Defined human primary cell model systems with growth dependence on oncogenes are highly requested to investigate tumor pathogenesis and to validate pharmacological inhibitors that specifically target oncoproteins and their executing protein complex partners. In acute myeloid leukemia (AML), transcription factors such as RUNX1 and MLL1, which are important for normal blood cell development, frequently harbor mutations including chromosomal translocations with other coding genes, resulting in tumor-promoting gain-of-function fusion proteins. These oncoproteins completely modify transcriptional programs, thereby inducing malignant cell phenotypes. A common theme of the chimeric gene products is their physical interaction with a variety of chromatin-modifying effector molecules, including histone acetyltransferases (HATs) and histone deacetylases (HDACs). These aberrant multiprotein machineries disturb gene expression and promote malignant cell growth. In this chapter, we briefly summarize the current understanding regarding AML-associated oncogene-driven human CD34+ blood progenitor cell expansion in ex vivo liquid cultures. We provide a step-by-step protocol to establish oncogene-induced human CD34+ blood progenitor cell cultures suitable to analyze the impact of transcriptional repressor/HDAC activity in these human AML cell models.