scholarly journals Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shuhua Cheng ◽  
Wei Zhang ◽  
Giorgio Inghirami ◽  
Wayne Tam

Background: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. Methods: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. Results: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%). Conclusion: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. Funding:R01 grant (CA194547) from the National Cancer Institute to WT.

2020 ◽  
Author(s):  
Shuhua Cheng ◽  
Wei Zhang ◽  
Giorgio Ga. Inghirami ◽  
Wayne Tam

We generated and compared the mutation profiles through targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with angioimmunoblastic T-cell lymphoma (AITL) and 2 with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Our results provided strong evidence that AITL/PTCL-NOS, clonal hematopoiesis (CH) as well as other concomitant myeloid and even B-cell hematologic neoplasms (CHN), frequently arose from common mutated hematopoietic stem cell clones. Aberrant AID/APOBEC activity-associated substitutions and tobacco smoking-associated substitutions were enriched in the early CH-associated mutations and late non-CH associated mutations during AITL/PTCL-NOS development, respectively. Moreover, survival analysis showed that the presence of CH harboring ≥2 pathogenic TET2 variants with ≥ 15% of allele burden conferred higher risk for CHN (P = 0.0034, hazard ratio = 10.81). These findings provide insights into the cell origin and etiology of AITL, and provide a novel stratification biomarker for CHN risk in AITL/PTCL-NOS patients.


2015 ◽  
Vol 8 (4) ◽  
pp. 235-241 ◽  
Author(s):  
Yi Zhou ◽  
Marc K. Rosenblum ◽  
Ahmet Dogan ◽  
Achim A. Jungbluth ◽  
April Chiu

2019 ◽  
Vol 36 (1) ◽  
pp. 57-59
Author(s):  
Cem Şimşek ◽  
Başak Bostankolu ◽  
Ece Özoğul ◽  
Arzu Sağlam Ayhan ◽  
Ayşegül Üner ◽  
...  

2006 ◽  
Vol 130 (11) ◽  
pp. 1707-1711
Author(s):  
Robert C. Hawley ◽  
Milena Cankovic ◽  
Richard J. Zarbo

Abstract Patients with angioimmunoblastic T-cell lymphoma can have profound immune dysfunction and immunodeficiency. Epstein-Barr virus–driven B-cell lymphoid proliferation can occur in angioimmunoblastic T-cell lymphoma, as in other immunodeficiency states. However, few cases of Epstein-Barr virus–positive B-cell lymphoma arising in patients with preexisting angioimmunoblastic T-cell lymphoma have been reported. We report a case of angioimmunoblastic T-cell lymphoma in which diffuse large B-cell lymphoma developed 56 months after the diagnosis of angioimmunoblastic T-cell lymphoma. The patient survived for 9 years after the initial diagnosis of angioimmunoblastic T-cell lymphoma, and molecular studies performed on multiple biopsy specimens during this period revealed the dynamic nature of clonal lymphoid expansion. Epstein-Barr virus latent membrane protein 1 and Epstein-Barr virus– encoded RNA were detected in the diffuse large B-cell lymphoma, suggesting that Epstein-Barr virus may have played a role in the pathogenesis of the diffuse large B-cell lymphoma.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3059-3059
Author(s):  
Yuhei Shibata ◽  
Nobuhiko Nakamura ◽  
Senji Kasahara ◽  
Toshiki Yamada ◽  
Michio Sawada ◽  
...  

Abstract BACKGROUND: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is relatively rare, accounting for only 10% to 15% of non–Hodgkin's lymphomas, and is characterized by disseminated disease, with systemic symptoms, bone marrow involvement, and extranodal disease. There is no general consensus regarding the preferred induction chemotherapy for PTCL-NOS. CHOP regimen consisting of cyclophosphamide (CPA), doxorubicin (DOX), vincristine (VCR) and prednisone (PSL) has been the most frequently employed regimen for PTCL-NOS, but the overall survival in each IPI category appears lower in patients with most PTCL-NOS than seen in diffuse large B-cell lymphoma. Pirarubicin (tetrahydropyranyladriamycin: THP), a derivative of DOX, is reportedly an anthracyclin with less cardiotoxicity than DOX, because the cardiac sympathetic dysfunction and cardiac mitochondrial damage were less common with THP than those with doxorubicin. We previously reported THP-COP regimen consisting of THP, CPA, VCR, and PSL produced resulted equivalent to CHOP regimen regarding efficacy and safety in patients with aggressive non-Hodgkin's lymphoma (Tsurumi H et al. JCRCO 2004). In addition The Japanese Clinical Study Group of THP Lymphomas in the Elderly reported that T-cell lymphomas had a significantly better response to THP-COP than CHOP, and no such difference was observed in B-cell lymphoma. Therefore, we conducted a retrospective analysis to confirm the efficacy of THP-COP in the treatment of PTCL-NOS. PATIENTS AND METHODS: The study protocol employed a retrospective, consecutive entry design. We retrospectively analyzed 61 patients with PTCL-NOS who had received THP-COP or CHOP in 5 institutes of Gifu Hematology Study Group between December 1995 and March 2013. A diagnosis of PTCL-NOS was confirmed histrogically according to the World Health Organization classification. We exclude patients who had previously treated with any chemotherapy for lymphoma, and were diagnosed as Adult T-cell leukemia/lymphoma or angioimmunoblastic T-cell lymphoma. CHOP regimen composed CPA (750 mg/m2), DOX (50 mg/m2), VCR (1.4 mg/m2, maximal dose 2.0 mg) and PSL (100mg/body, administered for 5 days). In THP-COP regimen, THP (50 mg/m2) was used instead of DOX. These regimens were performed every 14 to 21 days. Thirty patients received THP-COP, 31 received CHOP. There were no significant differences in known prognostic factors include the international prognostic index (IPI) and prognostic index for T-cell lymphoma (PIT) between two groups. The median cycles of treatment were 6 in both groups. The median follow-up times were 25 and 19 months, respectively. RESULT: Complete remission (CR) rates in the patients with THP-COP and CHOP were 53% and 55% (P=0.906), 3-yr overall survival (OS) rate 68% and 51% (P=0.096), and 3-yr progression free survival (PFS) rate 46% and 27% (P=0.078), respectively. Although there were no significant differences between two groups, THP-COP regimen had a tendency of better prognosis. In patients with low IPI (Low or Low-intermediate), THP-COP had significantly better 3yr-OS (100% vs 63%, P=0.002) and 3yr-PFS (69% vs 34%, P=0.002). Same difference was observed in patients with low PIT (group1 or 2), but was not observed in patients with high IPI (High-intermediate or High) or PIT (Group3 or 4). Fatal non-hematological adverse event did not occur in both groups. CONCLUSION: Our study showed THP-COP produced resulted equivalent to CHOP regarding efficacy and safety in patients with PTCL-NOS. Moreover, THP-COP had a tendency of better prognosis compared with CHOP. In patients with low IPI or PIT, THP-COP had significantly better prognosis. This result indicates that THP-COP is an effective and well tolerated regimen for patients with PTCL-NOS, and might be translated into improving survival in comparison with CHOP. Further large study is needed to clarify the difference between the two regimens. Disclosures No relevant conflicts of interest to declare.


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