Elucidating the Role of Mutated ASXL1 in Myeloproliferative Neoplasms

骨髓增生性肿瘤概括了某些类型的骨髓癌，具有至少一种髓系细胞类型的克隆扩增作为定义特征。JAK2、CALR或MPL的体细胞获得性突变已被确定为疾病驱动突变。在骨髓增殖性肿瘤中，额外的性梳状蛋白1 （ASXL1）基因的突变通常与造血干细胞的典型驱动突变共同发生。重要的是，ASXL1突变的共同发生会对预后产生不利影响，并促进向更具侵袭性的疾病（即骨髓纤维化或急性白血病）的转变。ASXL1是一种表观遗传调节剂，控制转录激活和抑制。不同的研究已经确定了ASXL1突变模型中的几种表观遗传变化，但是关于ASXL1突变如何在各自的疾病启动驱动突变的背景下加速骨髓增生性疾病的数据很少。因此，本研究旨在通过产生ASXL1/CALR双突变小鼠，确定突变ASXL1对突变CALR介导的骨髓增生性肿瘤的不利影响的机制。我将研究驱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，RNA测序，新的表观遗传学方法和成像技术将用于分析ASXL1/CALR突变在造血干细胞和骨髓微环境中的影响。

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.