Study on the bone marrow mesenchymal stem cells induced drug resistance in the U937 cells and its mechanism.
BACKGROUND
The hematopoietic microenvironment (HM) plays a critical role in malignant cell growth, patient survival, and response to chemotherapy in hematologic malignancies. However, mechanisms associated with this environmental influence remain unclear. In this study, we investigated the role of bone marrow derived mesenchymal stem cells (MSCs) in U937 cell line, to find out the relations between leukemia drug resistance and the MSCs.


METHODS
U937 cells were cultured in suspension or grew adherently with MSCs. The cell growth curve was drawn and the cell cycle was measured by flow cytometry. Apoptosis and sensitivity of U937 to daunoblastina (DNR) were quantified by DNA ladder detection and trypan blue exclusion assays, respectively. The gene expression profile chip technology was used to determine and analyze the changes in apoptosis-related gene expression after adherent culture and the expression of MDR1 mRNA was assessed by reverse transcriptional polymerase chain reaction (RT-PCR) at the same time.


RESULTS
In the adherent culture, the proliferation of the U937 cells was inhibited, the G0/G1 phase cells increased (F = 64.9726, P < 0.0001), G2/M phase cells were decreased (F = 98.1361, P < 0.0001) and the natural apoptosis rate was decreased (F = 24.0866, P < 0.0001) compared with those in the suspended culture. U937 cell viability was enhanced and cell apoptosis was blocked during DNR treatment in adherent culture with MSCs. Thirty-nine differently expressed genes were screened from the 487 apoptosis related genes in the adherent culture U937 cells. Among the 37 upregulated genes, Bcl-XL was upregulated most significantly. Two genes were downregulated. Adherent culture did not induce MDR1 mRNA expression in U937 cells.


CONCLUSIONS
MSCs play a role in modulating the proliferation of U937 cells and response of U937 cells to DNR, and Bcl-XL apoptosis-inhibiting gene may be most important in determining the sensitivity of leukemic cells to treatment, which is not related to MDR1.
Lin
Yu-mei
YM
Department of Hematology and Oncology China-Japan United Hospital of Jilin University, Changchun 130031, China.
Zhang
Gui-zhen
GZ
Leng
Zong-xiang
ZX
Lu
Zhen-xia
ZX
Bu
Li-sha
LS
Gao
Shen
S
Yang
Shao-juan
SJ
D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000502:physiology*; D049109:Cell Proliferation; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D019450:Genes, MDR; D006801:Humans; D016130:Immunophenotyping; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D020298:U937 Cells / Q000187:drug effects*
D003630:Daunorubicin