Johannessen Julie A, Formica Miriam, Haukeland Aina Louise C, Bråthen Nora Rojahn, Al Outa Amani, Aarsund Miriam, Therrien Marc, Enserink Jorrit M, Knævelsrud Helene
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
iScience. 2023 Aug 25;26(10):107726. doi: 10.1016/j.isci.2023.107726. eCollection 2023 Oct 20.
-rearranged (-r) leukemias are among the leukemic subtypes with poorest survival, and treatment options have barely improved over the last decades. Despite increasing molecular understanding of the mechanisms behind these hematopoietic malignancies, this knowledge has had poor translation into the clinic. Here, we report a model system to explore the pathways affected in -r leukemia. We show that expression of the human leukemic oncogene MLL-AF4 in the hematopoietic system resulted in increased levels of circulating hemocytes and an enlargement of the larval hematopoietic organ, the lymph gland. Strikingly, depletion of orthologs of known interactors of MLL-AF4, such as DOT1L, rescued the leukemic phenotype. In agreement, treatment with small-molecule inhibitors of DOT1L also prevented the MLL-AF4-induced leukemia-like phenotype. Taken together, this model provides an system to unravel the genetic interactors involved in leukemogenesis and offers a system for improved biological understanding of -r leukemia.
重排（-r）白血病是生存情况最差的白血病亚型之一，在过去几十年里治疗选择几乎没有改善。尽管对这些造血系统恶性肿瘤背后的机制在分子层面的理解不断增加，但这些知识在临床中的转化效果不佳。在此，我们报告了一个用于探索-r白血病中受影响通路的模型系统。我们发现，人类白血病致癌基因MLL-AF4在造血系统中的表达导致循环血细胞水平升高以及幼虫造血器官——淋巴腺增大。引人注目的是，MLL-AF4已知相互作用蛋白的直系同源物（如DOT1L）的缺失挽救了白血病表型。同样，用DOT1L的小分子抑制剂进行治疗也预防了MLL-AF4诱导的白血病样表型。综上所述，该模型提供了一个系统来揭示参与白血病发生的基因相互作用蛋白，并为增进对-r白血病的生物学理解提供了一个系统。
