2. Academic Validation
  3. Single-cell analysis of neoplastic plasma cells identifies myeloma pathobiology mediators and potential targets

Single-cell analysis of neoplastic plasma cells identifies myeloma pathobiology mediators and potential targets

  • Cell Rep Med. 2025 Jan 20:101925. doi: 10.1016/j.xcrm.2024.101925.
Luz Yurany Moreno Rueda 1,  Hua Wang 1,  Keiko Akagi 2,  Minghao Dang 1,  Amishi Vora 1,  Li Qin 1,  Hans C Lee 1,  Krina K Patel 1,  Pei Lin 3,  David E Mery 4,  Fenghuang Zhan 4,  John D Shaughnessy Jr 4,  Qing Yi 5,  Yang Song 1,  Bo Jiang 2,  Maura L Gillison 2,  Sheeba K Thomas 1,  Donna M Weber 1,  Lixia Diao 6,  Jing Wang 6,  Isere Kuiatse 1,  Elisabet E Manasanch 1,  David E Symer 7,  Robert Z Orlowski 8
Affiliations

Affiliations

  • 1 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Department of Thoracic-Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 5 Department of Cancer Biology in Medicine, Houston Methodist Dr. Mary and Ron Neal Cancer Center, Houston, TX, USA.
  • 6 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medicine, VA Boston Healthcare System, Boston, MA, USA.
  • 8 Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: rorlowski@mdanderson.org.
PMID: 39855192 DOI: 10.1016/j.xcrm.2024.101925
Abstract

Multiple myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors and has been studied utilizing approaches focused on CD138+ cells. By combining single-cell RNA Sequencing (scRNA-seq) with scB-cell receptor Sequencing (scBCR-seq), we differentiate monoclonal/neoplastic from polyclonal/normal PCs and find more dysregulated genes, especially in precursor patients, than we would have by analyzing bulk PCs. To determine whether this approach can identify oncogenes that contribute to disease pathobiology, mitotic arrest deficient-2 like-1 (MAD2L1) and S-adenosylmethionine synthase isoform type-2 (MAT2A) are validated as targets with drug-like molecules that suppress myeloma growth in preclinical models. Moreover, functional studies show a role of lysosomal-associated membrane protein family member-5 (LAMP5), which is uniquely expressed in neoplastic PCs, in tumor progression and aggressiveness via interactions with c-Myc. Finally, a monoclonal antibody recognizing cell-surface LAMP5 shows efficacy as an antibody-drug conjugate and in a chimeric antigen receptor-guided T-cell format. These studies provide additional insights into myeloma biology and identify potential targeted therapeutic approaches that can be applied to reverse myeloma progression.

Keywords

LAMP5; MAT2A; disease progression; myeloma precursors; scBCR-seq; scRNA-seq.

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