Navigation Links
Microenvironment a main driver of aggressive multi-lineage leukemia disease type
Date:6/9/2008

CINCINNATI 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.


'/>"/>

Contact: Nick Miller
nicholas.miller@cchmc.org
513-803-6035
Cincinnati Children's Hospital Medical Center
Source:Eurekalert

Related medicine news :

1. Human breast tumors microenvironment primes them for metastasis
2. End-to-End HR Performance Benchmarks: Metrics That Will Help Turn the HR Cost Center into a Productivity Driver
3. Coalition to Protect Floridas Drivers Applauds Governor Crist for Adding PIP to Special Session
4. Hospitals and the Coalition to Protect Floridas Drivers Applaud Lawmakers for Reviving No-Fault Insurance
5. Male Drivers are Hitting, Killing Most Child Pedestrians, New Study Shows
6. AUDIO from Medialink and The Hartford: When Alzheimers Puts Drivers at the Crossroads
7. DNA (driver of nicotine addiction)
8. Inverted DNA turns quiet developmental gene into a potent driver of t-cell lymphoma
9. Carnegie Mellon study shows just listening to cell phones significantly impairs drivers
10. Teen Driving Experts at The Childrens Hospital of Philadelphia Support New Recommendations From the New Jersey Teen Driver Study Commission
11. Many Teen Drivers Dont Think Theyre Inexperienced
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/13/2017)... Ky. (PRWEB) , ... October 13, 2017 , ... The ... MPH to become its next President and Chief Executive Officer, succeeding Dr. James C. ... CEO Elect beginning July 1, 2018 until Dr. Puffer’s retirement at the end of ...
(Date:10/13/2017)... ... ... PurhealthRX , a leading Health and Nutrition Company, is announcing the ... spectrum CBD oil will revolutionize the rapidly growing CBD market by reducing the amount ... into liquid products, while reducing costs to end users. , The team of researchers ...
(Date:10/13/2017)... ... 2017 , ... Lori R. Somekh, founder of the Law Office of ... elder law and special needs planning attorneys. “Membership in ElderCounsel helps our office remain ... to network with elder law attorneys nationwide,” said Somekh. , ElderCounsel ...
(Date:10/13/2017)... ... October 13, 2017 , ... Many families have long-term insurance that covers ... companies have a waiver for care if the client has a cognitive impairment diagnosis. ... pays for care, is often waived, so the benefits from their insurance start immediately,” ...
(Date:10/13/2017)... ... October 13, 2017 , ... Ellevate Network, the leading ... to advocate for action towards gender equality at their inaugural Summit in New York ... globe, and reached a social audience of over 3 million. To watch the Mobilize ...
Breaking Medicine News(10 mins):
(Date:9/28/2017)... 28, 2017 Hill-Rom Holdings, Inc. (NYSE: HRC), ... call and webcast on Friday, November 3, 2017, beginning ... ending at approximately 8:30 a.m. (CDT) / 9:30 a.m. ... 2017 financial performance and guidance for 2018, Hill-Rom executives ... enhance operational performance, and long-range financial outlook through 2020. ...
(Date:9/25/2017)... PROVIDENCE, R.I. , Sept. 25, 2017 /PRNewswire/ ... immunogenicity assessment, vaccine design, and immune-engineering today announced ... focused on the development of personalized therapeutic cancer ... and has provided exclusive access to enabling technologies ... MSc Eng., MBA will lead EpiVax Oncology as ...
(Date:9/19/2017)...   ZirMed Inc ., a recognized leader in cloud-based ... has been ranked #1 by its users for the seventh ... User Survey. ZirMed was recognized as the top-ranked end-to-end revenue ... centers over 200 beds and holds one of the longest ... history. ...
Breaking Medicine Technology: