Bone marrow stroma cells regulate TIEG1 expression in acute lymphoblastic leukemia cells: Role of TGFβ/BMP‐6 and TIEG1 in chemotherapy escape

Abstract

The bone marrow microenvironment regulates early B lymphopoiesis and protects leukemia cells against chemotherapy treatment, thus the microenvironment may serve as a sanctuary site for these cells. Yet, few factors that contribute to this process are known. We have explored the role of transforming growth factor b (TGFb) and bone morphogenetic protein-6 (BMP-6) and one target gene, TGFb inducible early gene 1 (TIEG1), in the communication between stroma cells and acute lymphoblastic leukemia (ALL) cell lines and their escape from chemotherapy. Here, we have demonstrated TIEG1 expression in both normal B progenitor cells and ALL cells, which increased rapidly upon TGFb and BMP-6 treatment. Stimulation with TGFb or BMP-6, as well as overexpression of TIEG1 inhibited proliferation. Furthermore, interaction with stroma cells induced TIEG1 expression in ALL cells, inhibited their proliferation and protected the cells against chemotherapeutic treatment. Similarly, treatment with TGFb or BMP-6, as well as overexpression of TIEG1, protected ALL cells against chemotherapy-induced cell death. These data suggest that TGFb and BMP-6 in the bone marrow microenvironment allow leukemia cells to escape therapy. Further, the data indicate that TIEG1 might be involved in mediating this effect from the microenvironment onto the leukemia cells.

Generation and Characterization of an Immortalized Human Mesenchymal Stromal Cell Line

“…The chondrogenic potential of iMSC#3 appears to be relatively low, but the iMSC#3 cells can stimulate chondrocyte differentiation of primary chondrocytes in cocultures in a similar manner as primary hMSCs [36]. The iMSC#3 cells also have been shown to support the proliferation and development of human B cell precursor cells in a coculture system to an equal or higher extent than primary hMSCs [49]. These other studies thus confirm further the MSC phenotypes of iMSC#3.…”

Hydroxyurea responsiveness in -thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity

“…Kruppel like factor 10 (KLF10) was identified as a protein that protects stromal cells and acute lymphoblastic leukemia blasts against chemotherapy. 46 KLF10 was expressed at elevated levels in R-HEPs compared to NRHEPs, and reached similar levels in both groups upon HU treatment (Online Supplementary Figure S3D). …”

Effect of TIEG1 on apoptosis and expression of Bcl-2/Bax and Pten in leukemic cell lines

“…The expression of TIEG1 was increased in malignant tumor tissues, including breast, pancreatic, and liver cancers, among others (Jiang et al, 2011;Jiang et al, 2012;Jin et al, 2012;Song et al, 2012). Various anticancer drugs that upregulate the expression of TIEG1 to induce cell apoptosis have been used to treat leukemia (Jin et al, 2004;Dosen-Dahl et al, 2008). These results of previous studies indicate that TIEG1 may inhibit cell proliferation and induce cell apoptosis when it is over-expressed; however, this hypothesis requires further study.…”