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Pten deficiency depletes hematopoietic stem cells (HSCs) but expands leukemia-initiating cells, as well as the mTOR inhibitor,DNA Methyltransferase rapamycin, blocks these results. Comprehending the opposite effects of mTOR activation selleck chem on HSCs versus leukemia-initiating cells could boost antileukemia therapies. We observed that the depletion of Pten-deficient HSCs was not triggered by oxidative anxiety and could not be blocked by N-acetyl-cysteine. As a substitute, Pten deletion induced, and rapamycin attenuated, the expression of p16(Ink4a) and p53 in HSCs, and p19(Arf) and p53 in other hematopoietic cells. p53 suppressed leukemogenesis and promoted HSC depletion after Pten deletion. p16(Ink4a) also promoted HSC depletion but had a limited purpose suppressing leukemogenesis. p19(Arf) strongly suppressed leukemogenesis but did not deplete HSCs. Secondary mutations attenuated this tumor suppressor response in some leukemias that arose immediately after Pten deletion. mTOR activation for that reason depletes HSCs by a tumor suppressor response that is definitely attenuated by secondary mutations in leukemogenic clones.