Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, LITA, Segrate, Italy.
Istituto FIRC di Oncologia Molecolare, IFOM, Milano, Italy.
Haematologica. 2019 Jul;104(7):1332-1341. doi: 10.3324/haematol.2018.200899. Epub 2019 Jan 10.
The nucleophosmin 1 gene () is the most frequently mutated gene in acute myeloid leukemia. Notably, mutations are always accompanied by additional mutations such as those in cohesin genes , , , and but not in the cohesin regulator, nipped B-like (). In this work, we analyzed a cohort of adult patients with acute myeloid leukemia and mutation and observed a specific reduction in the expression of but not in other cohesin genes. In our zebrafish model, overexpression of the mutated form of also induced downregulation of , the zebrafish ortholog of human To investigate the hematopoietic phenotype and the interaction between mutated and , we generated a zebrafish model with downregulation which showed an increased number of myeloid progenitors. This phenotype was due to hyper-activation of the canonical Wnt pathway: myeloid cells blocked in an undifferentiated state could be rescued when the Wnt pathway was inhibited by mRNA injection or indomethacin administration. Our results reveal, for the first time, a role for during zebrafish hematopoiesis and suggest that an interplay between may regulate myeloid differentiation in zebrafish and humans through the canonical Wnt pathway and that dysregulation of these interactions may drive leukemic transformation.
核仁磷酸蛋白 1 基因（）是急性髓系白血病中最常发生突变的基因。值得注意的是，突变总是伴随着其他突变，如黏着蛋白基因、、、和，但不伴有黏着蛋白调节剂，nipped B 样（）。在这项工作中，我们分析了一组急性髓系白血病伴突变的成年患者，观察到但不是其他黏着蛋白基因的表达特异性降低。在我们的斑马鱼模型中，突变型的过表达也诱导了人类的斑马鱼同源物的下调。为了研究造血表型和突变的相互作用，我们生成了下调的斑马鱼模型，显示出髓系祖细胞数量增加。这种表型是由于经典 Wnt 途径的过度激活：当 Wnt 途径被注射或吲哚美辛给药抑制时，处于未分化状态的髓系细胞可以被挽救。我们的结果首次揭示了在斑马鱼造血过程中的作用，并表明之间的相互作用可能通过经典 Wnt 途径调节斑马鱼和人类的髓系分化，而这些相互作用的失调可能导致白血病转化。
