TGF-β1 and CXCL12 modulate proliferation and chemotherapy sensitivity of acute myeloid leukemia cells co-cultured with multipotent mesenchymal stromal cells.
OBJECTIVES
Multipotent mesenchymal stromal cells (MSCs) play a central role within the bone marrow (BM) niche, supporting hematopoiesis via soluble factors like cytokines and chemokines. In our study, we sought to investigate the effect of blocking transforming growth factor beta 1 (TGF-β1) and C-X-C motif chemokine 12 (CXCL12) receptor CXCR4 on acute myeloid leukemia (AML) cells in an MSC co-culture system.


METHODS
Human MSCs were obtained by BM aspirates and their phenotype and functional properties were confirmed in vitro. Co-cultures of AML cells on MSCs were initiated and compared to those on mouse fibroblasts (MS-5) and liquid cultures. Additionally, the effect of blocking CXCR4 and TGF-β1 on AML cells was tested with and without the addition of cytarabine.


RESULTS
MSCs from BM showed a typical phenotype and differentiation pattern. Co-culture of AML cells on MSCs resulted in a significantly higher proliferation capacity than on MS-5 or liquid culture. Blockade of TGF-β1 increased AML cell proliferation and chemosensibility, while the CXCR4 antagonist plerixafor showed anti-proliferative effects and did not change cytarabine-induced cell death compared to control.


DISCUSSION
Human MSCs are potent feeder cells, able to maintain AML cells in long-term culture. This favorable co-existence seems to be due in part to molecules important for communication within the niche. Blockade of TGF-β1 and CXCL12 was associated with different effects on AML cell proliferation and chemotherapy resistance.


CONCLUSION
These findings suggest a strong supporting affinity between MSCs and AML cells within the leukemic niche, where TGF-β1 and CXCL12 pathways play an important role.
['Schelker|Roland Christian|RC|', 'Iberl|Sabine|S|', 'Müller|Gunnar|G|', 'Hart|Christina|C|', 'Herr|Wolfgang|W|', 'Grassinger|Jochen|J|']
D000328:Adult D000368:Aged D000818:Animals D000964:Antimetabolites, Antineoplastic D015415:Biomarkers D001853:Bone Marrow D001854:Bone Marrow Cells D045744:Cell Line, Tumor D049109:Cell Proliferation D002478:Cells, Cultured D054377:Chemokine CXCL12 D002869:Chromosome Aberrations D018920:Coculture Techniques D003561:Cytarabine D019008:Drug Resistance, Neoplasm D005260:Female D006801:Humans D016130:Immunophenotyping D015470:Leukemia, Myeloid, Acute D008297:Male D059630:Mesenchymal Stem Cells D051379:Mice D008875:Middle Aged D060787:Neoplasm Grading D053773:Transforming Growth Factor beta1
CXCL12 acute myeloid leukemia Multipotent mesenchymal stromal cell transforming growth factor beta 1 CXCR4