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 2

AML cells induce osteogenic differentiation in N-MSCs.

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AML cells induce osteogenic differentiation in N-MSCs. (A) N-MSCs were c...
(A) N-MSCs were cocultured with OCI-AML3 cells (red) or with cord blood–derived CD34+ cells (green) or N-MSCs cultured alone (blue) for 3, 5, or 7 days, and TNAP expression was analyzed by LSR-II flow cytometer (n = 3). Data were analyzed and histograms were generated by FlowJo software. (B) MFI of TNAP expression was quantified in N-MSCs cocultured with cord blood–derived CD34+ cells or OCI-AML3 for 3 or 5 days. (C and D) N-MSCs were cultured with or without OCI-AML3 cell–derived conditioned medium (OCI-AML3-CM) for 5 days before long-term (3 weeks) culture in osteogenic differentiation medium. N-MSCs were subjected to Alizarin Red S staining or ALP staining on days 0 (predifferentiation), 7 (week 1), 14 (week 2), and 21 (week 3) of differentiation. (E) mRNAs from N-MSCs cultured with or without OCI-AML3–conditioned medium were examined for expression of indicated osteolineage-associated genes by qRT-PCR (n = 3). GAPDH served as an equal loading control. Two-way ANOVA was used for comparisons of 3 or more groups and unpaired Student’s t test was used for comparisons of 2 groups (** P < 0.01, ***P < 0.001, ****P < 0.0001 versus control). In addition, Tukey’s multiple comparison test was also performed for the data in B and D.