Investigating a novel therapeutic strategy for preleukemic clonal hematopoiesis based on proinflammatory cytokine-mediated cell extrinsic mechanism of clonal expansion

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17864
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Yokohama City University
• Principal Investigator: KUNIMOTO Hiroyoshi 横浜市立大学, 医学部, 助教 (80464923)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: TET2 / GM-CSF / クローン性造血 / 慢性骨髄単球性白血病

Outline of Final Research Achievements

We first cultured wild-type (WT) or Tet2-null murine BM cells with or without proinflammatory (IL-1β, IL-6, IFNγ) or myelomonocytic (G-CSF, M-CSF, GM-CSF) cytokines in methylcellulose media. In contrast to our initial hypothesis, IL-1β did not induce enhanced replating capacity of Tet2-null hematopoietic stem/progenitor cells (HSPCs) in vitro. On the other hand, GM-CSF suppressed clonogenicity of WT cells while enhanced both clonogenicity and replating capacity of Tet2-null HSPCs. Intriguingly, GM-CSF stimulation induced differentiation toward CD11b+ myelomonocytes and increased both Annexin V+ apoptotic cells and proliferative cells in S/G2/M phase in WT cells, whereas Tet2-null cells were resistant to these differentiative/apoptotic/proliferative effects induced by GM-CSF. These data suggest that Tet2 loss confers HSPCs with functional resistance to GM-CSF stress, leading to enhanced self-renewal and decreased apoptosis of Tet2-null HSCs.

Free Research Field

血液腫瘍内科学

Academic Significance and Societal Importance of the Research Achievements

TET2変異陽性クローン性造血及び慢性骨髄単球性白血病の拡大・進展過程における骨髄単球系サイトカインGM-CSFの役割が明らかにされた。今後野生型及びTet2欠失細胞におけるGM-CSFシグナルの変化やその分子基盤に着目することで、TET2変異陽性クローン性造血や血液腫瘍発生過程におけるGM-CSFシグナルの重要性や治療標的としての可能性も明らかになると期待され、臨床医学的意義は大きいと考える。