Citations 2
Comprehensive Characterization of the Multiple Myeloma Immune Microenvironment Using Integrated scRNA-seq, CyTOF, and CITE-seq Analysis
Jayasinghe, Reyka G. , Lee, Brian , Bhasin, Swati S. , Pilcher, William , Dasari, Surendra , Fiala, Mark A. , Pita-Juárez, Yered , Strausbauch, Michael, Kelly, Geoffrey , Thomas, Beena , Kumar, Shaji , Anderson, Emilie, Wendl, Michael C. , Dawson, Travis , D’souza, Darwin , Cheloni, Giulia , Li, Ying , Dhodapkar, Kavita M. , Vij, Ravi , Vlachos, Ioannis S. , Mehr, Shaadi , Hamilton, Mark , Auclair, Daniel , Kourelis, Taxiarchis , Avigan, David , Dhodapkar, Madhav V. , Gnjatic, Sacha , Ding, Li , Jayasinghe, Reyka G , Bhasin, Swati S , Pilcher, William , Dasari, Surendra , Fiala, Mark A , Pita-Juarez, Yered , Kumar, Shaji K , Dawson, Travis , Oh, Stephen T , Li, Ying , Rahman, Adeeb H , Dhodapkar, Kavita M , Hamilton, Mark , Auclair, Daniel , Dhodapkar, Madhav V , Gnjatic, Sacha , Bhasin, Manoj K , Ding, Li , Vlachos, Ioannis S , Yao, Lijun , Doxie, Deon Bryant , Gonzalez‐Kozlova, Edgar , Thomas, Beena E., Cho, Hearn Jay , Oh, Stephen T. , DiPersio, John F. , Kim-Schulze, Seunghee
Cancer Research Communications | August 31, 2022 | Volume: 2 | Issue: 10 | Pages: 1255-1265
As part of the Multiple Myeloma Research Foundation (MMRF) immune atlas pilot project, we compared immune cells of multiple myeloma bone marrow samples from 18 patients assessed by single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to understand the concordance of measurements among single-cell techniques. Cell type abundances are relatively consistent across the three approaches, while variations are observed in T cells, macrophages, and monocytes. Concordance and correlation analysis of cell type marker gene expression across different modalities highlighted the importance of choosing cell type marker genes best suited to particular modalities. By integrating data from these three assays, we found International Staging System stage 3 patients exhibited decreased CD4+ T/CD8+ T cells ratio. Moreover, we observed upregulation of RAC2 and PSMB9, in natural killer cells of fast progressors compared with those of nonprogressors, as revealed by both scRNA-seq and CITE-seq RNA measurement. This detailed examination of the immune microenvironment in multiple myeloma using multiple single-cell technologies revealed markers associated with multiple myeloma rapid progression which will be further characterized by the full-scale immune atlas project. Significance: scRNA-seq, CyTOF, and CITE-seq are increasingly used for evaluating cellular heterogeneity. Understanding their concordances is of great interest. To date, this study is the most comprehensive examination of the measurement of the immune microenvironment in multiple myeloma using the three techniques. Moreover, we identified markers predicted to be significantly associated with multiple myeloma rapid progression.
Aberrant Extrafollicular B Cells, Immune Dysfunction, Myeloid Inflammation, and MyD88-Mutant Progenitors Precede Waldenstrom Macroglobulinemia
Kaushal, Akhilesh , Carr, Allison R. , Pendleton, Katherine E. , Barwick, Benjamin G. , Manalo, Renee Julia , McCachren, Samuel S. , Gupta, Vikas A. , Joseph, Nisha S. , Hofmeister, Craig C. , Heffner, Leonard T., Ansell, Stephen M. , Dhodapkar, Kavita M. , Dhodapkar, Madhav V. , Pendleton, Katherine E , Barwick, Benjamin G , Manalo, Julia , McCachren, Samuel S , Gupta, Vikas A , Hofmeister, Craig C , Kaufman, Jonathan L , Ansell, Stephen M , Boise, Lawrence H , Dhodapkar, Kavita M , Nooka, Ajay K. , Kaufman, Jonathan L. , Boise, Lawrence , Lonial, Sagar
Blood Cancer Discovery | September 1, 2021 | Volume: 2 | Issue: 6 | Pages: 600-615
Abstract Waldenstrom macroglobulinemia (WM) and its precursor IgM gammopathy are distinct disorders characterized by clonal mature IgM-expressing B-cell outgrowth in the bone marrow. Here, we show by high-dimensional single-cell immunogenomic profiling of patient samples that these disorders originate in the setting of global B-cell compartment alterations, characterized by expansion of genomically aberrant extrafollicular B cells of the nonmalignant clonotype. Alterations in the immune microenvironment preceding malignant clonal expansion include myeloid inflammation and naïve B- and T-cell depletion. Host response to these early lesions involves clone-specific T-cell immunity that may include MYD88 mutation–specific responses. Hematopoietic progenitors carry the oncogenic MYD88 mutations characteristic of the malignant WM clone. These data support a model for WM pathogenesis wherein oncogenic alterations and signaling in progenitors, myeloid inflammation, and global alterations in extrafollicular B cells create the milieu promoting extranodal pattern of growth in differentiated malignant cells. Significance: These data provide evidence that growth of the malignant clone in WM is preceded by expansion of extrafollicular B cells, myeloid inflammation, and immune dysfunction in the preneoplastic phase. These changes may be related in part to MYD88 oncogenic signaling in pre–B progenitor cells and suggest a novel model for WM pathogenesis. This article is highlighted in the In This Issue feature, p. 549