Abstract
Toll-like receptor 4 (TLR4) is a pattern-recognizing receptor that can bind exogenous and endogenous ligands. It is expressed by acute myeloid leukemia (AML) cells, several bone marrow stromal cells, and nonleukemic cells involved in inflammation. TLR4 can bind a wide range of endogenous ligands that are present in the bone marrow microenvironment. Furthermore, the TLR4-expressing nonleukemic bone marrow cells include various mesenchymal cells, endothelial cells, differentiated myeloid cells, and inflammatory/immunocompetent cells. Osteoblasts are important stem cell supporting cells localized to the stem cell niches, and they support the proliferation and survival of primary AML cells. These supporting effects are mediated by the bidirectional crosstalk between AML cells and supportive osteoblasts through the local cytokine network. Finally, TLR4 is also important for the defense against complicating infections in neutropenic patients, and it seems to be involved in the regulation of inflammatory and immunological reactions in patients treated with allogeneic stem cell transplantation. Thus, TLR4 has direct effects on primary AML cells, and it has indirect effects on the leukemic cells through modulation of their supporting neighboring bone marrow stromal cells (i.e., modulation of stem cell niches, regulation of angiogenesis). Furthermore, in allotransplant recipients TLR4 can modulate inflammatory and potentially antileukemic immune reactivity. The use of TLR4 targeting as an antileukemic treatment will therefore depend both on the biology of the AML cells, the biological context of the AML cells, aging effects reflected both in the AML and the stromal cells and the additional antileukemic treatment combined with HSP90 inhibition.
Highlights
Bone marrow stromal cells constitute an interacting hematopoiesis-supporting network
In a recent proteomic study, we investigated the effect of the constitutive acute myeloid leukemia (AML) cell release of soluble mediators on the proteomic profile of normal mesenchymal stem cells (MSCs) [35]
The downstream signaling of both the IL1 receptor and Toll-like receptor 4 (TLR4) is mediated through Myeloid differentiation primary response 88 (MyD88)/IRAK1 [120,121,122], and recent studies suggest that signaling through this pathway in primary AML cells is important for leukemic cell growth and survival [121,123] and for the AML-supporting effects in the stem cell niches that are formed by bone marrow stromal cells [124,125]
Summary
Bone marrow stromal cells constitute an interacting hematopoiesis-supporting network Several of these cells are important members of the stem cell niches [1,2]. Osteoblasts [3], mesenchymal stem cells [4,5] and endothelial cells [6] even support leukemic hematopoiesis, including the development of acute myeloid leukemia (AML). TLR4 is expressed by primary human AML cells as well as other AML supporting bone marrow stromal cells and osteoblasts. TLR4 is expressed by hematopoietic stem cells as well as myeloid progenitors and mature neutrophils/monocytes/macrophages [9,10,11] It is involved in the development of lymphoid cells [12], and it is expressed by various stromal cells [8]. TLR4 targeting will probably have both direct and indirect effects on leukemic hematopoiesis [8,14,16]
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