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CUT&Tag chromatin profiling of HLF-deficient YCUB2 cells

ABSTRACT: The TCF3::HLF fusion protein defines a subtype of incurable B cell acute lymphoblastic leukemia (B-ALL). Here, we identified self-reinforcing IL-1b networks in TCF3::HLF B-ALL cells using a newly-established mouse model that fully recapitulates human TCF3::HLF B-ALL, including osteolysis. We found significant upregulation of several inflammatory cytokines, including IL1B, IL6 and IFNG in the B-ALL mice. Deletion of IL1B or IL1R1 strongly inhibited the growth of the human TCF3::HLF B-ALL cells, reduced the expression of RANKL and ameliorated the destruction of bone in the transplanted mice. Genetic and epigenetic analyses identified a previously unknown regulatory region of the IL1B gene locus, where TCF3::HLF directly binds. Importantly, single cell RNA-seq profiling of TCF3::HLF B-ALL patients revealed a dramatic upregulation of IL1B at relapse compared to the time of diagnosis. These findings suggest a critical role of TCF3::HLF-IL-1b axis for the progression of TCF3::HLF B-ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303391 | GEO | 2025/10/03

REPOSITORIES: GEO

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Project description:Background: Based on the mounting evidence that Type 17 T-cells (T17 cells) and increased IL-17 play a key role in driving hidradenitis suppurativa (HS) lesion development, biologics previously used in psoriasis that block signaling of IL-17A and/or IL-17F isoforms have been repurposed to treat HS. Objective: Our aim was to characterize the transcriptome of HS T17 cells compared to the transcriptome of psoriasis T17 cells, and their ligand-receptor interactions with neighborhood immune cell subsets. Methods: Single-cell data of 12,300 cutaneous immune cells from 8 de-roofing surgical HS skin samples that included dermal tunnels were compared with single-cell data of psoriasis skin (19,525 cells from 11 samples) and control skin (11,920 cells from 10 samples). All the single-cell data were generated by the identical protocol. Results: HS T17 cells expressed lower levels of IL23R and higher levels of IL1R1 and IL17F compared to psoriasis T17 cells (p < 0.05). HS regulatory T-cells (Tregs) expressed higher levels of IL1R1 and IL17F compared to psoriasis Tregs (p < 0.05). Semimature dendritic cells (DCs) were the major immune cell subsets expressing IL1B in HS, and IL-1B ligand-receptor interactions between semimature DCs and T17 cells were increased in HS compared to psoriasis (p < 0.05). HS dermal tunnel keratinocytes (KCs) expressed inflammatory cytokines (IL17C, IL1A, IL1B, and IL6) different from HS epidermis KCs (IL36G) (p < 0.05). IL6, which synergizes with IL1B to maintain cytokine expression in T17 cells, was mainly expressed by fibroblasts in HS, which also expressed IL11+ inflammatory fibroblast genes (IL11, IL24, IL6, and POSTN) involved in paracrine IL-1/IL-6 loop. Conclusion: The IL-1B-T17 cell cytokine axis is likely a dominant pathway in HS with HS T17 cells activated by IL-1B signaling, unlike psoriasis T17 cells which are activated by IL-23 signaling. Clinical Implication: Biologics targeting IL-17 isoforms and IL-1B may be effective for HS but biologics targeting IL-23 may be less effective for HS.

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CUT&Tag chromatin profiling of HLF-deficient YCUB2 cells

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