Modulation of the p19Arf-pü53 tumor suppressor response to overcome persistence in CML

调节 p19Arf-pü53 肿瘤抑制反应以克服 CML 的持续存在

• 批准号: 81569118
• 负责人: Professor Dr. Andreas Burchert
• 金额: --
• 依托单位: Klinik für Hämatologie, Onkologie und Immunologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/81569118?language=en
• 关键词: Modulation; p19Arf; 53; tumor; suppressor

“Inherent” insensitivity of CML stem/progenitor cells against ABL-specific kinase inhibitors such as imatinib or the more potent second generation inhibitors, which target the causative oncogene of CML, BCR-ABL, causes persistence of chronic myeloid leukemia (CML). In the previous funding period, we have characterized in more detail the site of persisting disease in different bone marrow compartments of CML patients. We found that persisting CML precursors express low BCR-ABL level and that lack of expression of the interferonregulated gene ICSBP (IRF-8) leads to BCR-ABL-independent apoptosis resistance against ABL-specific kinase inhibitors. Importantly, we described that Interferon alpha (IFN) maintenance therapy – previously shown to upregulate IRF8 - was associated with stable molecular remissions even after discontinuation of imatinib.In this funding period we will ask, whether BCR-ABL expression level control elicitation of the p19Arf-p53-mediated tumor suppressive response, and thus enable persistence in CML. Secondly, we will study the hypothesis that IFN amplifies via induction of IRF8 sensing of oncogenic stress signals initiated by BCR-ABL. This could have important therapeutic implications to overcome stem cell persistence in CML.

CML干/祖细胞对ABL特异性激酶抑制剂如伊马替尼或更有效的第二代抑制剂（靶向CML的致病致癌基因BCR-ABL）的“固有”不敏感性导致慢性粒细胞白血病（CML）的持续存在。在上一个资助期，我们更详细地描述了CML患者不同骨髓室中持续存在疾病的部位。我们发现，持续存在的CML前体表达低BCR-ABL水平，干扰素调节基因ICSBP（IRF-8）表达的缺乏导致对ABL特异性激酶抑制剂的BCR-ABL非依赖性凋亡抵抗。重要的是，我们描述了干扰素α（IFN）维持治疗-先前显示上调IRF 8-与稳定的分子缓解相关，即使在伊马替尼停药后，在此资助期间，我们将询问，BCR-ABL表达水平是否控制p19 Arf-p53介导的肿瘤抑制反应的激发，从而使CML持续存在。其次，我们将研究IFN通过诱导IRF 8感受BCR-ABL启动的致癌应激信号而扩增的假设，这可能对克服CML中的干细胞持久性具有重要的治疗意义。

项目成果

Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia

• DOI: 10.1038/leu.2015.45
• 发表时间: 2015-06-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Burchert, A.;Saussele, S.;Hochhaus, A.
• 通讯作者: Hochhaus, A.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML

• DOI: 10.1038/leu.2017.9
• 发表时间: 2017-04-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Schuetz, C.;Inselmann, S.;Burchert, A.
• 通讯作者: Burchert, A.