AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth
V. Lokesh Battula, Phuong M. Le, Jeffrey C. Sun, Khoa Nguyen, Bin Yuan, Ximin Zhou, Sonali Sonnylal, Teresa McQueen, Vivian Ruvolo, Keith A. Michel, Xiaoyang Ling, Rodrigo Jacamo, Elizabeth Shpall, Zhiqiang Wang, Arvind Rao, Gheath Al-Atrash, Marina Konopleva, R. Eric Davis, Melvyn A. Harrington, Catherine W. Cahill, Carlos Bueso-Ramos, Michael Andreeff
V. Lokesh Battula, Phuong M. Le, Jeffrey C. Sun, Khoa Nguyen, Bin Yuan, Ximin Zhou, Sonali Sonnylal, Teresa McQueen, Vivian Ruvolo, Keith A. Michel, Xiaoyang Ling, Rodrigo Jacamo, Elizabeth Shpall, Zhiqiang Wang, Arvind Rao, Gheath Al-Atrash, Marina Konopleva, R. Eric Davis, Melvyn A. Harrington, Catherine W. Cahill, Carlos Bueso-Ramos, Michael Andreeff
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Research Article Bone biology Stem cells

AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth

Abstract

Genotypic and phenotypic alterations in the bone marrow (BM) microenvironment, in particular in osteoprogenitor cells, have been shown to support leukemogenesis. However, it is unclear how leukemia cells alter the BM microenvironment to create a hospitable niche. Here, we report that acute myeloid leukemia (AML) cells, but not normal CD34+ or CD33+ cells, induce osteogenic differentiation in mesenchymal stromal cells (MSCs). In addition, AML cells inhibited adipogenic differentiation of MSCs. Mechanistic studies identified that AML-derived BMPs activate Smad1/5 signaling to induce osteogenic differentiation in MSCs. Gene expression array analysis revealed that AML cells induce connective tissue growth factor (CTGF) expression in BM-MSCs irrespective of AML type. Overexpression of CTGF in a transgenic mouse model greatly enhanced leukemia engraftment in vivo. Together, our data suggest that AML cells induce a preosteoblast-rich niche in the BM that in turn enhances AML expansion.

Authors

V. Lokesh Battula, Phuong M. Le, Jeffrey C. Sun, Khoa Nguyen, Bin Yuan, Ximin Zhou, Sonali Sonnylal, Teresa McQueen, Vivian Ruvolo, Keith A. Michel, Xiaoyang Ling, Rodrigo Jacamo, Elizabeth Shpall, Zhiqiang Wang, Arvind Rao, Gheath Al-Atrash, Marina Konopleva, R. Eric Davis, Melvyn A. Harrington, Catherine W. Cahill, Carlos Bueso-Ramos, Michael Andreeff

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Figure 6

CTGF overexpression facilitates leukemia engraftment.

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CTGF overexpression facilitates leukemia engraftment. (A) MLL-ENL-GFP-Nr...
(A) MLL-ENL-GFP-Nras-FFluci-p53–/– syngeneic mouse AML cells (1 × 105 per mouse) were transplanted intravenously into control (WT C57/B6; n = 3) or Colla2-CTGF–transgenic mice (CTGF tg; n = 3). Leukemic growth was measured by IVIS bioluminescence imaging at 8, 12, and 16 days after AML cell injection. (B) Total photon flux, representing the mean leukemia burden in the mice, was determined. (C) On day 16, peripheral blood mononuclear cells remaining after lysis of red blood cells were analyzed for GFP+ mouse leukemia cells by flow cytometry. (D) Sections of mouse spleen and liver from WT (left) or Col1a2-CTGF–transgenic mice were subjected to H&E staining on day 16 after AML cell transplantation. Scale bar: 200 μm. (E) GFP immunofluorescence staining of spleens from WT mice (left) and Colla2-CTGF–transgenic mice (right) by the anti-GFP antibody on day 16 after AML cell transplantation. Scale bar: 200 μm. (F) Schematic representation of leukemia-stroma interaction in the BM microenvironment. Two-way ANOVA was used to test the data set in B and unpaired Student’s t test was used for the data set in C (** P < 0.01, ***P < 0.001 versus control). In addition, Tukey’s multiple comparison test was also performed for the data set in B.