PO-299 In vivo shRNA screening to identify quiescence-related genes required for AML growth

AML is hierarchically organised with at the apex Leukaemia Stem Cells (LSCs), a rare cell population able to initiate and sustain the tumour growth. LSCs share many functional properties with normal Hematopoietic Stem Cells (HSCs) including self-renewal capacity and quiescence. Quiescent LSCs can survive to radiation and chemotherapy acting as a reservoir for leukaemia relapse, the major cause of death for AML patients. Therefore, LSCs quiescence is critical for leukaemia maintenance and few evidences suggest that quiescence regulation in pre-leukemic phase plays a pivotal role for leukemogenic process as well. Material and methods We analysed the transcriptional deregulations induced by the expression of different leukemic oncogenes in HSCs and we examined the contribution of representative quiescence related genes in AML growth by in vivo RNA interference screening. Results and discussions The transcriptional profile of oncogene-expressing HSCs is enriched in a quiescent stem cell gene signature, compared to normal HSCs. Therefore, we hypothesised that enhancement of the quiescent phenotype in HSCs could be a shared mechanism for leukaemia development and maintenance. The in vivo shRNA screening allowed the identification of genes whose silencing in AML blasts was sufficient to significantly decrease in vitro self-renewal and delay leukaemia growth in vivo. Conclusion We identified quiescence-related genes, commonly deregulated by leukemic oncogenes at pre-leukemic level, which may offer new therapeutic targets in a wide group of AML patients.