多方向かつ段階的に進行する細胞分化における運命決定メカニズムの解明究領域略称:細胞運命制御

組織・研究内容

研究課題名
MDS原因遺伝子の同定と解析を通じた細胞分化制御システムの解明

稲葉 俊哉
研究代表者
稲葉 俊哉
広島大学原爆放射線医科学研究所・教授
E-mail
本田 浩章
研究分担者
本田 浩章
広島大学原爆放射線医科学研究所・教授
研究室HPE-mail

研究内容

骨髄異形成症候群(MDS)では、長寿命の造血前駆細胞に蓄積されたゲノムレベルの異常に、加齢等に伴うエピゲノム制御異常が合わさった「内因性の異常」により、正常の分化コースを逸脱したMDS細胞が誕生するところが疾患の出発点であると考えられる。一方、細胞死が多く増殖の遅いMDS細胞が、正常造血細胞を骨髄から駆逐する上で、造血環境(ニッチ)との相互作用など、「外界からのシグナル」応答の異常が関与していることは想像に難くない。本計画研究では、MDSの分子病態メカニズムの解明を通じて、内的・外的な細胞分化制御システムの解明を目指している。

MDSでは5q-, 7q-など、染色体の特定領域の欠失が大きな役割を果たす。研究代表者は、7q領域を対象に遺伝子単離とその機能解析を進めてきた。ここで、マウスモデルは機能解析の重要なツールであり、連携研究者の本田と連日議論をしながら研究を進めている。たとえば、7q欠失責任遺伝子候補Titan(Samd9L)の欠損マウスでは、生後1年半以上の高齢マウスの約半数がMDSを中心とした骨髄系腫瘍を発症する(図1)。このマウスの新生仔期にレトロウイルスを感染すると、Evi1転写因子やFBXL10(ヒストンH3脱メチル化酵素)の過剰発現により発症年齢は大幅に若返り、発症頻度もほぼ必発になる。このモデルを用いて、エピゲノム制御を中心とした、MDSが発症する上での年齢ファクターを解明していきたい。

図1 高齢マウスの日齢と骨髄系腫瘍累積発症頻度

Titanはサイトカインや接触因子由来のアクチンリモデリングに関与し、細胞の極性や遊走能を制御する。図2に示すように、Titan欠損細胞はアクチンフィラメントの走行が異常となり、極性が不明瞭となりながら、遊走能はむしろ亢進して「ちょこまか」動くようになる。このような、細胞運動能や細胞極性と、細胞分化の関わりを解明していくことも、本研究班の大きな目標である。

図2

主な論文

* correspondence
研究代表者
稲葉 俊哉

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研究分担者
本田 浩章

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Tazaki T, Sasaki T (These two authors contributed equally to this
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Hepatology 52, 1089-1099, 2010

Yamasaki N, Miyazaki K, Nagamachi A, Koller R, Oda H, Miyazaki M, Sasaki T, Honda Z Wolff L, Inaba T, *Honda H. Identification of Zfp521/ZNF521 as acooperative gene for E2A-HLF to develop acute B-lineage leukemia. Oncogene. 29: 1963-1975, 2010.

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A 5' untranslated region containing the IRES element in the Runx1 gene is required for angiogenesis hematopoiesis and leukemogenesis in a knock-in mouse model.
Dev Biol. 345:226-236, 2010.

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Haploinsufficiency and acquired loss of Bcl11b and H2AX induced blast crisis of chronic myelogenous leukemia in a transgenic mouse model.
Cancer Sci. 100: 1219-1226, 2009.

*Honda Zi, Suzuki T, and Honda H.
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Miyazaki K, Yamasaki N, Oda H, Kuwata T, Kanno Y, Miyazaki M, Komeno Y, Kitaura J, Honda Z, Warming S, Jenkins N,A, Copeland N,G, Kitamura T, Nakamura T, and *Honda H. Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia. Blood. 113:4702-4710, 2009.

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