Mesenchymal niche: the sensor and effector of leukemogenesis

which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Mesenchymal stromal cells (MSCs) are nonhematopoietic adherent cell populations in the bone marrow (BM) that exhibit multilineage differentiation potential towards diverse types of tissues. These MSCs are widely used for cell-therapy applications to stimulate injured tissues regeneration. The therapeutic effects of MSCs are primarily exerted through their paracrine secretion of various factors that can stimulate the regenerative potential of endogenous stem cells, promote angiogenesis, and inhibit apoptosis [1]. While ex-vivo expanded MSCs have been widely used for cell-therapy trials, the in vivo identity of these MSCs has been suggested to be a subset of pericytes, and they were demonstrated to be able to reconstitute both endosteal and the perivascular niche in heterologous implantation studies [2]. While geographically distinct, the perivascular and endosteal niche in BM exhibit both distinct and common characteristics in cellular entities and cross-talk molecules, comprising primarily of MSCs, endothelial cells, and some cells with neuronal origin [3]. Moreover, recent studies have further identified complex heterogeneity in the cellular entity of the mesenchymal niche. For example, studies have identified early-stage osteoblastic cells expressing runt-related transcription factor 2 (runx2), subsets of MSCs in periva-scular regions expressing nestin and leptin-receptor, and primitive (prx-1+) mesenchymal cells expressing C-X-C motif chemokine 12 (CXCL-12) as key functional cells in the niche. These niche cells express cross-talk molecules such as Jagged-1, CXCL-12, and angiopoietin-1 in order to interact with hematopoietic stem cells (HSCs). Thus, fine orchestration of this microenvironmental cross-talk exerts a key influence on HSCs, controlling their self-renewal, quiescence, and mobilization. While accumulating studies have established the functional impact of the mesenchymal cell niche in regulating normal HSCs, emerging interest is now focusing on its significance for leukemia stem cells (LSCs), the malignant counterpart of normal HSCs. The key question being addressed is whether the niche is affected under leukemic conditions and, in turn, whether the niche executes any functions in the leukemogenic process itself. The possible involvement of the niche in leukemogenesis was first suggested by the observation that LSCs, when transplanted into mice, engraft in BM and competes with normal HSCs [4]. Moreover, leukemia cells transplanted into mice create an abnormal niche in BM to usurp the transplanted normal HSCs into a tumor niche [5], suggesting the functional impact of leukemia cells on the niche. Recently, studies have shown that leukemia cells can …