ROS-Induced CXCR4 Signaling Regulates Mantle Cell Lymphoma (MCL) Cell Survival and Drug Resistance in the Bone Marrow Microenvironment via Autophagy.
OBJECTIVE
Patients with advanced stages of mantle cell lymphoma (MCL) have a poor prognosis after standard therapies. MCL cells in those patients often spread into tissues other than lymph nodes, such as the bone marrow. Apart from directed migration and homing, there is little understanding of the function of the CXCR4/SDF-1 signaling axis in MCL. In this report, we aim to understand mechanisms of MCL cell survival in the bone marrow.


METHODS
For comprehensive analyses of MCL interactions with bone marrow stromal cells, we have generated gene knockout cells using CRISPR-CAS9 system and gene knockdown cells to reveal novel roles of the CXCR4/SDF-1 signaling.


RESULTS
CXCR4 silencing in MCL cells led to a significant reduction in proliferation, cell adhesion to bone marrow stromal cells, and colony formation in PHA-LCM methylcellulose medium, which were reversed upon the addition of SDF-1-neutralizing antibodies. In addition, tracking MCL cell engraftment in vivo revealed that quiescent MCL cells are significantly reduced in the bone marrow upon CXCR4 silencing, indicating that CXCR4/SDF-1 signaling is required for the survival and maintenance of the quiescent MCL cells. Further analysis revealed novel mechanisms of ROS-induced CXCR4/SDF-1 signaling that stimulate autophagy formation in MCL cells for their survival.


CONCLUSIONS
Our data, for the first time, revealed new roles of the CXCR/SDF-1 signaling axis on autophagy formation in MCL, which further promoted their survival within the bone marrow microenvironment. Targeting the CXCR4/SDF-1/autophagy signaling axis may contribute to an enhanced efficacy of current therapies.
Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas-Health Science Center at Houston, Houston, Texas.
Zheng
Z
Chen
Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas-Health Science Center at Houston, Houston, Texas.
Albert E
AE
Teo
Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), University of Texas-Health Science Center at Houston, Houston, Texas. nami.mccarty@uth.tmc.edu.
Nami
N
McCarty
D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D054377:Chemokine CXCL12 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D059016:Tumor Microenvironment
D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; D017382:Reactive Oxygen Species; D019718:Receptors, CXCR4