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.

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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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VH-D (02))
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Forry, Suzanne L
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Children's Hospital of Los Angeles
Los Angeles
United States
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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