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GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant [ChIP-Seq]

ABSTRACT: Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are uniformly lethal malignancies lacking targeted therapies. These gliomas uniquely originate from interneuronal precursor cells, and leveraging this interneuronal lineage origin for mechanistic and therapeutic insights is a pressing need. Here, we elucidate the cell state composition of DHG-H3G34, resolving a cellular hierarchy along continuous interneuron lineage development. In the developing human brain, interneuron lineage precursors form characteristic histological patterns organized in streams of progenitor cells surrounding nests of migratory interneurons, and we find these same spatial patterns to be mirrored in primary DHG-H3G34 tumors. We integrated these findings with genome-wide CRISPR-Cas9 screens, which revealed the majority of dependencies to be genes upregulated in interneuron lineage progenitors, highlighting these as a driver of DHG-H3G34. We validated the essentiality of these lineage-associated targets in patient-derived in vitro and in vivo models. Among these, CDK6 emerged as a targetable dependency, and we demonstrated enhanced sensitivity of DHG-H3G34 tumor cells to CDK4/6 inhibitors and a CDK6-specific degrader. Inhibition of CDK6 shifted cells towards more mature interneuron-like cell states, reduced tumor growth, and prolonged survival of patient-derived xenografts. Concordantly, a patient with progressive DHG-H3G34 under second line therapy was treated with a CDK4/6 inhibitor, and exhibited stable disease for 17 months. Collectively, we identify interneuronal progenitor-like states, organized in characteristic developmental spatial niches, as a distinct vulnerability consistently upregulated in DHG-H3G34 tumors, and provide initial evidence for CDK6 as a clinically actionable target particularly relevant for its interneuronal developmental biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272262 | GEO | 2024/08/01

REPOSITORIES: GEO

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Project description:Cdk4 and Cdk6 are two related kinases that bind D-type cyclins and regulate cell cycle progression. Due to their relevance in cancer, Cdk4/6 inhibitors are currently in advanced clinical trials in multiple tumor types. Cdk4/6 are inhibited by INK4 proteins that exert tumor suppressing functions. To test the significance of this inhibitory mechanism we have generated knock-in mice that express a Cdk6 mutant (Cdk6 R31C) insensitive to INK4-mediated inhibition. Cdk6R/R mice display altered development of the hematopoietic system without resulting in enhanced tumor susceptibility, either in the presence or absence of p53. The presence of the Cdk6 R31C allele results in defective potential of hematopoietic progenitors in adoptive transfer assays or after induced damage. These defects are rescued after complete insensitivity to INK4 inhibitors in Cdk4R/R; Cdk6R/R double mutant mice, and INK4-resistant mice display increased susceptibility to hematopoietic and endocrine tumors. In BCR-ABL-transformed hematopoietic cells, the presence of the Cdk6 R31C allele results in increased binding of p16INK4a to wild-type Cdk4, whereas the double mutant is fully insensitive to INK4 inhibitors resulting in accelerated disease onset. Our observations reveal that Cdk4 and Cdk6 cooperate in tumor development and suggest a role for Cdk6 in buffering INK4 protein levels thus contributing to the development of hematopoietic tumors. The presence of the Cdk4 R24C and Cdk6 R31C alleles results in relevant changes in the expression profiles of cancer cells including deregulation of apoptosis and other processes. p185BCR-ABL1 was used to transform wild-type or double knock-in Cdk4 R24C; Cdk6 R31C fetal livers. Cell lines were isolated as spontaneous immortal and transformed clones after transduction of fetal liver with a p185 BCR-ABL1-transgene. RNA was isolated from asynchronous cultures. Two-condition experiment, Cdk4R-Cdk6R cells versus wild-type cells. Biological replicates: 3 control replicates, 3 transfected replicates.

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GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant [ChIP-Seq]

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