Eradication of chronic myelogenous leukemia stem cells and abnormal clone with T315I point mutation

根除慢性粒细胞白血病干细胞及T315I点突变异常克隆

• 批准号: 21390293
• 负责人: MAEKAWA Taira
• 金额: $ 11.07万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21390293/
• 关键词: 慢性骨髄性白血病; 幹細胞; 治療抵抗性; 分子標的治療; 慢性骨髄白血病; 低酸素; 低酸素環境; 白血病幹細胞; チロシンキナーゼ阻害剤; オーロラキナーゼ阻害剤; T315I遺伝子; Glyoxalase-I

Imatinib mesylate(IM, GleevecR), which specifically inhibits the autophosphorylation of the Abl tyrosine kinase(TK), has dramatically improved the treatment of chronic myelogenous leukemia(CML). However, resistance is often reported in patients with advanced-stage disease. Several novel TK inhibitors(TKI) of second generation such as dasatinib(SprycelR), nilotinib(TasignaR), and INNO-406(Bafetinib) have been developed that override IM resistance mechanisms caused by point mutations within the Abl kinase domain. Because of their strong affinities for the ATP-binding site compared to IM, these new TKIs may be effective in IM-resistant patients. However, they could not inhibit the phosphorylation of T315I Bcr-Abl harboring the mutation of threonine 315 to isoleucine. We describe the in vitro and in vivo effects of AT9283(1-cyclopropyl-3[5-morpholin-4yl methyl-1H-benzomidazol-2-yl]-urea), a potent inhibitor of kinases Aurora A and Aurora B. AT9283 showed potent antiproliferative activity o … More n cells transformed by BCR-ABL/T315I. CMLstem cells also survived in the bone marrow niche under severe hypoxia condition. We generated two hypoxia-adapted(HA)-CML cell lines. These HA-CML cells exhibited stem cell-like characteristics. Compared with the respective parental cells, HA-CML cells had higher levels of protein and higher enzyme activity of glyoxalase-I(Glo-I), that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-CML cells both in vitro and in vivo. Ii is likely that leukemic cells are able to survive and proliferate in severely hypoxic environments. The hypoxic conditions allow leukemic cells that reside there to become insensitive to cell death stimuli. To target leukemic cells in hypoxic conditions, we focused on the hypoxia-selective cytotoxin, Rakicidin A. produced by the Micromonospora strain. We describe Rakicidin A-induced cell death in HA-CML cells with stem cell-like characteristics. Rakicidin A is a promising compound for targeting TKI-resistant quiescent CML stem cells in the hypoxic environment. Less

甲磺酸伊马替尼（IM，GleevecR）特异性抑制Abl酪氨酸激酶（TK）的自磷酸化，显著改善了慢性髓性白血病（CML）的治疗。然而，在晚期疾病患者中经常报告耐药性。已经开发了几种新的第二代TK抑制剂（TKI），如达沙替尼（SprycelR）、尼洛替尼（TasignaR）和INNO-406（Bafetinib），这些抑制剂可克服Abl激酶结构域内点突变引起的IM耐药机制。由于与IM相比，这些新TKI对ATP结合位点的亲和力较强，因此可能对IM耐药患者有效。然而，它们不能抑制具有苏氨酸315突变为异亮氨酸的T315 IBcr-Abl的磷酸化。我们描述了激酶Aurora A和Aurora B的强效抑制剂AT 9283（1-环丙基-3 [5-吗啉-4基甲基-1H-苯并咪唑-2-基]-脲）的体外和体内作用。AT 9283显示出有效的抗增殖活性， ...更多信息 n BCR-ABL/T315 I转化的细胞。CML干细胞在严重缺氧条件下也能在骨髓龛中存活。我们产生了两个低氧适应（HA）-CML细胞系。这些HA-CML细胞表现出干细胞样特征。与各自的亲本细胞相比，HA-CML细胞具有更高水平的蛋白质和更高的酶活性的glycoproteinase-I（Glo-I），解毒甲基乙二醛，糖酵解的细胞毒性副产物。与Abl TKI相比，Glo-I抑制剂在体外和体内杀死HA-CML细胞都有效得多。白血病细胞很可能能够在严重缺氧的环境中存活和增殖。缺氧条件使白血病细胞在那里变得对细胞死亡刺激不敏感。为了在缺氧条件下靶向白血病细胞，我们将重点放在缺氧选择性细胞毒素Rakicidin A上。由小单孢菌属菌株产生。我们描述了Rakicidin A诱导的具有干细胞样特征的HA-CML细胞的细胞死亡。Rakicidin A是一种很有前途的化合物，用于靶向低氧环境中的TKI抗性静止CML干细胞。少

项目成果

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like 5characteristics in a hypoxic environment

乙二醛酶-I是针对Bcr-Abl白血病细胞的新靶标，在缺氧环境下获得干细胞样5个特征

• 发表时间: 2010
• 期刊: Cell Death Diff
• 作者: Takeuchi;M.;Kimura;S.;Kuroda;J.;Ashihara;E.;Kawatani;M.;Osada;H.;Umezawa;K.;Yasui;E.;Imoto;M.;Tsuruo;T.;Yokota;A.;Tanaka;T.;Nagao;R.;Nakahata;T.;Fujiyama;Y.
• 通讯作者: Y.

CREB Is Involved in the Regulation of C/EBP & beta ; During 'emergency' Granulopoiesis

CREB参与C/EBP监管

• 发表时间: 2009
• 作者: Hirai H;Kamio N;Matsusue A;Ogino S;Kimura N;Satake S;Ashihara E;Maekawa T;Tenen DG;Imanishi J
• 通讯作者: Imanishi J

低酸素環境とCML幹細胞厚生労働省がん研究助成金『成人白血病の難治機構の分子レベルでの解明とそれに基づく分子標的治療の開発に関する研究』班(直江班)

缺氧环境与CML干细胞厚生劳动省癌症研究补助金“在分子水平上阐明成人白血病的棘手机制的研究以及以此为基础的分子靶向治疗的开发”小组（Naoe小组）

• 发表时间: 2009
• 作者: Shimizu R;Kobayashi E;Engel JD;Yamamoto M;岩間厚志;前川平
• 通讯作者: 前川平

A phase I/II study of immunotherapy for elderly patients with acute myeloid leukemia using dendritic cells pulsed with autologous apoptotic leukemic cells

使用自体凋亡白血病细胞脉冲的树突状细胞对老年急性髓性白血病患者进行免疫治疗的 I/II 期研究

• 发表时间: 2011
• 期刊: Brit J Haematol
• 影响因子: 6.5
• 作者: Kitawaki;T.;Kadowaki;T.;Fukunaga;K.;Kasai;Y.;Maekawa;T.;Ohmori;K.;Itoh;T.;Tada;H.;Teramukai;S.;Shimizu;A.;Fukushima;M.;Kuzushima;K.;Kondo;T.
• 通讯作者: T.

Rapid automated detection of ABL kinase domain mutations in imatinib-resistant patients

快速自动检测伊马替尼耐药患者的 ABL 激酶结构域突变

• DOI: 10.1016/j.canlet.2011.08.009
• 发表时间: 2011
• 期刊: Cancer Letter
• 作者: Tanaka;R.;Kimura;S.;Ashihara;E.;Yoshimura;M.;Takahashi;N.;Wakita;H.;Itoh;K.;Nishiwaki;K.;Suzuki;K.;Nagao;R.;Yao;H.;Hayashi;Y.;Satake;S.;Hirai;H.;Sawada;K-I.;Ottmann;O. G.;Melo;J. V.
• 通讯作者: J. V.