Although advance has been made in understanding the pathogenesis of mature T-cell neoplasms, the initiation and progression of angioimmunoblastic T cell lymphoma (AITL) and peripheral T cell lymphoma, not otherwise specified (PTCL-NOS), remains poorly understood. A subset of AITL/PTCL-NOS patients develop concomitant hematologic neoplasms (CHN), and a biomarker to predict this risk is lacking.
We generated and analyzed the mutation profiles through 537-gene targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with AITL and 2 with PTCL-NOS.
Clonal hematopoiesis (CH)-associated genomic alterations, found in 70.4% of the AITL/PTCL-NOS patients, were shared among CH and T-cell lymphoma, as well as concomitant myeloid neoplasms or diffuse large B-cell lymphoma (DLBCL) that developed before or after AITL. Aberrant AID/APOBEC activity-associated and tobacco smoking-associated mutational signatures were respectively enriched in the early CH-associated mutations and late non-CH associated mutations during AITL/PTCL-NOS development. Moreover, analysis showed that the presence of CH harboring ≥ 2 pathogenic TET2 variants with ≥ 15% of allele burden conferred higher risk for CHN (P = 0.0006, hazard ratio = 14.01, PPV=88.9%, NPV=92.1%).
We provided genetic evidence that AITL/PTCL-NOS, CH, CHN can frequently arise from common mutated hematopoietic precursor clones. Our data also suggests smoking exposure as a potential risk factor for AITL/PTCL-NOS progression. These findings provide insights into the cell origin and etiology of AITL and PTCL-NOS and provide a novel stratification biomarker for CHN risk in AITL patients.
R01 grant (CA194547) from the National Cancer Institute to WT.
All relevant data are included in this manuscript and the supplementary files.
Clonal hematopoiesis in angioimmunoblastic T-cell lymphoma with divergent evolution to myeloid neoplasmsTable 2 and supplmental file 1.
- Wayne Tam
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: This study was conducted in accordance with the Declaration of Helsinki regulations of the protocols approved by the Institutional Review Board of Weill Cornell Medicine, New York, USA. Written consent for use of the samples for research was obtained from patients or their guardians.(#0107004999)
- Adam Olszewski, Brown University, United States
© 2021, Cheng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Apicobasal cell polarity loss is a founding event in epithelial–mesenchymal transition and epithelial tumorigenesis, yet how pathological polarity loss links to plasticity remains largely unknown. To understand the mechanisms and mediators regulating plasticity upon polarity loss, we performed single-cell RNA sequencing of Drosophila ovaries, where inducing polarity-gene l(2)gl-knockdown (Lgl-KD) causes invasive multilayering of the follicular epithelia. Analyzing the integrated Lgl-KD and wildtype transcriptomes, we discovered the cells specific to the various discernible phenotypes and characterized the underlying gene expression. A genetic requirement of Keap1-Nrf2 signaling in promoting multilayer formation of Lgl-KD cells was further identified. Ectopic expression of Keap1 increased the volume of delaminated follicle cells that showed enhanced invasive behavior with significant changes to the cytoskeleton. Overall, our findings describe the comprehensive transcriptome of cells within the follicle cell tumor model at the single-cell resolution and identify a previously unappreciated link between Keap1-Nrf2 signaling and cell plasticity at early tumorigenesis.
Sarcomas comprise approximately 1% of all human malignancies; treatment resistance is one of the major reasons for the poor prognosis of sarcomas. Accumulating evidence suggests that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs, and circular RNAs, are important molecules involved in the crosstalk between resistance to chemotherapy, targeted therapy, and radiotherapy via various pathways.
We searched the PubMed (MEDLINE) database for articles regarding sarcoma-associated ncRNAs from inception to August 17, 2022. Studies investigating the roles of host-derived miRNAs, long ncRNAs, and circular RNAs in sarcoma were included. Data relating to the roles of ncRNAs in therapeutic regulation and their applicability as biomarkers for predicting the therapeutic response of sarcomas were extracted. Two independent researchers assessed the quality of the studies using the Würzburg Methodological Quality Score (W-MeQS).
Observational studies revealed the ectopic expression of ncRNAs in sarcoma patients who had different responses to antitumor treatments. Experimental studies have confirmed crosstalk between cellular pathways pertinent to chemotherapy, targeted therapy, and radiotherapy resistance. Of the included studies, W-MeQS scores ranged from 3 to 10 (average score = 5.42). Of the 12 articles that investigated ncRNAs as biomarkers, none included a validation cohort. Selective reporting of the sensitivity, specificity, and receiver operating curves was common.
Although ncRNAs appear to be good candidates as biomarkers for predicting treatment response and therapeutics for sarcoma, their differential expression across tissues complicates their application. Further research regarding their potential for inhibiting or activating these regulatory molecules to reverse treatment resistance may be useful.
This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).