Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies - Current Concepts and Models

Abstract

The bone marrow stroma maintains hematopoiesis and coordinately regulates regenerative responses through dynamic interactions with hematopoietic stem and progenitor cells. Recent studies indicate that stromal components in the bone marrow of leukemia patients undergo a process of successive adaptation that in turn exerts dramatic effects on the hematopoietic stem cell compartment and promotes leukemic drug resistance. Functional changes in discrete marrow stromal populations can therefore be considered an aspect of leukemia biogenesis in that they create an aberrant, self-reinforcing microenvironment. In this review we will describe the current understanding of the remodeling of the hematopoietic stem cell niche following invasion by leukemia cells. We place emphasis on existing evidence of how mesenchymal stem cells and their progeny facilitate neoplastic growth and describe available models and analytical techniques to understand the conversion of the niche toward disease persistence. This article is protected by copyright. All rights reserved.

Niche adaptation is a component of leukemogenesis. A. Cell-cell crosstalk promotes the formation of a pro-leukemic niche whereby intrinsic aberrations can initiate leukemogenesis and drive subsequent microenvironmental remodeling. B. Reactive or primary microenvironmental aberrations such as Dicer^-/- mutations in osteolineage cells can promote neoplastic growth and leukemic evolution. C. Leukemia in the bone marrow remodels the microenvironment into a self-reinforcing niche by establishing reciprocal feedback loops that promote leukemic progression at the expense of normal hematopoiesis. HSC: Hematopoietic Stem Cell; LC: Leukemia Cell; MSC: Mesenchymal Stem Cell; OPC: Osteoblastic Progenitor Cells; EC: Endothelial Cells.

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