Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Microenvironment a main driver of aggressive multi-lineage leukemia disease type

10.06.2008
Study yields clues into different leukemia forms and possible therapeutic targets

Research led by scientists at Cincinnati Children's Hospital Medical Center has revealed new clues into what causes different types of a particularly aggressive group of blood cancers known as mixed lineage leukemias (MLL) and how the disease might be treated, according to a study in the June 9 issue of Cancer Cell.

"We document early biological processes where human leukemia stem cells can be altered to form a particular type, or lineage, of leukemia by the factors they are exposed to in the microenvironment of blood-forming tissues," said James Mulloy, Ph.D., a researcher in the division of Experimental Hematology/Cancer Biology at Cincinnati Children's and the study's corresponding author. "These new details about molecular events associated with MLL, and the new mouse model we developed for the study, will allow testing of novel therapeutic strategies for MLL patients. They will also yield information that may be directly translatable into clinical interventions."

Leukemia is the most common blood cancer and includes several diseases, according to the National Cancer Institute. The four major types are acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML).

Mixed lineage leukemia (MLL) results when chromosome mutations involving the MLL gene fuse with certain partner genes. These so-called translocations result in the MLL gene being rearranged to send instructions to create either AML or ALL. This process can start before birth, and while MLL translocations are associated with 7 percent of AML cases and 10 percent of ALL cases, they are found in a majority of infants with acute leukemia. In some instances the clinical disease is diagnosed within a few months of birth.

Dr. Mulloy and his colleagues discovered that disrupting a protein known to regulate cell growth (Rac1) has potential for curbing MLL. The discovery came about as they focused on the most common fusion partner in MLL, a gene called AF9. Previous research showed patients with MLL-AF9 fusions almost exclusively get AML, have an intermediate to poor prognosis, and that leukemia expressing MLL-AF9 is considered a more aggressive disease resistant to chemotherapy.

Although MLL-AF9 fusion is most commonly associated with AML in people, it is occasionally found in ALL as well. Dr. Mulloy's team programmed human umbilical cord blood cells to express MLL-AF9, resulting in diverse leukemia stem cells capable of transforming into either AML or ALL. The researchers influenced the transformation by altering the growth factor proteins that stimulate the differentiation and growth of blood cells, demonstrating how environmental conditions play a critical role in promoting leukemia progression and deciding disease type.

The researchers then built on this finding by adjusting the cell culture microenvironment to transform lymphoid cells into myeloid cells, as well as myeloid cells into lymphoid, highlighting the adaptability of the leukemia stem cell in mixed lineage leukemia.

"Our findings underscored that while some leukemia stem cells in MLL are diverse and able to transform into different lineages, others remain committed to a single disease type," Dr. Mulloy explained. "This information, and our ability to successfully develop human-based MLL models in mice, will be very useful in finding further insights into the early molecular events behind poor prognosis in mixed lineage leukemia."

Researchers also experimented with inducing AML or ALL in mice by using the MLL-AF9-expressing human cord blood cells. Although mouse models have been successful for studying leukemia stem cells in MLL-associated AML, their usefulness is considered limited for modeling the lymphocytic and mixed myeloid/lymphoid forms of the disease. The research team overcame this limitation by transplanting human MLL-AF9-expressing cells into two strains of mice. Both strains were bred for severe immunodeficiency (NS), which allowed human cells to be grafted into the mice. One of the strains also contained three human cytokine proteins that control blood cell formation and promote myeloid cell development (NS-SGM3).

NS-SGM3 mice receiving the MLL-AF9-programmed cells all developed AML (acute myeloid leukemia) in five to seven weeks, even when most of the MLL-AF9-expressing cells were lymphoid. The three cytokines in the mice were able to redirect the leukemia stem cells from lymphoid to myeloid. However, in the NS strain of mice, the same cells led to the development of a mix of ALL, AML and acute bi-phenotypic leukemia (ABL). In ABL, at least 20 percent of the cells have indications of both myeloid and lymphoid disease. These findings further demonstrated the importance of microenvironment in determining the lineage outcome of disease, the researchers said.

Relatively little is known about the important molecular events that are downstream of the MLL fusion gene. Previous research indicates that Rac1 – a protein that helps regulate cell growth – has increased activity in mice with AML expressing MLL-AF9. To test the importance of Rac1's downstream regulatory pathway in human AML expressing MLL-AF9, the research team experimented with a small molecule that inhibits Rac1's activity. They also tested genetic manipulation of Rac. Both interventions prevented MLL-AF9 cell growth and induced programmed cell death (apoptosis), suggesting Rac as a possible therapeutic target in AML involving rearrangement of the MLL gene, according to Dr. Mulloy and his fellow researchers.

"The exquisite sensitivity of the leukemia cells to Rac inhibition indicates that the MLL-AF9-expressing cells have become addicted to this signal, and this pathway is therefore a very good target for future drug development" said Junping Wei, M.D., Ph.D., a researcher at Cincinnati Children's and lead author of the study.

Nick Miller | EurekAlert!
Further information:
http://www.cchmc.org

Further reports about: AML MLL MLL-AF9 MLL-AF9-expressing Mulloy acute aggressive blood leukemia lineage lymphoid myeloid

More articles from Life Sciences:

nachricht NUI Galway highlights reproductive flexibility in hydractinia, a Galway bay jellyfish
24.02.2020 | National University of Ireland Galway

nachricht Shaping the rings of molecules
24.02.2020 | University of Montreal

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A step towards controlling spin-dependent petahertz electronics by material defects

The operational speed of semiconductors in various electronic and optoelectronic devices is limited to several gigahertz (a billion oscillations per second). This constrains the upper limit of the operational speed of computing. Now researchers from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg, Germany, and the Indian Institute of Technology in Bombay have explained how these processes can be sped up through the use of light waves and defected solid materials.

Light waves perform several hundred trillion oscillations per second. Hence, it is natural to envision employing light oscillations to drive the electronic...

Im Focus: Freiburg researcher investigate the origins of surface texture

Most natural and artificial surfaces are rough: metals and even glasses that appear smooth to the naked eye can look like jagged mountain ranges under the microscope. There is currently no uniform theory about the origin of this roughness despite it being observed on all scales, from the atomic to the tectonic. Scientists suspect that the rough surface is formed by irreversible plastic deformation that occurs in many processes of mechanical machining of components such as milling.

Prof. Dr. Lars Pastewka from the Simulation group at the Department of Microsystems Engineering at the University of Freiburg and his team have simulated such...

Im Focus: Skyrmions like it hot: Spin structures are controllable even at high temperatures

Investigation of the temperature dependence of the skyrmion Hall effect reveals further insights into possible new data storage devices

The joint research project of Johannes Gutenberg University Mainz (JGU) and the Massachusetts Institute of Technology (MIT) that had previously demonstrated...

Im Focus: Making the internet more energy efficient through systemic optimization

Researchers at Chalmers University of Technology, Sweden, recently completed a 5-year research project looking at how to make fibre optic communications systems more energy efficient. Among their proposals are smart, error-correcting data chip circuits, which they refined to be 10 times less energy consumptive. The project has yielded several scientific articles, in publications including Nature Communications.

Streaming films and music, scrolling through social media, and using cloud-based storage services are everyday activities now.

Im Focus: New synthesis methods enhance 3D chemical space for drug discovery

After helping develop a new approach for organic synthesis -- carbon-hydrogen functionalization -- scientists at Emory University are now showing how this approach may apply to drug discovery. Nature Catalysis published their most recent work -- a streamlined process for making a three-dimensional scaffold of keen interest to the pharmaceutical industry.

"Our tools open up whole new chemical space for potential drug targets," says Huw Davies, Emory professor of organic chemistry and senior author of the paper.

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

70th Lindau Nobel Laureate Meeting: Around 70 Laureates set to meet with young scientists from approx. 100 countries

12.02.2020 | Event News

11th Advanced Battery Power Conference, March 24-25, 2020 in Münster/Germany

16.01.2020 | Event News

Laser Colloquium Hydrogen LKH2: fast and reliable fuel cell manufacturing

15.01.2020 | Event News

 
Latest News

NUI Galway highlights reproductive flexibility in hydractinia, a Galway bay jellyfish

24.02.2020 | Life Sciences

KIST researchers develop high-capacity EV battery materials that double driving range

24.02.2020 | Materials Sciences

How earthquakes deform gravity

24.02.2020 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>