[Jun. 19] 111th IRCMS Seminar

May 23 2024

We would like to inform you that the 110th IRCMS seminar has been scheduled as below.
* This IRCMS seminar is open to everyone.

Date      : June 19, 2024 (Wednesday)

Time      : 16:00-17:00

ZOOM　: Meeting ID: 974 7672 2394
            　Passcode: Semi19Jun

Speaker : Dr. Yuko Kawano (The University of Tokyo)

Title        : Direct Signal of IL1RI/IL-18 on Mesenchymal stromal cells Regulate the Pathology of Murine MDS Model

Abstract 

Myelodysplastic syndromes (MDS) are age-related and characterized by bone marrow (BM) dysfunction that could develop acute leukemia. While recent studies are highlighting the crucial role of the BM microenvironment (BMME) in MDS, detailed mechanism remains to be elucidated. We previously reported interleukin-1 (IL-1) as a driver of aging in BM characterized by expansion of dysfunctional mesenchymal stromal cells (MSCs) and hematopoietic stem and progenitor cells (HSPCs) and found that similar disruption of BMME as aging can be seen in MDS. In this study, we found that protein level of IL-1 family cytokines including IL-18 were upregulated in BM from MDS patients. Utilizing highly purified primary BM-derived MSCs, both IL-1b and IL-18 were found to exert direct effects on MSCs in the signaling pathways, which resulted in the retaining of HSPCs at myeloid progenitor stage, and erythroid progenitors at immature stage in our coculture system. We also employed an age-appropriate model of MDS by transplanting NUP98-HOXD13 transgenic (NHD13+) cells into aged recipient mice. Interleukin-1 receptor-associated kinase 4 (IRAK4) and NLR family pyrin domain containing 3 (NLRP3) inhibitors reversed the proliferation of dysfunctional MSCs and enhanced their functionality. Additionally, IRAK4 inhibition selectively suppressed MDS clonal cells while sparing non-MDS cells in the BM. These findings suggest that targeting IL-1 signaling holds promise for MDS treatment by addressing the underlying myeloid malignancy and restoring the altered BMME via BM-MSCs.       

2-3 major papers:

1. Kawano Y, Fukui C, Shinohara M, Wakahashi K, Ishii S, Suzuki T, Sato M, Asada N, Kawano H, Minagawa K, Sada A, Furuyashiki T, Uematsu S, Akira S, Uede T, Narumiya S, Matsui T, Katayama Y. G-CSF-induced sympathetic tone provokes fever and primes anti-mobilizing functions of neutrophils via PGE2.  Blood. 2017 Feb 2;129(5):587-597
2. Kawano Y, Kawano H, Ghoneim D, Fountaine TJ, Byun DK, LaMere MW, Mendler JH, Ho T-C, Salama NA, Frisch BJ, Myers JR, Hussein SE, Ashton JM, Azadniv M, Liesveld JL, Kfoury Y, Scadden DT, Becker MW, Calvi LM  Myelodysplastic syndromes disable support of human hematopoietic stem and progenitor cells by CD271, VCAM- 1 and CD146 expressing marrow niche cells bioRxiv 2023.04.09.536176; doi: https://doi.org/10.1101/2023.04.09.536176
3. Kawano H, Kawano Y, Yu C, LaMere MW, McArthur MJ, Becker MW, Ballinger SW, Gojo S, Eliseev RA, Calvi LM Mitochondrial Transfer to Host Cells from Ex Vivo Expanded Donor Hematopoietic Stem Cells Cells. 2023 May 25;12(11):1473. doi: 10.3390/cells12111473.

Flyer: (Click to enlarge)