Drug Resistance in Primary Leukemia Due to Nanotube Signaling with Mesenchymal Stromal Cells

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Disruption of tunneling nanotubules reduces the survival benefit that mesenchymal cells provide to primary ALL.
Disruption of tunneling nanotubules reduces the survival benefit that mesenchymal cells provide to primary ALL.

SAN FRANCISCO—The disruption of tunneling nanotubules inhibits the release of cytokines, reduces the survival benefit that mesenchymal cells provide to primary acute lymphoblastic leukemia (ALL) cells, and sensitizes ALL cells to prednisolone, a study (Abstract 64) presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition has shown.

Signaling between ALL cells and the bone marrow microenvironment is essential for the nurturing and protection that the bone marrow niche provides to the ALL cells; however, researchers lack understanding of the mechanisms that regulate and control this signaling.

Recently, tunneling nanotubes have been identified as a mode of communication between eukaryotic cells, so researchers from Erasmus MC – Sophia Children's Hospital in Rotterdam, Netherlands, and Princess Maxima Center for Pediatric Oncology in Utrecht, Netherlands, sought to investigate the presence and role of tunneling nanotubes in the setting of ALL.

Results of the study show that tunneling nanotube signaling occurs between primary patient-derived ALL cells and primary mesenchymal stromal cells (MSCs).

By using flow cytometry and time-lapse confocal microscopy, the researchers found that the nanotubes formed rapidly from the start of co-culture and transferred lipophilic carbocyanine dye Dil from ALL cells to MSCs. When tunneling nanotube signaling was inhibited, dye transfer was significantly reduced.

In addition, tunneling nanotubes were found to change their bone marrow microenvironment by instructing non-malignant MSCs to produce cytokines that promote survival. Inhibition of the tunneling nanotubes significantly reduced cytokine production (P≤0.001).

Tunneling nanotube signaling was also found to be necessary for ALL cell survival and stroma-driven drug resistance.

“Tunneling nanotube signaling is important for survival benefit of primary BCP-ALL cells in co-culture,” Bob De Rooij, MSc, of Erasmus MC – Sophia Children's Hospital said while presenting at the meeting. Inhibition of tunneling nanotube signaling decreased the survival of ALL cells in co-culture with MSCs while being exposed to prednisolone (P≤0.01).

Co-culture of the B-cell precursor ALL cell line NALM6 with primary MSCs resulted in 2.5-fold resistance to prednisolone compared with mono-culture. “This shows that drug resistance is largely regulated by tunneleing nanotube signaling,” De Rooji said.


  1. Polak, Roel, MD, et al. "64 Primary Acute Lymphoblastic Leukemia Cells Create a Drug-Resistant Niche By Tunneling Nanotube Signaling with Mesenchymal Stromal Cells." ASH 2014. Oral Presentation. December 7, 2014.

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