Cell-Cycle Restriction Sustains Therapy-Resistant Pre-Leukemic Stem Cells. Cell-Cycle Restriction Sustains Therapy-Resistant Pre-Leukemic Stem Cells

Pre-leukemic stem cells (pre-LSCs) provide a reservoir of cells that evolve to acute leukemia and cause relapse following chemotherapy. We postulated that quiescence of pre-LSCs is an important mechanism of therapeutic resistance. Using a doxycycline-inducible H2B-GFP transgene in a mouse model of T-cell acute lymphoblastic leukemia, we show that long-term self-renewal, clonal evolution and resistance to chemo-radiation are intrinsically linked to restricted cell cycle. We show that restricted cell cycle of pre-LSCs requires the presence of the CDK inhibitor p21, with absence of p21 leading to chemosensitivity and clonal extinction by loss of asymmetric cell division and terminal differentiation. These results provide a model to identify and test strategies to eradicate an important source of clonal evolution and leukemic relapse. Overall design: Three pooled replicates from LSC (GFP-High) and non-LSC (GFP-Low) populations. Profiled by mRNA Seq