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 3

AML cells inhibit adipogenic differentiation in MSCs.

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AML cells inhibit adipogenic differentiation in MSCs. (A) N- and AML-MSC...
(A) N- and AML-MSCs were cultured in adipogenic differentiation medium for 3 weeks. mRNA expression of adipocyte-associated genes, aP2, lipoprotein lipase, and PPARγ, in N- and AML-MSCs before and after induction of differentiation was analyzed weekly by qRT-PCR. (B) N- or AML-MSCs (n = 5 each group) were cultured in adipogenic differentiation medium for 28 days. On day 28, the adipocytes were stained with Oil Red O. Scale bar: 100 μm. (C) Oil Red O–positive cells (i.e., adipocytes) were counted in 10 microscopic fields per sample. (D) N-MSCs were pretreated with OCI-AML3–conditioned medium for 5 days before they were cultured in adipogenic differentiation medium for 7 days. Expression of indicated adipogenic lineage–associated genes before induction of differentiation and on day 7 was analyzed by qRT-PCR. 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 multiple data sets.