Using a custom pooled lentiviral library with sgRNAs tiling the coding region of DNMT1 and DNMT3B, we performed CRISPR-Cas9 knockout tiling screens across a panel of AML cell lines either wild-type or mutant for DNTM3A. While knockout mutations of DNMT3B had minimal effects on cell proliferation across the AML cell lines screened, we identified sgRNAs spanning DNMT1 that resulted in decreased cell proliferation. Here, DNMT3B is linked to acute myeloid leukemia.