A Novel Cellular Pathway of SCL T-Leukemogenesis Revealed by a Conditional Transgenic Mouse Model.

The acquired activation of stem cell leukemia (SCL) during T-lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia. Here, we generated a novel tamoxifen-inducible transgenic mouse model (lck-ER^T2-SCL) to study the cellular targets of acquired SCL activation during T-cell development. Upon tamoxifen treatment we observed the thymic emergence of abnormal, non-cycling CD8⁺TCRβ^low and immature CD4⁺CD8⁺ (double-positive, DP) cells displaying increased viability. Unexpectedly, fetal thymic organ culture analysis of lck-ER^T2-SCL thymi revealed the development of DP cells before the emergence of CD8⁺TCRβ^low cells, which implied the derivation of CD8⁺TCRβ^low cells from DPs rather than immature CD8 single-positive (SP) thymocytes. Interestingly, histone deacetylase (HDAC) inhibition with trichostatin A (TSA) had a divergent effect on SCL perturbed thymopoiesis: TSA increased T-cell receptor surface expression within DP and CD8 SP cells however did not alter the CD8 shifted CD4/CD8-ratio. Furthermore, we studied the expression of NOTCH1 in SCL induced TCRβ^low thymocytes. Strikingly, we found that SCL induced NOTCH1-upregulation in DP TCRβ^low cells. We therefore conclude that SCL promotes the emergence of abnormal CD8⁺TCRβ^low cells by an only partially HDAC dependent mechanism from DP TCRβ^low cells. Moreover, SCL induced DP TCRβ^low cells are characterized by upregulated NOTCH1, which in turn might promote the effect of acquired NOTCH1 mutations during T-leukemogenesis.