| Summary: | We recently characterised the <i>NUP98-HOXD13</i> (<i>NHD13</i>) 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 <i>Lyl1</i> did not result in any loss of leukemogenesis activity. In the present study, we observe that <i>NHD13</i> thymocytes overexpress EPHA3, and we characterise thymocyte behaviour in <i>NHD13</i> mice with deletion of <i>EphA3</i>, which show a markedly reduced incidence of T-ALL. Deletion of <i>EphA3</i> from the <i>NHD13</i> 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 <i>EphA3</i><sup>+/+</sup> <i>NHD13</i> thymocytes, which block the progression of incoming WT progenitors past the DN1 stage. Therefore, <i>EphA3</i> 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 <i>EphA3</i>. 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.
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