What we investigated. We started from an asset rather than a disease: a genome-scale CD4⁺ T-cell Perturb-seq dataset (a CRISPR knockout screen read out in single cells). The question we set was inverted from the usual pipeline — instead of picking a disease and hunting for data, we asked which disease would let this perturbation asset reveal a high-impact drug target? We chose Sézary syndrome (SS), a leukemic cutaneous T-cell lymphoma driven by a circulating malignant CD4⁺ T cell, because it satisfied three criteria: public clinical single-cell transcriptomes are available, blood CD4⁺ T cells are central to the pathology, and the CD4⁺ T cell itself is the therapeutic target. What we built. On a 7 GB laptop, we integrated five public SS scRNA-seq datasets (≈180,000 cells) with Harmony, isolated the malignant Sézary T-cell population (63,127 cells) with a signature score, and defined the SS-specific expression profile — reproducing the known diagnostic hallmarks (loss of CD7; gain of KIR3DL2, TOX, GATA3). We then defined a reversal score: for each of ~34,000 knockouts we compared its transcriptional effect to the SS disease signature by weighted cosine similarity and flipped the sign, so a positive score means the knockout pushes cells from the disease state back toward healthy (connectivity-map logic). What we found. IL2RB (CD122) is the single largest disease-axis mover among 7,822 high-confidence knockouts — reversing the disease signature ~2× more than the targets of drugs already approved for SS (bexarotene/RXR, HDAC inhibitors). This target is invisible to standard analysis. The reversal score is essentially uncorrelated with a gene's own expression change in SS (Spearman ρ = +0.055) — so IL2RB would never surface from differential-expression or enrichment analysis. It only appears through functional perturbation. A route to drug it. IL2RB is a membrane protein with no small-molecule pocket, and existing IL-2-receptor antibodies act by cell depletion, not signal blockade. Because Perturb-seq measures loss-of-function, the faithful pharmacological equivalent is degradation. Screening degradation machinery in SS T cells, only RNF43/RNF149/RNF167 are expressed in CD4⁺ T cells; RNF149 stands out — expressed in 42% of malignant cells and ~8× restricted to blood/lymphoid tissue, offering potential T-cell selectivity and reduced off-target toxicity. Why it matters. SS has high unmet need and no IL2RB-targeted, degradation-based therapy in the competitive landscape. Our conclusion — degradation of IL2RB via RNF149 would be a promising therapeutic strategy for SS — is a reproducible, computationally derived hypothesis that demonstrates a generalizable discovery pattern: pairing a disease's clinical transcriptome with a functional perturbation screen surfaces targets that expression-based analysis alone cannot.
Team
Placement
Participant
