Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance

Jácamo, Rodrigo; Chen, Ye; Wang, Zhiqiang; Ma, Wencai; Zhang, Min; Spaeth, Erika L.; Wang, Ying; Battula, Venkata Lokesh; Mak, Po Yee; Schallmoser, Katharina; Ruvolo, Peter P.; Schober, Wendy; Shpall, Elizabeth J.; Nguyen, Martin; Strunk, Dirk; Bueso‐Ramos, Carlos E.; Konoplev, Sergej; Davis, R. Eric; Konopleva, Marina; Andreeff, Michael

doi:10.1182/blood-2013-06-511527

Cited by 241 publications

(230 citation statements)

References 44 publications

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“…There is a large body of evidence indicating that the AML cell genotype underlies observed variations in the response of patients to chemotherapy; it is therefore not surprising that leukemia cells can modify their BM microenvironment, and thus "educate it" to promote leukemia progression. We have previously demonstrated that reciprocal interactions between the BM microenvironment and AML cells can modify the BM-MSC transcriptome promoting resistance to chemotherapy via processes involving cell-to-cell and cell/matrix interactions, as well as paracrine and autocrine signaling [1]. Similarly, several reports have described critical molecular changes in the stroma of solid tumors [2][3][4] and more recently; it has been shown in colorectal cancer (CRC) that genes expressed by stromal cells are better predictors of response to therapy and disease prognosis than genes expressed by epithelial tumor cells [4].…”

Section: Introductionmentioning

confidence: 99%

Untitled

2017

Oncotarget

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The genetic heterogeneity of acute myeloid leukemia (AML) and the variable responses of individual patients to therapy suggest that different AML genotypes may influence the bone marrow (BM) microenvironment in different ways. We performed gene expression profiling of bone marrow mesenchymal stromal cells (BM-MSC) isolated from normal C57BL/6 mice or mice inoculated with syngeneic murine leukemia cells carrying different human AML genotypes, developed in mice with Trp53 wild-type or null genetic backgrounds. We identified a set of genes whose expression in BM-MSC was modulated by all four AML genotypes tested. In addition, there were sets of differentially-expressed genes in AML-exposed BM-MSC that were unique to the particular AML genotype or Trp53 status. Our findings support the hypothesis that leukemia cells alter the transcriptome of surrounding BM stromal cells, in both common and genotype-specific ways. These changes are likely to be advantageous to AML cells, affecting disease progression and response to chemotherapy, and suggest opportunities for stroma-targeting therapy, including those based on AML genotype.

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Section: Introductionmentioning

confidence: 99%

Untitled

2017

Oncotarget

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“…133 Reciprocal activation of NF-kB signaling via VCAM-1/very late antigen 4 (VLA-4) interaction occurs in BMSCs and AML cells, and blockade of stromal NF-kB signaling can sensitize AML cells to chemotherapy. 134 Likewise, leukemic and stromal cell interaction via VLA-4 and fibronectin interferes with druginduced apoptosis. Combined treatment of cocultures with VLA-4-specific antibodies and cytarabine improves survival, and patients with VLA-4-negative AML have a favorable prognosis.…”

Section: The Niche In Response To Chemotherapymentioning

confidence: 99%

Myeloid malignancies and the microenvironment

Korn

Méndez-Ferrer

2017

Blood

140

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Research in the last few years has revealed a sophisticated interaction network between multiple bone marrow cells that regulate different hematopoietic stem cell (HSC) properties such as proliferation, differentiation, localization, and self-renewal during homeostasis. These mechanisms are essential to keep the physiological HSC numbers in check and interfere with malignant progression. In addition to the identification of multiple mutations and chromosomal aberrations driving the progression of myeloid malignancies, alterations in the niche compartment recently gained attention for contributing to disease progression. Leukemic cells can remodel the niche into a permissive environment favoring leukemic stem cell expansion over normal HSC maintenance, and evidence is accumulating that certain niche alterations can even induce leukemic transformation. Relapse after chemotherapy is still a major challenge during treatment of myeloid malignancies, and cure is only rarely achieved. Recent progress in understanding the niche-imposed chemoresistance mechanisms will likely contribute to the improvement of current therapeutic strategies. This article discusses the role of different niche cells and their stage- and disease-specific roles during progression of myeloid malignancies and in response to chemotherapy.

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“…Due to this effect, elderly leukemia patients have relatively few BM adipocytes, which tend to increase with age. Additionally, a growing body of evidence indicates that leukemia cells can regulate their microenvironment to increase their chances of proliferation and survival [10,11]. Therefore, the mechanisms used by leukemic cells to inhibit the differentiation of BM-MSCs into adipocytes could prove useful for HSC engrafts during the transplantation process.…”

Section: Introductionmentioning

confidence: 99%