Analysis_of_the_chromatin_state_of_BCMX_mouse_stem_and_progenitor_cell_compartment______. Analysis_of_the_chromatin_state_of_BCMX_mouse_stem_and_progenitor_cell_compartment______

AML is an unmet medical need and therapeutic progress will not be made without a greater understanding of this heterogeneous disease. The largest subgroup of AML patients lack a cytogenetic abnormality (AML with normal Karyotype, AML-NK). For this reason, the biology of this subtype have been historically poorly understood. Recently, next generation sequencing efforts in AML-NK genomes has described a number of recurrent abnormalities. In parallel, mouse models have dramatically improved our understanding of disease and due to the great similarities between mouse and human haematopoiesis, have been particularly informative for leukaemia. We aim to model 4 of the most frequent AML-NK mutations using sophisticated mouse models. We will assess the preleukaemic/leukaemic cellular characteristics of these models, particularly their effects on the homeostasis of the haematopoietic stem and progenitor cell (HSPC) compartment. We will also perform integrated genomic analysis to link the mutations and their altered cellular phenotype to aberrant epigenetic control and pre/leukaemic gene expression programmes.急性髓系白血病（Acute Myeloid Leukemia, AML）是一类存在未被满足的临床医疗需求的疾病，若要推动其治疗进展，必先深化对这一异质性疾病的认知。AML最大的患者亚群不存在细胞遗传学异常，即伴正常核型的AML（AML with normal Karyotype, AML-NK）。正因如此，长期以来该亚型的生物学特征始终未得到充分阐释。近期，针对AML-NK基因组的下一代测序研究已鉴定出多种复发性遗传异常。与此同时，小鼠模型极大地拓展了我们对白血病的认知；鉴于小鼠与人类造血系统存在高度相似性，该模型在白血病研究中尤为具有参考价值。本研究拟采用精密的小鼠模型，针对4种最常见的AML-NK突变构建疾病模型。我们将对这些模型的白血病前期/白血病细胞特征展开评估，重点考察其对造血干细胞与祖细胞（hematopoietic stem and progenitor cell, HSPC）稳态的影响。此外，我们还将开展整合基因组学分析，以关联上述突变及其诱导的细胞表型改变与异常表观遗传调控及白血病前期/白血病基因表达程序。