Analysis of the resistant mechanism of AML stem cells for tyrosine kinase inhibitor in bone marrow microenvironment

骨髓微环境中AML干细胞对酪氨酸激酶抑制剂的耐药机制分析

• 批准号: 23591537
• 负责人: SHIMADA AKIRA
• 金额: $ 3.24万
• 依托单位: Okayama University (2012-2013)Nagoya University (2011)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591537/
• 关键词: AML; TKI; MSC; drug resistance; 抗メチル化薬; HDAC阻害剤; チロシンキナーゼ; 薬剤耐性; FLT3; 骨髄微小環境; JAK阻害剤

The mechanism of drug resistance for Tyrosine kinase inhibitor (TKI) in AML cells remains unkown. AML cells showed the drug resistance in coculture model with mesenchimal stroma cells(MSCs). AML cells became more resistant for TKI in direct contact with MSC than in floating condition. For this reason, adhesion molecule such as integrin, or several cytokines and chemokines affected the up-regulation of AKT, MAPK and JAK/STAT signaling pathway. When AML cells were cocultured with MSC for more than 4 weeks, the fraction of side population increased and showed TKI resistance. To overcome this drug resistance, we found the synergistic effect in TKI with PI3K/mROR/AKT inhibitor or in TKI with JAK/STAT inhibitor.

AML细胞对酪氨酸激酶抑制剂(TKI)耐药的机制尚不清楚。AML细胞与间充质基质细胞(MSCs)共培养模型显示耐药。与MSC直接接触的AML细胞对TKI的抵抗力强于漂浮状态。因此，黏附分子如整合素或几种细胞因子和趋化因子影响AKT、MAPK和JAK/STAT信号通路的上调。当AML细胞与MSC共培养4周以上时，侧群比例增加，并表现出TKI耐药。为了克服这种耐药性，我们发现了TKI与PI3K/mROR/AKT抑制剂或TKI与JAK/STAT抑制剂的协同作用。

项目成果

High FLT3 mRNA expression without FLT3-ITD in infants with acute myeloid leukemia

急性髓系白血病婴儿中无 FLT3-ITD 的高 FLT3 mRNA 表达

• 发表时间: 2012
• 作者: Shimada A;Yamada M;Yamashita Y;et al
• 通讯作者: et al

Poor Prognosis With Different Induction Rate Was Observed In Children With Acute Myeloid Leukemia and FLT3-ITD According To The ITD/WT Allelic Ratio: A Result From The Japanese Pediatric Leukemia/Lymphoma Study Group.

根据 ITD/WT 等位基因比率，在患有急性髓性白血病和 FLT3-ITD 的儿童中观察到不同诱导率的不良预后：日本小儿白血病/淋巴瘤研究组的结果。

• 发表时间: 2013
• 作者: Shimada A;Yamashita Y;Tomizawa D;Tawa A;Watanabe T;Yokozawa T;Kudo K;Taga T;Iwamoto S;Terui K;Moritake H;Kinoshita A;Takahashi H;Nakayama H;Koh K;Goto H;Kosaka Y;Moriya Saito A;Fujimoto J;Horibe K;Oki K;Hayashi Y;SAdachi S.
• 通讯作者: SAdachi S.

小児Ph陽性急性リンパ性白血病４例のABLキナーゼ変異解析

4例Ph阳性急性淋巴细胞白血病儿童ABL激酶突变分析

• 发表时间: 2013
• 作者: 青江伯規;嶋田 明;村岡倫子;鷲尾佳奈;中村佳弥;高橋孝英;今田昌秀;渡部俊幸;岡田 健;西内律雄;宮村能子;茶山公祐;小田 慈;森島恒雄
• 通讯作者: 森島恒雄

Analysis of ABL kinase mutation in 4 pediatric philadelphia chromosome-positive acute lymphoblastic leukemia

费城4例染色体阳性急性淋巴细胞白血病患儿ABL激酶突变分析

• 发表时间: 2014
• 作者: Aoe M;Shimada A;Muraoka M;et al
• 通讯作者: et al

Chemotherapy prior to HSCT is effective for pediatric RAEB/RAEB-T

HSCT 之前的化疗对儿童 RAEB/RAEB-T 有效

• 发表时间: 2014
• 作者: Shimada A;Kinoshita A;Manabe A;et al
• 通讯作者: et al