ZEB1 expression was downregulated in AML patients, and Zeb1 KO in the malignant counterparts of HSCs — leukemic stem cells (LSCs) — accelerated MLL-AF9– and Meis1a/Hoxa9-driven AML progression, implicating Zeb1 as a tumor suppressor in AML LSCs. Here, ZEB1 is linked to acute myeloid leukemia.