Modulation of the myeloid differentiation block in acute myeloid leukemia II

急性髓系白血病 II 中髓系分化阻滞的调节

• 批准号: 226299880
• 负责人: Professor Dr. Michael Heuser
• 金额: --
• 依托单位: Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226299880?language=en
• 关键词: Modulation; myeloid; differentiation; block; acute

Current treatments for acute myeloid leukemia (AML) are myelotoxic and leave patients unprotected against infectious complications for several weeks with often fatal consequences. To quickly restore immune function in AML patients, we need to directly induce differentiation of leukemic blasts to functioning immune cells. The major obstacle of such treatments has been our insufficient understanding of the differentiation block in AML, exemplified by the resistance to retinoic acid (ATRA) signaling. During the last three years we have made considerable progress in understanding the components of blocked myeloid differentiation by studying the mechanism of the oncogene MN1. MN1 induces ATRA resistance in human cells and transforms human hematopoietic progenitor cells. MN1 represses genes of the immune response signature in concert with the oncogene MEIS1, but not with RARA, the receptor for ATRA. Moreover, we found evidence that RARA is displaced by MN1 and therefore hypothesize that RARA displacement induces resistance to retinoic acid signaling in AML. We propose to 1) verify RARA displacement in primary human AML cells, 2) functionally characterize the proteins that displace RARA and 3) develop lipid/siRNA formulations as differentiation-inducing therapeutic targets. Our project addresses a critical aspect of leukemogenesis that is poorly understood so far and may have wider implications for other areas like differentiation of induced pluripotent stem cells to functioning immune cells.

目前治疗急性髓系白血病(AML)的方法是骨髓毒性的，使患者几周内没有感染并发症的保护，往往会造成致命的后果。为了快速恢复AML患者的免疫功能，我们需要直接诱导白血病原始细胞向有功能的免疫细胞分化。这种治疗的主要障碍是我们对AML的分化阻断缺乏了解，例如对维甲酸(ATRA)信号的抵抗。在过去的三年里，我们通过研究癌基因MN1的机制，在了解阻止髓系分化的成分方面取得了相当大的进展。MN1可诱导人细胞对全反式维甲酸耐药，并可转化人造血祖细胞。MN1与癌基因Meis1协同抑制免疫反应信号的基因，但不与ATRA的受体RARA协同作用。此外，我们发现有证据表明，RARA被MN1取代，因此假设RARA置换在AML中诱导了对维甲酸信号的抵抗。我们建议1)验证RARA在原代人类AML细胞中的移位，2)从功能上表征取代RARA的蛋白质，以及3)开发脂类/siRNA制剂作为诱导分化的治疗靶点。我们的项目解决了白血病发生的一个关键方面，到目前为止人们对此知之甚少，并可能对其他领域有更广泛的影响，如诱导多能干细胞向功能免疫细胞的分化。

项目成果

Combination treatment of an IDH1 inhibitor with chemotherapy in IDH1 mutant acute myeloid leukemia

IDH1抑制剂与化疗联合治疗IDH1突变型急性髓系白血病

• DOI: 10.1007/s00277-020-04001-w
• 发表时间: 2020
• 期刊: Annals of Hematology
• 影响因子: 3.5
• 作者: Gupta C;Kaulfuss S;Görlich K;Othman B;Chaturvedi A;Heuser M
• 通讯作者: Heuser M

Meningioma 1 is indispensable for mixed lineage leukemia-rearranged acute myeloid leukemia

• DOI: 10.3324/haematol.2018.211201
• 发表时间: 2019-08
• 期刊: Haematologica
• 影响因子: 10.1
• 作者: Amit Sharma;N. Jyotsana;R. Gabdoulline;D. Heckl;F. Kuchenbauer;R. Slany;A. Ganser;M. Heuser

Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo

• DOI: 10.1007/s00277-019-03713-y
• 发表时间: 2019-08-01
• 期刊: ANNALS OF HEMATOLOGY
• 影响因子: 3.5
• 作者: Jyotsana, Nidhi;Sharma, Amit;Heuser, Michael
• 通讯作者: Heuser, Michael

In vivo efficacy of mutant IDH1 inhibitor HMS-101 and structural resolution of distinct binding site

• DOI: 10.1038/s41375-019-0582-x
• 发表时间: 2020-02-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Chaturvedi, Anuhar;Goparaju, Ramya;Heuser, Michael
• 通讯作者: Heuser, Michael