Pathogenic role of niche aging in the development of age-associated hematological malignancies

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K19555
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Iwama Atsushi 東京大学, 医科学研究所, 教授 (70244126)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Keywords: 造血幹細胞 / ニッチ / 加齢 / 造血腫瘍

Outline of Final Research Achievements

The polycomb group protein Bmi1 maintains hematopoietic stem cell (HSC) functions. We previously reported that Bmi1-deficient mice exhibited progressive fatty changes in bone marrow (BM). A large portion of HSCs reside in the perivascular niche created partly by endothelial cells and leptin receptor+ (LepR+) BM stromal cells. To clarify how Bmi1 regulates the HSC niche, we specifically deleted Bmi1 in LepR+ cells in mice. The Bmi1 deletion promoted the adipogenic differentiation of LepR+ stromal cells and caused progressive fatty changes in the BM of limb bones with age, resulting in reductions in the numbers of HSCs and progenitors in BM and enhanced extramedullary hematopoiesis. This adipogenic change was also evident during BM regeneration after irradiation. Our results indicate that Bmi1 keeps the adipogenic differentiation program repressed in BM stromal cells to maintain the integrity of the HSC niche.

Free Research Field

造血幹細胞

Academic Significance and Societal Importance of the Research Achievements

ヒト骨髄ニッチは加齢とともに脂肪化が進行し、造血幹細胞の支持機能が低下する。その結果、造血幹細胞は減少し、ドライバー遺伝子変異を獲得した異常クローンの増殖優位性が促進される。すなわち、加齢に伴うニッチ変化が、造血幹細胞を発症母地とする骨髄球系腫瘍の発症を促進する原因の一つである可能性がある。本マウスモデルは、加齢ヒト骨髄モデルとして有用である。ヒトで認められる加齢脂肪化骨髄における造血幹細胞クローンの拡大と加齢関連骨髄球系腫瘍発症に至る過程の解析に有用と考えられ、その成果は、加齢ニッチ因子を標的とした、加齢関連骨髄球系腫瘍の発症の予防法の開発につながることが期待される。