TY - JOUR
T1 - AML-induced osteogenic differentiation in mesenchymal stromal cells supports leukemia growth
AU - Battula, Venkata Lokesh
AU - Le, Phuong M.
AU - Sun, Jeffrey C.
AU - Nguyen, Khoa
AU - Yuan, Bin
AU - Zhou, Ximin
AU - Sonnylal, Sonali
AU - McQueen, Teresa
AU - Ruvolo, Vivian
AU - Michel, Keith A.
AU - Ling, Xiaoyang
AU - Jacamo, Rodrigo
AU - Shpall, Elizabeth
AU - Wang, Zhiqiang
AU - Rao, Arvind
AU - Al-Atrash, Gheath
AU - Konopleva, Marina
AU - Davis, R. Eric
AU - Harrington, Melvyn A.
AU - Cahill, Catherine W.
AU - Bueso-Ramos, Carlos
AU - Andreeff, Michael
N1 - Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/7/6
Y1 - 2017/7/6
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85042346186
UR - https://www.scopus.com/pages/publications/85042346186#tab=citedBy
U2 - 10.1172/jci.insight.90036
DO - 10.1172/jci.insight.90036
M3 - Article
C2 - 28679949
AN - SCOPUS:85042346186
SN - 2379-3708
VL - 2
JO - JCI Insight
JF - JCI Insight
IS - 13
M1 - e90036
ER -