Objective: The study aimed to compare the biological characteristics of bone marrow mesenchymal cells (MSCs) in patients with Ph-positive acute lymphoblastic leukemia (Ph+ ALL) with different disease states, to identify the differences in cyto-protective effects of MSCs with different disease states on leukemia cells and explore the possible mechanisms.
Methods: Bone marrow samples were collected from patients with Ph+ B-ALL and healthy donors, cultured to obtain primary MSCs, passaged and identified. The proliferation ability of MSCs in vitro and the impact on the migration ability of Ph+ ALL cell line SUP-B15 in each group were tested. MSCs from different groups were co-cultured with SUP-B15, and apoptosis of SUP-B15 cells after treated with drugs (imatinib, dasatinib, dexamethasone) was detected. Transcriptome sequencing was performed on MSC cells from different disease states. RT-PCR method was used to detect the expression level of target gene in MSCs.
Results: (1) Donor (DR) MSCs proliferated more strongly than ALL - MSCs in vitro (P < 0.01). Proliferation ability in vitro of MSCs from relapsed and refractory (RR-MSCs) ALL patients was stronger than that of MSCs from complete remission group (CR-MSCs) and MSCs in newly diagnosed ALL group (ND-MSCs) (P <0.05, P <0.05).
(2) After treatment with the drugs, proportion of apoptosis in SUP-B15 cells was significantly reduced in co-culture group. The protective ability of DR-MSCs and ND-MSCs were more marked than CR-MSCs (P < 0.001, P < 0.05, P < 0.01, P < 0.0001; P < 0.05, P < 0.05, P < 0.05, P < 0.001).(3) GO enrichment analysis of transcriptome sequencing results showed that BMP4 was significantly up-regulated in ND-MSCs compared with DR-MSCs (FC=3.311, P. adj=0.024). The expression levels of BMP4 in ND-MSCs and RR-MSCs were higher than those in DR- MSCs (P<0.05, P<0.01); RR-MSCs showed higher expression levels of BMP4 than CR-MSCs (P<0.05); CR-MSCs showed lower expression levels of BMP6 than ND-MSCs (P<0.05), CR- MSCs BMP6 expression was also lower in ND-CR matched MSCs than ND- MSCs (P<0.05).
Conclusion: Ph + ALL-MSCs showed weaker proliferative ability than DR-MSCs in vitro. MSCs derived from different disease states showed different protective effect of SUP-B15 cells from apoptosis (the protective effect of DR-MSCs and ND-MSCs are stronger than CR-MSCs). This protection was associated with the expression of genes involved in the BMP/SMADs signaling pathway.
No relevant conflicts of interest to declare.
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