Osteoblasts Protect AML Cells From SDF‐1‐Induced Apoptosis

Abstract

The bone marrow provides a protective environment for acute myeloid leukemia (AML) cells that often allows leukemic stem cells to survive standard chemotherapeutic regimens. Targeting these leukemic stem cells within the bone marrow is critical for preventing relapse. We recently demonstrated that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis in AML cell lines and in patient samples expressing high levels of its receptor, CXCR4. Here we show that a subset of osteoblast lineage cells within the bone marrow can protect AML cells from undergoing apoptosis in response to the SDF-1 naturally present in that location. In co-culture systems, osteoblasts at various stages of differentiation protected AML cell lines and patient isolates from SDF-1-induced apoptosis. The differentiation of the osteoblast cell lines, MC3T3 and W-20-17, mediated this protection via a cell contact-independent mechanism. In contrast, bone marrow-derived mesenchymal cells, the precursors of osteoblasts, induced apoptosis in AML cells via a CXCR4-dependent mechanism and failed to protect AML cells from exogenously added SDF-1. These results indicate that osteoblasts in the process of differentiation potently inhibit the SDF-1-driven apoptotic pathway of CXCR4-expressing AML cells residing in the bone marrow. Drugs targeting this protective mechanism could potentially provide a new approach to treating AML by enhancing the SDF-1-induced apoptosis of AML cells residing within the bone marrow microenvironment.

Histone Deacetylase Inhibitors Target the Leukemic Microenvironment by Enhancing a Nherf1-Protein Phosphatase 1α-TAZ Signaling Pathway in Osteoblasts

“…Cells-After informed consent was obtained on an IRB approved protocol, samples of bone marrow were harvested from AML patients prior to chemotherapy and utilized in cocultures as described (8). MC3T3 sc4 murine calvarial osteoblasts (30) (ATCC) were cultured and differentiated as described (8).…”

“…The endosteum, the tissue between the bone marrow and ossified surface, has been particularly implicated as a protective niche because AML stem cells are localized to this region following chemotherapeutics (6,7). Within the endosteal niche, cells of the osteoblast (bone-generating) lineage have been identified as critical mediators of AML cell survival in the bone marrow (4,8). Transgenic mice expressing activated ␤-catenin specifically in osteoblasts develop myeloid malignancy, consistent with the idea that osteoblasts promote this disease (9).…”

“…Here, we investigated how to prevent this protective interaction. We previously showed that SDF-1, a chemokine abundant in the bone marrow, induces apoptosis of AML cells, unless the leukemic cells receive protective signals provided by differentiating osteoblasts (8,10). We now identify a novel signaling pathway in differentiating osteoblasts that can be manipulated to disrupt the osteoblast-mediated protection of AML cells.…”

“…This lack of knowledge prevents effective therapeutic manipulation of the bone marrow microenvironment as a way to enhance targeting of AML cells within the bone marrow. We previously reported that SDF-1, a chemokine abundantly secreted by multiple cell types within the bone marrow, induces apoptosis of AML cell lines and patient isolates that express high levels of its receptor CXCR4 (8,10). Because AML cells thrive in the bone marrow, this apparent contradiction indicated that a cell type within the bone marrow must provide signals that protect AML cells from SDF-1-induced apoptosis.…”

“…Because AML cells thrive in the bone marrow, this apparent contradiction indicated that a cell type within the bone marrow must provide signals that protect AML cells from SDF-1-induced apoptosis. Utilizing co-culture systems, we previously demonstrated that co-culturing differentiating osteoblasts, but not earlier precursors of the osteoblast lineage, with the AML cells completely abrogated SDF-1-induced apoptosis of the AML cells (8). These results prompted us to utilize this co-culture system to identify strategies to inhibit osteoblast-mediated protection of AML cells.…”