Annotation of immunologic gene function in vivo typically requires the generation of knockout mice, which is time-consuming and low-throughput. We previously developed CHimeric IMmune Editing (CHIME), a CRISPR-Cas9 bone marrow delivery system for constitutive, ubiquitous deletion of single genes. Here we describe X-CHIME, four new CHIME-based systems for modular and rapid interrogation of gene function combinatorially (C-CHIME), inducibly (I-CHIME), lineage-specifically (L-CHIME), or sequentially (S-CHIME). We use C-CHIME and S-CHIME to delete PTP1B and PTPN2 in immune cells. PTPN2 is of therapeutic interest, but has a similar catalytic site as PTP1B, making development of specific catalytic site inhibitors challenging. Thus, we modeled potential toxicities resulting from deletion of both genes. We find that constitutive deletion of PTP1B and PTPN2 leads to bone marrow hypoplasia and lethality, while inducible deletion after immune development leads to enteritis and lethality. These findings demonstrate that X-CHIME can be used for rapid mechanistic evaluation of genes in distinct in vivo contexts and that catalytic inhibitors of both PTP1B/PTPN2 may cause toxicity.