Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy

Yao Te Hsieh, Eun Ji Gang, Huimin Geng, Eugene Park, Sandra Huantes, Doreen Chudziak, Katrin Dauber, Paul Schaefer, Carlton Scharman, Hiroyuki Shimada, Seyedmehdi Shojaee, Lars Klemm, Reshmi Parameswaran, Mignon Loh, Eun Suk Kang, Hong Hoe Koo, Wolf Karsten Hofmann, Jacob Andrade, Gay M. Crooks, Cheryl L. WillmanMarkus Müschen, Thalia Papayannopoulou, Nora Heisterkamp, Halvard B̈onig, Yong Mi Kim

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1814-1818
Number of pages5
Issue number10
StatePublished - Mar 7 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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