TY - JOUR
T1 - Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy
AU - Hsieh, Yao Te
AU - Gang, Eun Ji
AU - Geng, Huimin
AU - Park, Eugene
AU - Huantes, Sandra
AU - Chudziak, Doreen
AU - Dauber, Katrin
AU - Schaefer, Paul
AU - Scharman, Carlton
AU - Shimada, Hiroyuki
AU - Shojaee, Seyedmehdi
AU - Klemm, Lars
AU - Parameswaran, Reshmi
AU - Loh, Mignon
AU - Kang, Eun Suk
AU - Koo, Hong Hoe
AU - Hofmann, Wolf Karsten
AU - Andrade, Jacob
AU - Crooks, Gay M.
AU - Willman, Cheryl L.
AU - Müschen, Markus
AU - Papayannopoulou, Thalia
AU - Heisterkamp, Nora
AU - B̈onig, Halvard
AU - Kim, Yong Mi
PY - 2013/3/7
Y1 - 2013/3/7
N2 - Bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells, contributing to lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates stromal adhesion of normal and malignant B-cell precursors, and according to gene expression analyses from207 childrenwithminimal residual disease, is highly associatedwith poorest outcome. We tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment. Twomodels of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 [p2+01] leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary ALL). Conditional deletion of alpha4 sensitized leukemia cell tonilotinib.Adhesionof primarypre-BALLcellswasalpha4-dependent;alpha4 blockade sensitized primaryALLcells toward chemotherapy.Chemotherapy combinedwith Natalizumab prolonged survival of NOD/SCID recipients of primary ALL, suggesting adjuvant alpha4 inhibition as a novel strategy forpre-B ALL.
AB - Bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells, contributing to lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates stromal adhesion of normal and malignant B-cell precursors, and according to gene expression analyses from207 childrenwithminimal residual disease, is highly associatedwith poorest outcome. We tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment. Twomodels of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 [p2+01] leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary ALL). Conditional deletion of alpha4 sensitized leukemia cell tonilotinib.Adhesionof primarypre-BALLcellswasalpha4-dependent;alpha4 blockade sensitized primaryALLcells toward chemotherapy.Chemotherapy combinedwith Natalizumab prolonged survival of NOD/SCID recipients of primary ALL, suggesting adjuvant alpha4 inhibition as a novel strategy forpre-B ALL.
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U2 - 10.1182/blood-2012-01-406272
DO - 10.1182/blood-2012-01-406272
M3 - Article
C2 - 23319569
AN - SCOPUS:84875677396
SN - 0006-4971
VL - 121
SP - 1814
EP - 1818
JO - Blood
JF - Blood
IS - 10
ER -