Oo Zaw Min, Illendula Anuradha, Grembecka Jolanta, Schmidt Charles, Zhou Yunpeng, Esain Virginie, Kwan Wanda, Frost Isaura, North Trista E, Rajewski Roger A, Speck Nancy A, Bushweller John H
a Abramson Family Cancer Research Institute , Philadelphia , PA , USA.
b Department of Cell and Molecular Biology , University of Pennsylvania , Philadelphia , PA , USA.
Leuk Lymphoma. 2018 Sep;59(9):2188-2200. doi: 10.1080/10428194.2017.1410882. Epub 2017 Dec 18.
The core binding factor (CBF) gene RUNX1 is a target of chromosomal translocations in leukemia, including t(8;21) in acute myeloid leukemia (AML). Normal CBF function is essential for activity of AML1-ETO, product of the t(8;21), and for survival of several leukemias lacking RUNX1 mutations. Using virtual screening and optimization, we developed Runt domain inhibitors which bind to the Runt domain and disrupt its interaction with CBFβ. On-target activity was demonstrated by the Runt domain inhibitors' ability to depress hematopoietic cell formation in zebrafish embryos, reduce growth and induce apoptosis of t(8;21) AML cell lines, and reduce progenitor activity of mouse and human leukemia cells harboring the t(8;21), but not normal bone marrow cells. Runt domain inhibitors had similar effects on murine and human T cell acute lymphocytic leukemia (T-ALL) cell lines. Our results confirmed that Runt domain inhibitors might prove efficacious in various AMLs and in T-ALL.
核心结合因子（CBF）基因RUNX1是白血病中染色体易位的靶点，包括急性髓系白血病（AML）中的t(8;21)。正常的CBF功能对于t(8;21)产物AML1-ETO的活性以及几种缺乏RUNX1突变的白血病的存活至关重要。通过虚拟筛选和优化，我们开发了与Runt结构域结合并破坏其与CBFβ相互作用的Runt结构域抑制剂。Runt结构域抑制剂能够抑制斑马鱼胚胎中的造血细胞形成、降低t(8;21) AML细胞系的生长并诱导其凋亡，以及降低携带t(8;21)的小鼠和人类白血病细胞而非正常骨髓细胞的祖细胞活性，从而证明了其靶向活性。Runt结构域抑制剂对鼠类和人类T细胞急性淋巴细胞白血病（T-ALL）细胞系具有相似的作用。我们的结果证实，Runt结构域抑制剂可能在各种AML和T-ALL中证明有效。
