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.

Public Health Relevance

Acute lymphoblastic leukemia is the most common childhood cancer and the 10th most common adult cancer in the United States. Resistance to chemotherapy and resulting relapse of the disease remains a major problem. This project investigates the bone marrow and leukemia interactions to overcome drug resistance and focus on validating preclinically targeting integrin-mediated adhesion as a new adjuvant therapy in ALL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA172896-01A1
Application #
8579820
Study Section
Special Emphasis Panel (ZRG1-VH-D (02))
Program Officer
Forry, Suzanne L
Project Start
2013-08-01
Project End
2018-05-31
Budget Start
2013-08-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$347,041
Indirect Cost
$132,818
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Gang, E J; Hsieh, Y-T; Pham, J et al. (2014) Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene 33:2169-78
Hsieh, Y T; Gang, E J; Shishido, S N et al. (2014) Effects of the small-molecule inhibitor of integrin ?4, TBC3486, on pre-B-ALL cells. Leukemia 28:2101-4
Ring, Alexander; Kim, Yong-Mi; Kahn, Michael (2014) Wnt/catenin signaling in adult stem cell physiology and disease. Stem Cell Rev 10:512-25
Shishido, Stephanie; Bönig, Halvard; Kim, Yong-Mi (2014) Role of integrin alpha4 in drug resistance of leukemia. Front Oncol 4:99