Identifying NF-kB Targets in Cutaneous T Cell Lymphoma

Project: Research project

Description

[Pending] Cutaneous T cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing CD4+ T cell. The Choi lab elucidated the genomic landscape of CTCL in a recent set of hallmark articles published in Nature Genetics and Blood. Many putative driver genes encode T cell lineage-relevant molecules such as T cell receptor (TCR)-associated costimulatory receptors, enzymes, and scaffolding proteins. Unexpectedly, our functional work has shown that these mutations converge on the NF-B signaling pathway. These data are congruent with small-scale clinical trials, which suggest efficacy of NF-B inhibitors in a subset of patients with CTCL. Unfortunately, due to the historical absence of genomically annotated patient samples, the patients whom NF-B inhibitors benefit and the molecular mechanisms underlying therapeutic responses remain unclear.

Cutaneous T cell lymphoma (CTCL) is an incurable non-Hodgkin lymphoma of the skin-homing CD4+ T cell. The Choi lab elucidated the genomic landscape of CTCL in a recent set of hallmark articles published in Nature Genetics and Blood. Many putative driver genes encode T cell lineage-relevant molecules such as T cell receptor (TCR)-associated costimulatory receptors, enzymes, and scaffolding proteins. Unexpectedly, our functional work has shown that these mutations converge on the NF-kB signaling pathway. These data are congruent with small-scale clinical trials, which suggest efficacy of NF-kB inhibitors in a subset of patients with CTCL. Unfortunately, due to the historical absence of genomically annotated patient samples, the patients whom NF-kB inhibitors benefit and the molecular mechanisms underlying therapeutic responses remain unclear.

To elucidate the potential therapeutic targets of NF-kB signaling pathway in CTCL, we will train Sara Choi, MD/MS candidate from Stanford, on bioinformatics, cancer genomics, and cancer biology through a series of formal meetings where she will present and discuss her work with the PI and the lab. This training will be supplemented by her active participation at relevant intramural meetings in Northwestern’s Department of Dermatology and Biochemistry and Molecular Genetics and national meetings. She will utilize this training to analyze orthogonal RNA and chromatin-Seq datasets from patient samples to identify putative NF-kB targets. She will then perform a series of functional experiments to elucidate the NF-kB target genes that are necessary for lymphomagenesis and to elucidate the patient cohorts that are most likely to benefit from NF-kB inhibitors.
StatusActive
Effective start/end date5/1/1812/31/19

Funding

  • Doris Duke Charitable Foundation (2018041)

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Cutaneous T-Cell Lymphoma
NF-kappa B
Costimulatory and Inhibitory T-Cell Receptors
T-Lymphocytes
Cell Lineage
Non-Hodgkin's Lymphoma
Clinical Trials
Genes
Skin
Mutation
Enzymes
Dermatology
Genomics
Computational Biology
Biochemistry
Chromatin
Molecular Biology
Neoplasms
Proteins
Therapeutics