PMID- 36752202 OWN - NLM STAT- MEDLINE DCOM- 20230209 LR - 20230303 IS - 2379-3708 (Electronic) IS - 2379-3708 (Linking) VI - 8 IP - 3 DP - 2023 Feb 8 TI - Heterogeneity of B cell lymphopoiesis in patients with premalignant and active myeloma. LID - 10.1172/jci.insight.159924 [doi] LID - e159924 AB - 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), Kruppel-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 alpha2 (RARalpha2). This study provides the rationale for precise molecular profiling of patients with MM by CyTOF technology to define disease heterogeneity and prognosis. FAU - Jakubikova, Jana AU - Jakubikova J AD - Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. AD - Department of Tumor Immunology, Cancer Research Institute, Biomedical Research Center. AD - Centre for Advanced Materials Application, and. FAU - Cholujova, Danka AU - Cholujova D AD - Department of Tumor Immunology, Cancer Research Institute, Biomedical Research Center. AD - Centre for Advanced Materials Application, and. FAU - Beke, Gabor AU - Beke G AD - Institute of Molecular Biology, Slovak Academy of Sciences, Bratislava, Slovakia. FAU - Hideshima, Teru AU - Hideshima T AD - Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. FAU - Klucar, Lubos AU - Klucar L AD - Institute of Molecular Biology, Slovak Academy of Sciences, Bratislava, Slovakia. FAU - Leiba, Merav AU - Leiba M AD - Department of Hematology, Samson Assuta Ashdod University Hospital, Ashdod, Israel. AD - Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel. FAU - Jamroziak, Krzysztof AU - Jamroziak K AD - Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. FAU - Richardson, Paul G AU - Richardson PG AD - Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. FAU - Kastritis, Efstathios AU - Kastritis E AD - Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. FAU - Dorfman, David M AU - Dorfman DM AD - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. FAU - Anderson, Kenneth C AU - Anderson KC AD - Dana-Farber Cancer Institute, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Boston, Massachusetts, USA. AD - Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230208 PL - United States TA - JCI Insight JT - JCI insight JID - 101676073 RN - 0 (CD47 Antigen) RN - 0 (Myeloid Differentiation Factor 88) SB - IM MH - Humans MH - *Multiple Myeloma/pathology MH - CD47 Antigen/metabolism MH - Myeloid Differentiation Factor 88/metabolism MH - Lymphopoiesis MH - B-Lymphocytes/metabolism PMC - PMC9977435 OTO - NOTNLM OT - Bone marrow OT - Clonal selection OT - Hematology OT - Oncology COIS- Conflict of interest: PGR declares a consulting or advisory role (Celgene, Janssen, Takeda, Karyopharm Therapeutics, Oncopeptides, Sanofi, Jazz Pharmaceuticals, and Secura Bio) and receiving research funding from Celgene, Takeda, Bristol Myers Squibb, and Oncopeptides; EK declares honoraria (Amgen, Janssen, Pfizer, Takeda, and GlaxoSmithKline) and research support (Amgen, Janssen, and Pfizer); and KCA declares an advisory role (Pfizer, Amgen, AstraZeneca, Janssen, and Precision Biosciences), board membership (C4 Therapeutics, Raqia, NextRNA, Window, Mana, and Starton), and ownership interests (C4 Therapeutics, Oncopep, NextRNA, and Raqia). EDAT- 2023/02/09 06:00 MHDA- 2023/02/10 06:00 PMCR- 2023/02/08 CRDT- 2023/02/08 06:03 PHST- 2022/03/04 00:00 [received] PHST- 2022/12/15 00:00 [accepted] PHST- 2023/02/08 06:03 [entrez] PHST- 2023/02/09 06:00 [pubmed] PHST- 2023/02/10 06:00 [medline] PHST- 2023/02/08 00:00 [pmc-release] AID - 159924 [pii] AID - 10.1172/jci.insight.159924 [doi] PST - epublish SO - JCI Insight. 2023 Feb 8;8(3):e159924. doi: 10.1172/jci.insight.159924.