Team #4: Mouse Models
Studying Therapy-Related Leukemia Using Mouse Models
Team 4 researchers will transplant t-AMLcells from patients into mouse models to isolate stem cells. These stem cells will be used to identify targets for effective through the work of Team 1,Team 2, Team 3, and Team 6. University of Chicago researchers believe that current t-AML treatments are unsuccessful because they fail to kill these leukemia stem cells, which quickly re-establish cancer. By modeling human leukemia in the mouse, the team can use these models to pre-clinically validate new therapies before they are brought to clinical trials (Team 5).
Leukemia stem cells (LSCs) are cells that are capable of regenerating leukemia. Until recently, researchers did not have the appropriate techniques to isolate and study LSCs. Therefore, very little is known about theof these cells and their drug sensitivity. University of Chicago researchers hypothesize that patients with t-AML, as well as the elderly with AML, are resistant to chemotherapy because most drugs attack proliferating cells but fail to kill LSCs.
Although mouse leukemia has provided many insights into the biology of the human disease, it has many drawbacks, especially when predicting therapeutic efficacy of new agents. However, recent scientific advances have enabled researchers to identify and isolate human LSCs following the transplantation of human AMLcells into genetically-altered mice (NOG mice) that cannot reject human cells. Indeed, studies in these NOG mice are allowing researchers to understand and develop new therapies not only for human cancer, but for other devastating diseases.
Team 4 researchers are using NOG mice to model AML. They are transplanting t-AML cells from patients into the mice and isolating the LSCs that grow and give rise to the disease. The isolated cells will be studied in a variety of assays, includingby Team 1 investigators [link to Team 1 page]. Using robotic technology, researchers will also screen the sensitivity of LSCs to a library of chemical compounds, including promising agents identified by Team 3 for the treatment of AML.
In addition, Team 4 will investigate the function ofregulatory networks identified by Team 2 in LSCs. To do this, researchers will perturb the function of key regulatory genes and examine the effect on leukemic cells using inhibitory RNAs (RNAi). These are short molecules that block the production of proteins encoded by specific genes. They will screen thousands of RNAi molecules by introducing them into cells and examining whether they can induce cancer . Genes and their encoded proteins identified in this fashion are potential targets for therapy.
Leukemia stem cells isolated by Team 4 will be used by Teams 1 and 2 to identify aand Team 6 to validate the function of newly-identified gene regulatory networks in the development of AML. By modeling human AML in the mouse, researchers can also validate new therapies (identified by Teams 3 and 4), which is a necessary step for bringing these therapies to clinical trials led by Team 5.
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