The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1

Cell-extrinsic effects in T cell acute lymphoblastic pre-leukemia stem cells mediated by EphA3

“…Consistent with previous studies [21], the NHD13 thymuses showed an abnormal accumulation of thymocytes in the DN2A (CD44 hi , CD25 + ) stage (Fig.1B). We also observed an abnormally high level of expression of the c-kit protein in the CD25 + fraction (Fig.…”

“…4). This is similar to what was previously described for NHD13 thymocytes prior to transplantation [21]. However, there were no differences in the cell cycle status in the NHD13-EphA3 -/cells compared to the NHD13-EphA3 + / + cells (Fig.…”

“…We also observed an abnormally high level of expression of the c-kit protein in the CD25 + fraction (Fig. 1B) as previously described [21]. We examined the expression of EphA3 by flow cytometry and found that EphA3 is specifically expressed in the DN2A (CD4 -, CD8 -, CD44 + , CD25 -) self-renewing population of NHD13-EphA3 + / + thymocytes (Fig.1C).…”

“…This capacity requires the transcription factor Lyl1, yet NHD13-Lyl1 -/mice still develop T-ALL [21]. This self-renewal capacity is therefore not necessary for transformation to occur, and is not the only mechanism by which NHD13 thymus result in the development of T-ALL.…”

“…Specifically, NHD13 thymocytes self-renew (ie engraft upon transplantation), accumulate in the DN2 differentiation stage and, in one third of cases, lead to the development of T-ALL [19][20][21]. NHD13 thymocytes require the Lyl1 gene for self-renewal, but although NHD13 Lyl1 knockout (KO) thymocytes cannot engraft, these mice still succumb to T-ALL [21]. Therefore, it appears that the ability of NHD13 thymocytes to engraft is not required for the induction of T-ALL, and other mechanisms must be considered.…”