Functional analysis of SAMD9/9L mutations in hematopoiesis and generation of a novel humanized SAMD9/9L mouse model

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08395
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Hiroshima University
• Principal Investigator: Nagamachi Akiko 広島大学, 原爆放射線医科学研究所, 助教 (20585153)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 骨髄異形成症候群 / SAMD9/9L症候群

Outline of Final Research Achievements

Samd9 and Samd9L (Samd9/9L) are located in 7q and are genes responsible for 7q-/MDS. "Samd9/9L syndromes" are a currently established large subgroup of the inherited BM failure (IBMF) syndromes. Patients with Samd9/9L syndromes carry a gain-of-function mutation in the Samd9/9L genes. We established mice carrying a Samd9LD764N g/f mutation that exhibit IBMF. Evaluation of hematopoietic function in the Samd9L mutated mouse revealed significant reduction in lymphocytes due to differentiation defects of B cells from the Pro-B cell stage onward, along with accelerated cell cycle progression in hematopoietic stem cells. Furthermore, abnormalities in TGFβ signaling mediated by Samd9L mutations were identified in hematopoietic stem cells.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

SAMD9/9L症候群は2016年頃より提唱された新しい疾患概念で、現在は先天性骨髄不全症のカテゴリーの中でファンコニー貧血と並ぶ代表的疾患となったが、疾患原因となるSamd9/9L変異体の生化学的機能は未だ不明な状況にある。今回得られた結果は、症候群の発症メカニズム解明に向けた第一歩であり、加えて、SAMD9/9Lの機能亢進と機能低下による病態解析を通じて、造血幹細胞を中心とする造血系におけるTGFβの機能に対する新たな知見となった。