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 Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex

nachricht New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Graphene assembled film shows higher thermal conductivity than graphite film

22.06.2018 | Materials Sciences

Fast rising bedrock below West Antarctica reveals an extremely fluid Earth mantle

22.06.2018 | Earth Sciences

Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View

22.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>