Migration arrest of chemoresistant leukemia cells mediated by MRTF-SRF pathway

Maho Morimatsu; Erika Yamashita; Shigeto Seno; Takao Sudo; Junichi Kikuta; Hiroki Mizuno; Daisuke Okuzaki; Daisuke Motooka; Masaru Ishii

doi:10.1186/s41232-020-00127-6

Migration arrest of chemoresistant leukemia cells mediated by MRTF-SRF pathway

Inflamm Regen. 2020 Jul 6:40:15. doi: 10.1186/s41232-020-00127-6. eCollection 2020.

Authors

Maho Morimatsu¹, Erika Yamashita^{1

2

3}, Shigeto Seno⁴, Takao Sudo^{1

2

3}, Junichi Kikuta^{1

2

3}, Hiroki Mizuno^{1

2}, Daisuke Okuzaki^{2

5}, Daisuke Motooka⁵, Masaru Ishii^{1

2

3}

Affiliations

¹ Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan.
² WPI-Immunology Frontier Research Center, Osaka University, Osaka, Japan.
³ Laboratory of Bioimaging and Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
⁴ Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Osaka, Japan.
⁵ Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.

Abstract

Background: Dormant chemotherapy-resistant leukemia cells can survive for an extended period before relapse. Nevertheless, the mechanisms underlying the development of chemoresistance in vivo remain unclear.

Methods: Using intravital bone imaging, we characterized the behavior of murine acute myeloid leukemia (AML) cells (C1498) in the bone marrow before and after chemotherapy with cytarabine.

Results: Proliferative C1498 cells exhibited high motility in the bone marrow. Cytarabine treatment impaired the motility of residual C1498 cells. However, C1498 cells regained their migration potential after relapse. RNA sequencing revealed that cytarabine treatment promoted MRTF-SRF pathway activation. MRTF inhibition using CCG-203971 augmented the anti-tumor effects of chemotherapy in our AML mouse model, as well as suppressed the migration of chemoresistant C1498 cells.

Conclusions: These results provide novel insight into the role of cell migration arrest on the development of chemoresistance in AML, as well as provide a strong rationale for the modulation of cellular motility as a therapeutic target for refractory AML.

Keywords: Bone marrow; Cancer therapy; Cell migration; Cell motility; Chemoresistance; In vivo imaging; Leukemia; Microscopic imaging; Serum response factor (SRF).