Research Paper Volume 14, Issue 22 pp 9264—9279

CD229 interacts with RASAL3 to activate RAS/ERK pathway in multiple myeloma proliferation

Zigen Lin1,2, *, , Xiaozhu Tang2, *, , Yuhao Cao2, , Lijin Yang2, , Mingmei Jiang2, , Xinying Li2, , Jie Min2, , Bing Chen1, &, , Ye Yang2, , Chunyan Gu1,2, ,

  • 1 Department of Hematology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
  • 2 School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
* Equal contribution

Received: August 17, 2022       Accepted: November 16, 2022       Published: November 28, 2022      

https://doi.org/10.18632/aging.204405
How to Cite

Copyright: © 2022 Lin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy, while CAR-T therapy offers a new direction for the treatment of MM. Recently, signaling lymphocytic activation molecule family 3 (CD229), a cell surface immune receptor belonging to the signaling lymphocyte activating molecule family (SLAMF), is emerging as a CAR-T therapeutic target in MM. However, a clear role of CD229 in MM remains elusive. In this study, MM patients with elevated CD229 expression achieved poor prognosis by analyzing MM clinical databases. In addition, CD229 promoted MM cell proliferation in vitro as well as in xenograft mouse model in vivo. Mechanism study revealed that CD229 promoted MM cell proliferation by regulating the RAS/ERK signaling pathway. Further exploration employed co-immunoprecipitation coupled with mass spectrometry to identify RASAL3 as an important downstream protein of CD229. Additionally, we developed a co-culture method combined with the immunofluorescence assay to confirm that intercellular tyrosine phosphorylation mediated self-activation of CD229 to activate RAS/ERK signaling pathway via interacting with RASAL3. Taken together, these findings not only demonstrate the oncogenic role of CD229 in MM cell proliferation, but also illustrate the potential of CD229 as a promising therapeutic target for MM treatment.

Abbreviations

BCMA: B-cell maturation antigen; CAR-T: chimeric antigen receptor T; CD229: signaling lymphocytic activation molecule family 3; GEP: gene expression profiling; HY: hyperdiploidy; ITSM: immune receptor tyrosine signal motif; LB: low bone disease; MGUS: monoclonal gammopathy of undetermined significance; MM: Multiple myeloma; NP: normal plasma; OS: overall survival; PAF: platelet-activating factor; p-ERK: phosphorylated ERK; RNA-seq: transcriptomic RNA sequencing; RASAL3: RAS Protein Activator Like 3; SLAMF: signaling lymphocyte activating molecule family; SLE: systemic lupus erythematosus; TCR: T cell receptor.