In this study, we conducted an unbiased domain-focused CRISPR library screen (13) [a custom built 992–single guide RNA (sgRNA) library targeting 59 Tudor domains] and identified the requirement of the Spt-Ada-Gcn5 acetyltransferase (SAGA)–associated factor 29 (SGF29; also known as CCDC101) in leukemia initiation and maintenance. The gene discussed is SGF29; the disease is leukemia.