3′ READS was performed on human AML samples with and without t(8;21) that were enriched for CD34⁺ cells and on healthy CD34⁺ HSPCs to define global APA profiles. In AML samples, shortening of 3′ UTRs and lengthening of CDSs was detected. Mechanistic analysis revealed FIP1L1 as a major regulator of APA in AML that mediates global 3′ UTR shortening. In AML cells with t(8;21), this leads to increased levels of AML1-ETO, whereas in AML cells without t(8;21), mTORC1 and MYC levels are increased. This mechanism contributes to the characteristic block of AML cell differentiation. Knockdown of FIP1L1 reversed the characteristic APA patterns and induced differentiation of AML cells. dPAS, distal poly(A) site; pPAS, proximal poly(A) site.