapy-resistant form of AML were cured by inhibiting Myb. The protein's suppression had no adverse impact upon normal white blood cells.

To identify and study genes that are specifically required in cancer cells, the researchers took a systematic approach that demonstrates the power of a series of technological advances made by Lowe's group in concert with several other groups at CSHL. These advances play an important role in CSHL's new Cancer Therapeutic Initiative. The Initiative aims to rapidly identify new therapeutic targets and validate them in mouse models specific for genetic subtypes of human cancer.

In the paper published July 31, Lowe's team first implemented a rapid strategy to introduce common human AML mutations in mice so that they closely mimicked human AML, both in terms of symptoms and response to treatment. These genetically reprogrammed mice are called "mosaic mice." As a next step, the team used a genetic switch to inactivate the oncogene that gives rise to the "addictive" MLL-AF9 oncoprotein. When MLL-AF9 was suppressed in living mice, the cancers shrank and were soon eliminated altogether from all affected organs. This result confirmed the cancer cells' addiction to MLL-AF9, and provided a unique system to reveal the underlying genetic networks.

To further explore components of these networks, the team used RNA interference, or RNAi, an experimental tool to suppress gene function, which in prior work they had adapted for use in animal models. These recent advances now provide a means to switch off virtually any gene in an established cancer, and thereby enable the identification and evaluation of new potential drug targets. While the current study focused on the dramatic effects of suppressing Myb in AML, the approach validates a general method for understanding oncogene addiction in vivo that can be applied in other cancer types.

The RNA interference technique used in the experiments to block Myb is not applicable in humans, for a variety of still-daunting technical reasons. The hope is to find a small molecule that specifically targets the Myb protein, which can be the basis for a human drug. None has yet been developed, although the search is on.

But, says Lowe, "our results show that suppressing a single mediator of aberrant self-renewal can re-establish pre-existing cell-fate programs and eliminate aggressive AML. This suggests that pre-existing cell-fate programs remain hard-wired even in cancer cells, and raises our hope that agents that inhibit these programs will be less prone to resistance mechanisms that prevent targeted therapies from producing a lasting effect in other cancers."


Story Source:

The above story is based on materials provided by Cold Spring Harbor Laboratory. Note: Materials may be edited for content and length.


Journal Reference:

  1. Johannes Zuber, Amy R. Rappaport, Weijun Luo, Eric Wang, Chong Chen, Angelina V. Vaseva, Junwei Shi, Susann Weissmueller, Meredith J. Taylor, Martina Weissenboeck, Thomas G. Graeber, Scott C. Kogan, Christopher R. Vakoc and Scott W. Lowe. An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance. Genes & Development, 2011 DOI: 10.1101/gad.17269211

Cite This Page:

Cold Spring Harbor Laboratory. "Scientists reveal mechanism behind 'oncogene addiction' in acute leukemia." ScienceDaily. ScienceDaily, 1 August 2011. <www.sciencedaily.com/releases/2011/07/110731221447.htm>.
Cold Spring Harbor Laboratory. (2011, August 1). Scientists reveal mechanism behind 'oncogene addiction' in acute leukemia. ScienceDaily. Retrieved July 25, 2014 from www.sciencedaily.com/releases/2011/07/110731221447.htm
Cold Spring Harbor Laboratory. "Scientists reveal mechanism behind 'oncogene addiction' in acute leukemia." ScienceDaily. www.sciencedaily.com/releases/2011/07/110731221447.htm (accessed July 25, 2014).

Share This




More Health & Medicine News

Friday, July 25, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Beatings and Addiction: Pakistan Drug 'clinic' Tortures Patients

Beatings and Addiction: Pakistan Drug 'clinic' Tortures Patients

AFP (July 24, 2014) A so-called drugs rehab 'clinic' is closed down in Pakistan after police find scores of ‘patients’ chained up alleging serial abuse. Duration 03:05 Video provided by AFP
Powered by NewsLook.com
Too Few Teens Receiving HPV Vaccination, CDC Says

Too Few Teens Receiving HPV Vaccination, CDC Says

Newsy (July 24, 2014) The Centers for Disease Control and Prevention is blaming doctors for the low number of children being vaccinated for HPV. Video provided by Newsy
Powered by NewsLook.com
New Painkiller Designed To Discourage Abuse: Will It Work?

New Painkiller Designed To Discourage Abuse: Will It Work?

Newsy (July 24, 2014) The FDA approved Targiniq ER on Wednesday, a painkiller designed to keep users from abusing it. Like any new medication, however, it has doubters. Video provided by Newsy
Powered by NewsLook.com
Doctor At Forefront Of Fighting Ebola Outbreak Gets Ebola

Doctor At Forefront Of Fighting Ebola Outbreak Gets Ebola

Newsy (July 24, 2014) Sheik Umar Khan has treated many of the people infected in the Ebola outbreak, and now he's become one of them. 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:
from the past week

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