Here we show that in t(8;21) acute myelogenous leukemia (AML), hematopoietic stem cells (HSCs) transform into LSCs via definitively-ordered acquisition of Class II (AML1/ETO) and then Class I (c-KIT mutant) abnormalities.     ///    "Thus, in t(8;21) AML, the acquisition of AML1/ETO is not sufficient, and the subsequent upregulation of AML1/ETO and the additional c-KIT mutant signaling are critical steps for transformation into LSCs.. "    ///    "At diagnosis, all single LSCs had both AML1/ETO and c-KIT mutations. "    ///    "These cells had wild-type c-KIT, which expressed AML1/ETO at a low level, and could differentiate into mature blood cells, suggesting that they may be the persistent preleukemic stem cells. "    ///    "However, in remission, 16 out of 1,728 CD34(+)CD38(-) HSCs and 89 out of 7,187 single HSC-derived myeloerythroid colonies from these patients had AML1/ETO, whose breakpoints were identical to those found in LSCs. "