Therapeutic targeting of microenvironmental interactions in leukemia: mechanisms and approaches.
In hematological malignancies, there are dynamic interactions between leukemic cells and cells of the bone marrow microenvironment. Specific niches within the bone marrow microenvironment provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. This review focuses on molecular and cellular biology of the normal hematopoietic stem cell and the leukemia stem cell niche, and of the molecular pathways critical for microenvironment/leukemia interactions. The key emerging therapeutic targets include chemokine receptors (CXCR4), adhesion molecules (VLA4 and CD44), and hypoxia-related proteins HIF-1alpha and VEGF. Finally, the genetic and epigenetic abnormalities of leukemia-associated stroma will be discussed. This complex interplay provides a rationale for appropriately tailored molecular therapies targeting not only leukemic cells but also their microenvironment to ensure improved outcomes in leukemia.
Konopleva
Marina
M
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. mkonople@mdanderson.org
Tabe
Yoko
Y
Zeng
Zhihong
Z
Andreeff
Michael
M
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000517:prevention & control
D000970:Antineoplastic Agents