Therapeutic targeting of microenvironmental interactions in leukemia: Mechanisms and approaches

Konopleva, Marina; Tabe, Yoko; Zeng, Zhihong; Andreeff, Michael

doi:10.1016/j.drup.2009.06.001

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Volume 12, Issue 4 , Pages 103-113, August 2009

Therapeutic targeting of microenvironmental interactions in leukemia: Mechanisms and approaches

Marina Konopleva
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States
- Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States
- Corresponding author at: Department of Leukemia, Unit 428, M.D. Anderson Cancer Center, Holcombe blvd 1515, Houston, TX 77030, United States. Tel.: +1 713 794 1628; fax: +1 713 745 5372.
Yoko Tabe
- Department of Clinical Pathology, Juntendo University School of Medicine, Tokyo, Japan
Zhihong Zeng
- Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States
Michael Andreeff
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States
- Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States

Received 16 June 2009; received in revised form 29 June 2009; accepted 29 June 2009. published online 27 July 2009.

Abstract

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-1α 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.

Keywords: Bone marrow microenvironment, Leukemia, Molecular targeted therapy, CXCR4, AMD3100, Stem cell niche, Drug resistance