TY - JOUR
T1 - Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma
AU - Song, Xiaofei
AU - Chang, Shiun
AU - Seminario-Vidal, Lucia
AU - Mingo Pulido, Alvaro De
AU - Tordesillas, Leticia
AU - Song, Xingzhi
AU - Reed, Rhianna A.
AU - Harkins, Andrea
AU - Whiddon, Shannen
AU - Nguyen, Jonathan V.
AU - Segura, Carlos Moran
AU - Zhang, Chaomei
AU - Yoder, Sean
AU - Sayegh, Zena
AU - Zhao, Yun
AU - Messina, Jane L.
AU - Harro, Carly M.
AU - Zhang, Xiaohui
AU - Conejo-Garcia, José R.
AU - Berglund, Anders
AU - Sokol, Lubomir
AU - Zhang, Jianhua
AU - Rodriguez, Paulo C.
AU - Mulé, James J.
AU - Futreal, Andrew P.
AU - Tsai, Kenneth Y.
AU - Chen, Pei Ling
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/5/1
Y1 - 2022/5/1
N2 - Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided in situ evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74. SIGNIFICANCE: Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma.
AB - Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided in situ evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74. SIGNIFICANCE: Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma.
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U2 - 10.1158/2159-8290.CD-21-1207
DO - 10.1158/2159-8290.CD-21-1207
M3 - Article
C2 - 35247891
AN - SCOPUS:85129781361
SN - 2159-8274
VL - 12
SP - 1294
EP - 1313
JO - Cancer discovery
JF - Cancer discovery
IS - 5
ER -