All in all, the studies discussed above:1) provide further evidence of the “non-canonical” function of PIWI pathways acting as gene expression regulators beyond the germline, 2) reveal that, while PIWIL4 executes its role of guarding of genomic stability in LSCs in a piRNA-independent manner it does not seem to impact normal hematopoiesis and 3) uncover a potential therapeutic avenue for the treatment of AML by targeting PIWIL4 in LSCs. Here, PIWIL1 is linked to acute myeloid leukemia.