Darwinian Fitness of Acute Lymphoblastic Leukaemia

Clinically, relapsed ALL is characterized by a very poor treatment response and is, thus, considered to be more aggressive. We have competitively transplanted matched presentation and relapse material derived from a t(17;19) ALL. Relapse cells were discriminated from presentation cells by a 5q deletion of 5 genes (NR3C1, HMHB1, ARHGAP26, FGF1 and YIPF5). Surprisingly, presentation cells always outcompeted relapse cells. Only under dexamethasone treatment, relapse cells were able to compete with presentation cells. These findings suggest that one or a combination of the deleted genes significantly improve the fitness of ALL cells in vivo. Furthermore, they show that genetic changes resulting in drug resistance may only be advantageous under drug exposure conditions. Currently, we are investigating the contribution of these genes to leukaemic fitness. To that end, we have now transduced the pre B ALL cell lines SEM (t(4;11)) and 697(t(1;19)) with pTRIPZ containing shRNA targeting these 5 genes to examine how the composition of the shRNA pool changes in the presence and absence of Dexamethasone.