Heterogeneity of B cell lymphopoiesis in patients with premalignant and active myeloma
Jana Jakubikova, Danka Cholujova, Gabor Beke, Teru Hideshima, Lubos Klucar, Merav Leiba, Krzysztof Jamroziak, Paul G. Richardson, Efstathios Kastritis, David M. Dorfman, Kenneth C. Anderson
Jana Jakubikova, Danka Cholujova, Gabor Beke, Teru Hideshima, Lubos Klucar, Merav Leiba, Krzysztof Jamroziak, Paul G. Richardson, Efstathios Kastritis, David M. Dorfman, Kenneth C. Anderson
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Resource and Technical Advance Hematology Oncology

Heterogeneity of B cell lymphopoiesis in patients with premalignant and active myeloma

Abstract

To better characterize the heterogeneity of multiple myeloma (MM), we profiled plasma cells (PCs) and their B cell lymphopoiesis in the BM samples from patients with monoclonal gammopathy of undetermined significance, smoldering MM, and active MM by mass cytometry (CyTOF) analysis. Characterization of intra- and interneoplastic heterogeneity of malignant plasmablasts and PCs revealed overexpression of the MM SET domain (MMSET), Notch-1, and CD47. Variations in upregulation of B cell signaling regulators (IFN regulatory factor 4 [IRF-4], CXCR4, B cell lymphoma 6 [Bcl-6], c-Myc, myeloid differentiation primary response protein 88 [MYD88], and spliced X box-binding protein 1 [sXBP-1]) and aberrant markers (CD319, CD269, CD200, CD117, CD56, and CD28) were associated with different clinical outcomes in clonal PC subsets. In addition, prognosis was related to heterogeneity in subclonal expression of stemness markers, including neuroepithelial stem cell protein (Nestin), SRY-box transcription factor 2 (Sox2), Krüppel-like factor 4 (KLF-4), and Nanog. Furthermore, we have defined significantly elevated levels of MMSET, MYD88, c-Myc, CD243, Notch-1, and CD47 from hematopoietic stem cells to PCs in myeloma B cell lymphopoiesis, noted even in premalignant conditions, with variably modulated expression of B cell development regulators, including IRF-4, Bcl-2, Bcl-6, and sXBP-1; aberrant PC markers (such as CD52, CD44, CD200, CD81, CD269, CD117, and CXCR4); and stemness-controlling regulators, including Nanog, KLF-4, octamer-binding transcription factor 3/4 (Oct3/4), Sox2, and retinoic acid receptor α2 (RARα2). This study provides the rationale for precise molecular profiling of patients with MM by CyTOF technology to define disease heterogeneity and prognosis.

Authors

Jana Jakubikova, Danka Cholujova, Gabor Beke, Teru Hideshima, Lubos Klucar, Merav Leiba, Krzysztof Jamroziak, Paul G. Richardson, Efstathios Kastritis, David M. Dorfman, Kenneth C. Anderson

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Figure 6

Inter- and intratumor signaling heterogeneity of clonal PCs in MM by CyTOF analysis.

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Inter- and intratumor signaling heterogeneity of clonal PCs in MM by CyT...
(A) Violin plots show normalized median expression for B cell regulators (MMSET, Notch-1, CD184, c-Myc, IRF-4, MYD88, Bcl-6, sXBP-1, Blimp-1, and FGFR3), stem cell markers (RARα2, Nanog, Sox2, Oct3/4, KLF-4, and Nestin), ABC transporters (CD243 and CD338), and PC aberrant markers (CD47, CD81, CD44, CD200, CD28, CD329, CD362, CD56, CD52, CD289, CD117, CD269, CD24, and CD319) in MGUS (n = 16), SMM (n = 25), NDMM (n = 43), and RRMM (n = 104) versus HDs (n = 10) in PB/PC clusters (PB/PC1–2) and PC clusters (PC1–7) defined by color code (bottom). Significant differences between MGUS, SMM, NDMM, and RRMM versus HDs are defined by Dunn’s multiple comparison test after the Kruskal-Wallis 1-way ANOVA by ranks, with *P value < 0.05. (B) Circle diagram shows schematic summary of statistically significant normalized expression of signaling markers either downregulated (blue rectangle) or upregulated (red rectangle) within PB/PC clusters (PB/PC1–2) and PC clusters (PC1–7) in MGUS, SMM, NDMM, and RRMM versus HDs by Dunn’s multiple comparison test after the Kruskal-Wallis 1-way ANOVA by ranks, with P value < 0.05. (C) Venn diagram shows 15 intersections among 4 MM disease stages — MGUS, SMM, NDMM, and RRMM. Each intersection shows statistically significant downregulation (blue circle in table) or upregulation (red circle in table) within PC clonal clusters (PC1–7) in MGUS, SMM, NDMM, and RRMM versus HDs.