Abstract
The interaction between leukemia cells and the bone microenvironment is known to provide drug resistance in leukemia cells. This phenomenon, called cell adhesion-mediated drug resistance (CAM-DR), has been demonstrated in many subsets of leukemia including B- and T-acute lymphoblastic leukemia (B- and T-ALL) and acute myeloid leukemia (AML). Cell adhesion molecules (CAMs) are surface molecules that allow cell–cell or cell–extracellular matrix (ECM) adhesion. CAMs not only recognize ligands for binding but also initiate the intracellular signaling pathways that are associated with cell proliferation, survival, and drug resistance upon binding to their ligands. Cadherins, selectins, and integrins are well-known cell adhesion molecules that allow binding to neighboring cells, ECM proteins, and soluble factors. The expression of cadherin, selectin, and integrin correlates with the increased drug resistance of leukemia cells. This paper will review the role of cadherins, selectins, and integrins in CAM-DR and the results of clinical trials targeting these molecules.
Highlights
Despite the improved overall survival of leukemia patients, relapsed and refractory leukemia still remain a problem
Evaluation of GMI-1271 treatment combined with mitoxantrone, etoposide, cytarabine and idarubicin in acute myeloid leukemia (AML) patients Efficacy of uproleselan (GMI–1271) in combination with mitoxantrone etoposide and cytarabine (MEC), or fludarabine, cytarabine and idarubicin (FAI) in relapsed/refractory AML patients Evaluation of uproleselan combined with cytarabine or daunorubicin in older AML patients receiving intensive induction chemotherapy
GMI1271 will be administered in combination with existing chemotherapies, which highlights how targeting both the microenvironment and leukemia cells may be necessary in order to ameliorate cell adhesionmediated drug resistance (CAM-DR)
Summary
Despite the improved overall survival of leukemia patients, relapsed and refractory leukemia still remain a problem. Leukemia cells can aberrantly express CAM to facilitate surface molecule-mediated interaction with BM microenvironment, thereby inducing cell-adhesion mediated drug resistance (CAM-DR). Stromal cells upregulate VE-cadherin expression in BCR-ABL+ leukemia cell lines (K562 and SUP-B15) and increase resistance to imatinib by stabilizing b-catenin [95].
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