CXCR4 Chemokine Receptor Signaling Induces Apoptosis in Acute Myeloid Leukemia Cells via Regulation of the Bcl-2 Family Members Bcl-XL, Noxa, and Bak

Kremer, Kimberly N.; Peterson, Kevin; Schneider, Paula A.; Meng, Xue; Dai, Haiming; Hess, Allan D.; Smith, B. Douglas; Rodriguez-Ramirez, Christie; Karp, Judith E.; Kaufmann, Scott H.; Hedin, Karen E.

doi:10.1074/jbc.m113.449926

Cited by 61 publications

(78 citation statements)

References 68 publications

(49 reference statements)

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“…The human bone marrowderived tert-immortalized bone marrow stromal cell line (t-BMSC) (31) was a gift from Dario Campana (St. Jude, Memphis, TN) and was maintained as described (8). The CXCR4-expressing KG1a cells (KG1a-CXCR4) were generated via transient transfection of a plasmid encoding a CXCR4-YFP fluorescent fusion protein (32) into the AML cell line KG1a (ATCC), as previously described (10).…”

Section: Methodsmentioning

confidence: 99%

“…We previously demonstrated that AML patient isolates and cell lines expressing high levels of CXCR4 underwent apoptosis in response to treatment with SDF-1 (10). Preliminary studies conducted predominantly in AML cell lines also suggested that osteoblasts protect AML cells expressing high levels of CXCR4 from this SDF-1-induced apoptosis (8).…”

Section: Osteoblasts Protect Aml Isolates From Apoptosis In a Co-cultmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 98%

“…This model (8,10) utilizes the previously described differentiating MC3T3 osteoblasts, which can be pharmacologically or genetically altered to characterize the cellular mechanisms mediating protection of AML cells. Additionally, this model utilizes the human KG1a AML cell line transiently transfected with CXCR4-YFP (KG1a-CXCR4 cells), which mimics primary AML patient isolates that express cell-surface CXCR4 and respond to SDF-1 by undergoing apoptosis.…”

Section: Osteoblasts Protect Aml Isolates From Apoptosis In a Co-cultmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Kremer

Dudakovic

Hess

et al. 2015

Journal of Biological Chemistry

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Disrupting the protective signals provided by the bone marrow microenvironment will be critical for more effective combination drug therapies for acute myeloid leukemia (AML). Cells of the osteoblast lineage that reside in the endosteal niche have been implicated in promoting survival of AML cells. 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. Treating differentiating osteoblasts with histone deacetylase inhibitors (HDACi) abrogated their ability to protect co-cultured AML cells from SDF-1-induced apoptosis. HDACi prominently upregulated expression of the Nherf1 scaffold protein, which played a major role in preventing osteoblast-mediated protection of AML cells. Protein phosphatase-1␣ (PP1␣) was identified as a novel Nherf1 interacting protein that acts as the downstream mediator of this response by promoting nuclear localization of the TAZ transcriptional modulator. Moreover, independent activation of either PP1␣ or TAZ was sufficient to prevent osteoblast-mediated protection of AML cells even in the absence of HDACi. Together, these results indicate that HDACi target the AML microenvironment by enhancing activation of the Nherf1-PP1␣-TAZ pathway in osteoblasts. Selective drug targeting of this osteoblast signaling pathway may improve treatments of AML by rendering leukemic cells in the bone marrow more susceptible to apoptosis.For decades, research into drug treatments for acute myeloid leukemia (AML) 2 has focused on directly targeting AML cells for destruction. Even though complete remission rates have improved, relapse remains a problem in the majority of patients with this disease. The bone marrow microenvironment has gained attention as a protective environment that promotes survival of AML stem cells, despite the killing of the majority of AML cells by standard chemotherapeutics (1-5). 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). Unfortunately, the molecular mechanisms responsible for osteoblast-mediated protection of AML cells are incompletely understood. 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...

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Section: Methodsmentioning

confidence: 99%

Section: Osteoblasts Protect Aml Isolates From Apoptosis In a Co-cultmentioning

confidence: 99%

mentioning

confidence: 98%

Section: Osteoblasts Protect Aml Isolates From Apoptosis In a Co-cultmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Kremer

Dudakovic

Hess

et al. 2015

Journal of Biological Chemistry

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Functional Tumor Targeting Nano‐Systems for Reprogramming Circulating Tumor Cells with In Situ Evaluation on Therapeutic Efficiency at the Single‐Cell Level

Ren

et al. 2022

Advanced Science

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Tumor heterogeneity is primarily responsible for treatment resistance and cancer relapses. Being critically important to address this issue, the timely evaluation of the appropriateness of therapeutic actions at the single-cell level is still facing challenges. By using multi-functionalized nano-systems with the delivery vector composed of histone for plasmids loading, hyaluronic acid for tumor targeting, and a fusion peptide for C-X-C motif chemokine receptor 4 (CXCR4) targeting as well as nuclear localization, the reprogramming of circulating tumor cells (CTCs) with in situ detection on biomarkers at the single-cell level is realized. By efficient co-delivery of the genome editing plasmid for CXCR4 knockout and molecular beacons for detection of upregulated mRNA biomarkers into CTCs in unprocessed whole blood, the therapeutic outcomes of genome editing at the single-cell level can be in situ evaluated. The single-cell analysis shows that CXCR4 in CTCs of cancer patients is efficiently downregulated, resulting in upregulated anticancer biomarkers such as p53 and p21. The study provides a facile strategy for in-depth profiling of cancer cell responses to therapeutic actions at single-cell resolution to evaluate the outcomes of treatments timely and conveniently.

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Osteoblasts Protect AML Cells From SDF‐1‐Induced Apoptosis

Kremer

Dudakovic

McGee‐Lawrence

et al. 2014

J of Cellular Biochemistry

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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.

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CXCR4 Chemokine Receptor Signaling Induces Apoptosis in Acute Myeloid Leukemia Cells via Regulation of the Bcl-2 Family Members Bcl-XL, Noxa, and Bak

Cited by 61 publications

References 68 publications

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

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

Functional Tumor Targeting Nano‐Systems for Reprogramming Circulating Tumor Cells with In Situ Evaluation on Therapeutic Efficiency at the Single‐Cell Level

Osteoblasts Protect AML Cells From SDF‐1‐Induced Apoptosis

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