Negative feedback loop model of Fli-1 and SHIP-1 regulation. During Epo-induced differentiation of erythroid progenitor cells, SHIP-1 expression is high and is able to negatively regulate the PI 3-K/Akt pathway, leading to lower Fli-1 expression. Upon activation of Fli-1 as a result of insertional mutagenesis, the PI 3-K/Akt and the Ras/MAPK pathways are activated. Increased activity of Akt through the PI 3-K/Akt and/or Ras/PI 3-K/Akt pathways further increases transcription of fli-1, leading to a block in differentiation and acceleration of proliferation by Epo. As Fli-1 levels increase, SHIP-1 transcription is suppressed to a greater extent, eventually resulting in complete repression in late stage erythroleukemia.