Pliego Zamora Adriana C, Ranasinghe Hansini, Lisle Jessica E, Ng Chun Ki, Huang Stephen, Wadlow Racheal, Scott Andrew M, Boyd Andrew W, Slape Christopher I
The University of Queensland Diamantina Institute, The University of Queensland, Brisbane 4102, Australia.
Olivia Newton-John Cancer Research Institute and La Trobe University, Heidelberg 3084, Australia.
Cancers (Basel). 2021 Jul 31;13(15):3858. doi: 10.3390/cancers13153858.
We recently characterised the () mouse as a model of T-cell pre-leukaemia, featuring thymocytes that can engraft in recipient animals and progress to T-cell acute lymphoblastic leukaemia (T-ALL). However, loss of this engraftment ability by deletion of did not result in any loss of leukemogenesis activity. In the present study, we observe that thymocytes overexpress EPHA3, and we characterise thymocyte behaviour in mice with deletion of , which show a markedly reduced incidence of T-ALL. Deletion of from the mice does not prevent the abnormal accumulation or transplantation ability of these thymocytes. However, upon transplantation, these cells are unable to block the normal progression of recipient wild type (WT) progenitor cells through the normal developmental pathway. This is in contrast to the thymocytes, which block the progression of incoming WT progenitors past the DN1 stage. Therefore, is not critical for classical self-renewal, but is essential for mediating an interaction between the abnormally self-renewing cells and healthy progenitors-an interaction that results in a failure of the healthy cells to differentiate normally. We speculate that this may orchestrate a loss of healthy cell competition, which in itself has been demonstrated to be oncogenic, and that this may explain the decrease in T-ALL incidence in the absence of . We suggest that pre-leukaemic self-renewal in this model is a complex interplay of cell-intrinsic and -extrinsic factors, and that multiple redundant pathways to leukaemogenesis are active.
我们最近将（）小鼠鉴定为T细胞白血病前期模型，其特征是胸腺细胞能够植入受体动物体内并发展为T细胞急性淋巴细胞白血病（T-ALL）。然而，通过缺失（）来丧失这种植入能力并未导致白血病发生活性的任何丧失。在本研究中，我们观察到（）胸腺细胞过表达EPHA3，并且我们对缺失（）的（）小鼠中的胸腺细胞行为进行了表征，这些小鼠显示T-ALL的发病率显著降低。从（）小鼠中缺失（）并不能阻止这些胸腺细胞的异常积累或移植能力。然而，在移植后，这些细胞无法阻止受体野生型（WT）祖细胞通过正常发育途径的正常进展。这与（）胸腺细胞形成对比，后者会阻止进入的WT祖细胞越过DN1阶段的进展。因此，（）对于经典的自我更新并不关键，但对于介导异常自我更新的细胞与健康祖细胞之间的相互作用至关重要——这种相互作用导致健康细胞无法正常分化。我们推测，这可能会导致健康细胞竞争的丧失，而健康细胞竞争本身已被证明具有致癌性，这可能解释了在没有（）的情况下T-ALL发病率的降低。我们认为，该模型中白血病前期的自我更新是细胞内在和外在因素的复杂相互作用，并且多种冗余的白血病发生途径是活跃的。
