Navigation Links
Key player found for a cancer typical in Down syndrome

Boston, Mass. Between 5 and 10 percent of babies with Down syndrome develop a transient form of leukemia that usually resolves on its own. However, for reasons that haven't been clear, 20 to 30 percent of these babies progress to a more serious leukemia known as Down syndrome acute megakaryoblastic leukemia (DS-AMKL), which affects the blood progenitor cells that form red blood cells and platelets. Now, researchers at Children's Hospital Boston have found a gene regulator they believe to be a key player in DS-AMKL, advancing understanding of how the disease develops and how to treat it.

The study findings, published in the March 1 issue of Genes and Development, may also help in understanding other forms of leukemia, the researchers say.

The gene regulator, miR-125b-2, belongs to a class of molecules known as microRNAs, which silence gene expression by halting the manufacturing of different proteins. While microRNAs are important to normal cell function, unusual amounts of them can lead to disease. "DS-AMKL has a very strong genetic basis," says senior investigator Stuart Orkin, MD, of the Division of Hematology/Oncology at Children's. "However, there aren't that many cancers in which a particular microRNA can be pointed to as contributing."

Because children with Down syndrome have three copies of chromosome 21 rather than the usual two copies, the researchers focused on the five microRNAs produced by this chromosome, and zeroed in on miR-125b-2.

"In human primary DS-AMKL cells, this microRNA is quite dramatically over-expressed," says Zhe Li, PhD, of Children's Division of Hematology/Oncology and first author of the paper. "We then went back and studied how over-expression or downregulation of this microRNA affects the phenotype of leukemia cells."

DS-AMKL is always associated with mutations in the gene GATA1, which helps make and regulate red blood cells and megakaryocytes (the cells that produce platelets). The increased incidence of this leukemia in children with Down syndrome convinced the researchers that a GATA1 mutation may be joining forces with some genetic factor on chromosome 21 specifically, miR-125b-2.

"GATA1 is always mutated, while miR-125b-2 is always over-expressed in leukemic cells," Li says. "Do they cooperate?"

The researchers experimented on genetically engineered mice that specifically expressed the mutant version of GATA1. Cells were taken from the fetal livers of these mice and induced into becoming blood progenitor cells that either made both red blood cells and megakaryocytes (MEP) or only made megakaryocytes (MP). The researchers then used a virus to over-express miR-125b-2 in these cells and compared them to MEP and MP cells without a GATA1 mutation.

Although over-expression of miR-125b-2 caused increased growth and replication of MEP and MP cells with or without the GATA1 mutation, the growth was further enhanced in the presence of the GATA1 mutation. But once the researchers down-regulated this microRNA in DS-AMKL leukemic cells, which have both GATA1 mutation and miR-125b-2 over-expression, the aberrant growth stopped. These observations support the notion that GATA1 mutation and over-expression of miR-125b-2 are both needed for DS-AMKL to develop.

Further tests on these cells suggested that over-expression of miR-125b-2 spurs the leukemia by silencing two genes: one for tumor-suppression, and another for producing other regulatory microRNAs.

Genetic analyses of leukemia cells taken from DS-AMKL patients confirmed the results seen in the mouse models. The next step is for researchers to model DS-AMKL in vivo, using animal cells and, eventually, fetal cells.

Studying leukemia in Down syndrome patients may help scientists understand and treat other forms of the cancer, says Orkin. Past research has shown that other genes on chromosome 21 may be involved in other types of leukemia. "Learning more about the genetics of leukemia will then lead to some thoughts about other ways to interfere with the growth of the cells," Orkin says.


Contact: Rob Graham
Children's Hospital Boston

Related biology news :

1. Little-known protein found to be key player
2. New study finds lowfat chocolate milk is effective post-exercise recovery aid for soccer players
3. New estrogen receptor found to be key player in tamoxifen resistance
4. Frost & Sullivan Recognizes Precise Biometrics as a Key Player in the Non-AFIS Fingerprint Market
5. Vitamin D a key player in overall health of several body organs, says UC Riverside biochemist
6. Black carbon pollution emerges as major player in global warming
7. Scientists discover a new player in innate immune response
8. Rockefeller Foundation supports expansion, training of e-health work force in developing world
9. Lymphoma Research Foundation announces publication of Mantle Cell report
10. Anorexics found to have excess fat-- in their bone marrow
11. Scripps Research scientists find two compounds that lay the foundation for a new class of AIDS drug
Post Your Comments:
(Date:11/18/2015)...  As new scientific discoveries deepen our understanding of ... providers face challenges in better using that knowledge to ... as more children continue to survive pediatric cancer, that ... age. John M. Maris, M.D ., a ... (CHOP) . --> John M. Maris, ...
(Date:11/17/2015)... PARIS , November 17, 2015 ... 17 au 19 novembre  2015.  --> Paris ... 2015.  --> DERMALOG, le leader de l,innovation ... à la fois passeports et empreintes sur la même ... pour les passeports et l,autre pour les empreintes digitales. ...
(Date:11/16/2015)... , Nov 16, 2015  Synaptics Inc. ... human interface solutions, today announced expansion of its ... ™ touch controller and display driver integration ... of smartphones. These new TDDI products add to ... (HD resolution), TD4302 (WQHD resolution), and TD4322 (FHD ...
Breaking Biology News(10 mins):
(Date:12/1/2015)... , Dec. 1, 2015  The Minnesota High ... of the 2015 Tekne Award in the Small and ... at the Minneapolis Convention Center, ... played a significant role in developing new technologies that ... around the world. Clostridium difficile infection ...
(Date:12/1/2015)... ... December 01, 2015 , ... RURO, Inc., ... selling system laboratory animal colony management software solution, ezColony®, is now available as ... IT resources., , Many organizations are moving to cloud-hosting ...
(Date:12/1/2015)... Harry Lander , President of Regen, expands his role to ... and recruits five distinguished scientists to join advisory ... expands his role to include serving as ... scientists to join advisory team --> Dr. Harry Lander ... serving as Chief Science Officer and ...
(Date:11/30/2015)... ... November 30, 2015 , ... ... physicians, aesthetic practitioners and aesthetics professionals from Central America and abroad for the ... in Panama City, Panama Feb. 17-19, 2016. Testart will present and discuss new ...
Breaking Biology Technology: