Title |
Investigating the mechanism of ITGA4/6-mediated chemoprotection of ALL cells
|
Institution |
CHILDREN'S HOSPITAL OF LOS ANGELES, LOS ANGELES, CA
|
Principal Investigator |
Kim, Yong-Mi
|
NCI Program Director |
Suzanne Forry
|
Cancer Activity |
Biochemistry and Pharmacology
|
Division |
DCTD
|
Funded Amount |
$347,041
|
Project Dates |
08/01/2013 - 05/31/2018
|
Fiscal Year |
2013
|
Project Type |
Grant
|
Research Topics w/ Percent Relevance |
Cancer Types w/ Percent Relevance |
Cancer (100.0%)
Chemoprevention (100.0%)
Chemotherapy (100.0%)
Childhood Cancers (100.0%)
|
Childhood Leukemia (100.0%)
Leukemia (100.0%)
|
Research Type |
Chemoprevention
|
Abstract |
DESCRIPTION (provided by applicant): Acute lymphoblastic leukemia is the most common childhood cancer and the 10th most common adult cancer in the United States. Drug resistance remains a major problem in the treatment of acute lymphoblastic leukemia (ALL). The bone marrow (BM) environment, consisting of endosteal and perivascular niches, has been shown to promote cell adhesion-mediated drug resistance (CAM-DR) in leukemia cells. Incomplete response to chemotherapy results in persistence of resistant clones and minimal residual disease (MRD). The exact mechanisms for CAM-DR leading to MRD and approaches to address this problem remain elusive. Integrin ¿4 mediates adhesion of hematopoietic cells onto bone marrow cells and has been implicated in CAM- DR of leukemia cells. We have determined that integrins ¿4 and ¿6 are the most upregulated integrins in pre-B ALL. We hypothesize that ¿4 and ¿6 integrin-mediated adhesion of ALL cells to bone marrow stromal niches contributes to the persistence of MRD. Integrin ¿4 and ¿6 loss-of-function studies in a BCR-ABL1+ pre-B ALL mouse model resulted in loss of adhesion, increased chemo-sensitivity and decreased self-renewal capacity of ALL cells. Using FDA approved Natalizumab as ¿4 blocking antibody, we demonstrated in a xenogeneic ALL model that ¿4-blockade with chemotherapy can eradicate leukemia. Delineating the mechanistic basis for this concept will enable us to validate and further develop this treatment approach towards patient care. |