Elucidating the Role of Mutated ASXL1 in Myeloproliferative Neoplasms

阐明突变 ASXL1 在骨髓增生性肿瘤中的作用

• 批准号: 441954047
• 负责人: Dr. Frederike Kramer
• 金额: --
• 依托单位: Division of Hematology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/441954047?language=en
• 关键词: Elucidating; Role; Mutated; ASXL1; Myeloproliferative

Myeloproliferative neoplasms summarize certain types of bone marrow cancer, with the clonal expansion of at least one cell type of the myeloid lineage as a defining feature. Somatic, acquired mutations in JAK2, CALR or MPL have been identified as disease driver mutations. In myeloproliferative neoplasms, mutations in the additional sex combs-like protein 1 (ASXL1) gene often co-occur with the canonical driver mutations in hematopoietic stem cells. Importantly, co-occurrence of ASXL1 mutation adversely impacts prognosis and promotes transformation to a more aggressive disease (i.e. bone marrow fibrosis or acute leukemia). ASXL1 is an epigenetic regulator, controlling both transcriptional activation and repression. Different studies have identified several epigenetic changes in ASXL1 mutant models, but data on how ASXL1 mutation accelerates myeloproliferative disease in the context of the respective disease-initiating driver mutations are sparse. The research presented here therefore aims at identifying the mechanisms underlying the adverse impact of mutated ASXL1 on mutant CALR-mediated myeloproliferative neoplasms by generating ASXL1/CALR double mutant mice. I will investigate cell-intrinsic effects which drive leukemic transformation, and cell-extrinsic effects that promote myelofibrosis. In particular, RNA sequencing, novel epigenetic approaches and imaging techniques will be used to analyze effects of ASXL1/CALR mutation in hematopoietic stem cells and in the bone marrow microenvironment.

骨髓增殖性肿瘤总结了某些类型的骨髓癌，以至少一种类型的髓系细胞的克隆性增殖为特征。JAK2、CALR或MPL的体细胞获得性突变已被确定为疾病驱动突变。在骨髓增生性肿瘤中，附加性梳状蛋白1(ASXL1)基因的突变经常与造血干细胞中的典型驱动突变共存。重要的是，ASXL1突变的并存对预后产生不利影响，并促进向更具侵袭性的疾病(如骨髓纤维化或急性白血病)的转化。ASXL1是一种表观遗传调控因子，控制转录激活和抑制。不同的研究已经确定了ASXL1突变模型中的几个表观遗传学变化，但关于ASXL1突变如何在各自的致病驱动因素突变的背景下加速骨髓增殖性疾病的数据很少。因此，本研究旨在通过产生突变的ASXL1/CALR双突变小鼠来确定突变的ASXL1对突变的CALR介导的骨髓增殖性肿瘤的不利影响的机制。我将研究推动白血病转化的细胞内在效应，以及促进骨髓纤维化的细胞外在效应。特别是，将使用RNA测序、新的表观遗传学方法和成像技术来分析ASXL1/CALR突变对造血干细胞和骨髓微环境的影响。

项目成果

Mutant Srsf2 Diminishes Jak2V617F-Induced Erythrocytosis in Mice and Is Associated with Lower Hemoglobin in Patients with Chronic Phase JAK2-Mutant MPN

突变型 Srsf2 可减少 JAK2V617F 诱导的小鼠红细胞增多症，并与慢性期 JAK2 突变型 MPN 患者的血红蛋白降低相关

• DOI: 10.1182/blood-2022-158823
• 发表时间: 2022
• 期刊: Blood
• 影响因子: 20.3
• 作者: Marneth AE;Jutzi JS;Kim CJ;Laurore C;Tishena A;Kramer F;Rocha AV
• 通讯作者: Rocha AV

Mutant Asxl1 Exacerbates the MPN Phenotype of Calrdel52 Mutant Mice with Distinct Effects on Histone H3 Modifications in Megakaryocytes

突变 Asxl1 加剧 Calrdel52 突变小鼠的 MPN 表型，对巨核细胞中组蛋白 H3 修饰具有明显影响

• DOI: 10.1182/blood-2022-167735
• 发表时间: 2022
• 期刊: Blood
• 影响因子: 20.3
• 作者: Kramer F;Marneth AE;Pozdnyakova O;Papanastasiou M;Reiter A;Carr SA;Mullally A
• 通讯作者: Mullally A