Here we use an IKZF1 loss-of-function and re-expression approach in human and mouse T-ALL, along with primary human T-ALL, and normal human and mouse thymocytes to determine the roles of IKAROS and HDAC1 in global regulation of facultative heterochromatin and transcriptional repression in T-ALL. Here, HDAC1 is linked to acute lymphoblastic leukemia.