John G. Doench

Oct 16, 2024 | nature.com | Martin W. LaFleur |Rocky M. Barilla |Ayshwarya Subramanian |Yoon-Chul Kye |John G. Doench |Isaac M. Chiu | +2 more

AbstractThe balance between T helper type 1 (TH1) cells and other TH cells is critical for antiviral and anti-tumour responses1,2,3, but how this balance is achieved remains poorly understood. Here we dissected the dynamic regulation of TH1 cell differentiation during in vitro polarization, and during in vivo differentiation after acute viral infection.

May 8, 2024 | nature.com | Qingyu Luo |Miguel Prado |Xiaowei Wu |Ran Xu |Peter van Galen |John G. Doench | +4 more

AbstractPhosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1,2,3,4. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid and dendritic lineages.

Apr 27, 2024 | nature.com | Nazanin Esmaeili Anvar |John G. Doench

AbstractGenetic interactions mediate the emergence of phenotype from genotype, but technologies for combinatorial genetic perturbation in mammalian cells are challenging to scale. Here, we identify background-independent paralog synthetic lethals from previous CRISPR genetic interaction screens, and find that the Cas12a platform provides superior sensitivity and assay replicability.

Mar 8, 2024 | jbc.org | Aaron Embry |John G. Doench |Nicholas Heaton |Craig B. Wilen

AbstractThe innate immune system features a web of interacting pathways that require exquisite regulation. To identify novel nodes in this immune landscape we conducted a gain of function, genome-wide CRISPR activation screen with influenza A virus. We identified both appreciated and novel antiviral genes, including JADE3 a protein involved in directing the histone acetyltransferase HBO1 complex to modify chromatin and regulate transcription.

Dec 4, 2023 | nature.com | Keene L. Abbott |Audrey J. Muscato |Kathleen B. Yates |Juan Dubrot |John G. Doench |Marcela V. Maus | +3 more

AbstractCAR-T therapy is a promising, novel treatment modality for B-cell malignancies and yet many patients relapse through a variety of means, including loss of CAR-T cells and antigen escape. To investigate leukemia-intrinsic CAR-T resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screens in an immunocompetent murine model of B-cell acute lymphoblastic leukemia (B-ALL) utilizing a modular guide RNA library.