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Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):424-436
Hematopoiesis
Signal-transducing adaptor protein-2 delays recovery of B-lineage lymphocytes during hematopoietic stress
Michiko Ichii,1 Kenji Oritani,2 Jun Toda,1 Hideaki Saito,1 Henyun Shi,1 Hirohiko Shibayama,1 Daisuke Motooka,3 Yuichi Kitai,4 Ryuta Muromoto,4 Jun-ichi Kashiwakura,4 Kodai Saitoh,4 Daisuke Okuzaki,3 Tadashi Matsuda,4 and Yuzuru Kanakura1,5
1Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita; 2Department of Hematology, Graduate School of Medical Science, International University of Health and Welfare, Narita; 3Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita; 4Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo and 5Sumitomo Hospital, Osaka, Japan
ABSTRACT
Signal-transducing adaptor protein-2 (STAP-2) was discovered as a C-FMS/M-CSFR interacting protein and subsequently found to func- tion as an adaptor of signaling or transcription factors. These include STAT5, MyD88 and IκB kinase in macrophages, mast cells, and T cells. There is additional information about roles for STAP-2 in several types of malignant diseases including chronic myeloid leukemia; however, none have been reported concerning B-lineage lymphocytes. We have now exploited gene targeted and transgenic mice to address this lack of knowl- edge, and demonstrated that STAP-2 is not required under normal, steady- state conditions. However, recovery of B cells following transplantation was augmented in the absence of STAP-2. This appeared to be restricted to cells of B-cell lineage with myeloid rebound noted as unremarkable. Furthermore, all hematologic parameters were observed to be normal once recovery from transplantation was complete. In addition, overexpression of STAP-2, specifically in lymphoid cells, resulted in reduced numbers of late- stage B-cell progenitors within the bone marrow. While numbers of mature peripheral B and T cells were unaffected, recovery from sub-lethal irradia- tion or transplantation was dramatically reduced. Lipopolysaccharide (LPS) normally suppresses B precursor expansion in response to interleukin 7; however, STAP-2 deficiency made these cells more resistant. Preliminary RNA-sequencing analyses indicated multiple signaling pathways in B pro- genitors to be STAP-2-dependent. These findings suggest that STAP-2 mod- ulates formation of B lymphocytes in demand conditions. Further study of this adapter protein could reveal ways to speed recovery of humoral immu- nity following chemotherapy or transplantation.
Introduction
Production of blood cells in bone marrow (BM) is highly regulated. Billions of blood cells are derived from multipotent hematopoietic stem cells (HSC). Indeed, a wide spectrum of hematologic lineages is produced on a daily basis over an indi- vidual’s lifetime.1,2 Hematopoiesis is flexible enough to respond to various types of stress, including chemotherapy, acute or chronic infections, and injuries.3 In such situations, myeloid lineage cells often respond first to resolve inflammatory events, after which they need to be rapidly regenerated.4 Recent studies have shown that HSC play an important role in driving this emergency myelopoiesis. For example, hematopoietic progenitors (HPC) and HSC in BM can respond to stimulation of toll-like receptors (TLR) that detect microbial products. This results in HSC expan- sion, increased myeloid differentiation and depletion of lymphoid progenitors via direct and indirect ways.5-8 Besides this, proinflammatory cytokines such as inter- leukin (IL)-1, IL-6, tumor necrosis factor alpha (TNFα), interferons (IFN), and gran- ulocyte-colony stimulating factor (G-CSF) impact the fate of multipotent
Correspondence:
MICHIKO ICHII
michii@bldon.med.osaka-u.ac.jp
Received: April 26, 2019. Accepted: January 23, 2020. Pre-published: January 23, 2020.
https://doi.org/10.3324/haematol.2019.225573
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