Absence of terminal deoxynucleotidyl transferase expression identifies a subset of high-risk adult T-lymphoblastic leukemia/lymphoma

Zhou, Yanxiang; Fan, Xiangshan; Routbort, Mark J.; Yin, C. Cameron; Singh, Rajesh; Bueso‐Ramos, Carlos E.; Thomas, Deborah A.; Milton, Denái R.; Medeiros, L. Jeffrey; Lin, Pei‐Chen

doi:10.1038/modpathol.2013.78

Cited by 36 publications

(42 citation statements)

References 33 publications

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“…In contrast, H-SB2 and DU.528, which are PIM inhibitor sensitive cells, had an ETP-ALL-like phenotype (CD4 − /CD8 − and TdT − ). However, interestingly the immunophenotype of the KOPT-K1 cells, which also were sensitive to PIM inhibitors and had increased PIM1 levels, was similar to a non-ETP-ALL phenotype [1, 4, 35, 36]. This result is consistent with the concept that immunophenotyping may not rigorously define ETP-ALL and that there may be some cases that represent an “intermediate” category of T-ALL with a non-ETP phenotype but elevated PIM1 levels.…”

Section: Resultsmentioning

confidence: 99%

Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset

Padi

Luevano

et al. 2017

Oncotarget

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New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors. Gene profiling using a publically available T-ALL dataset demonstrated overexpression of PIM1 in the majority of early T-cell precursor (ETP)-ALLs and a small subset of non-ETP ALL. While the PIM inhibitors blocked growth, they also stimulated ERK and STAT5 phosphorylation, demonstrating that activation of additional signaling pathways occurs with PIM inhibitor treatment. To block these pathways, Ponatinib, a broadly active tyrosine kinase inhibitor (TKI) used to treat chronic myelogenous leukemia, was added to this PIM-inhibitor regimen. The combination of Ponatinib with a PIM inhibitor resulted in synergistic T-ALL growth inhibition and marked apoptotic cell death. Treatment of mice engrafted with human T-ALL with these two agents significantly decreased the tumor burden and improved the survival of treated mice. This dual therapy has the potential to be developed as a novel approach to treat T-ALL with high PIM expression.

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Section: Resultsmentioning

confidence: 99%

Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset

Padi

Luevano

et al. 2017

Oncotarget

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“…67 The latter might be related to early thymic progenitor T-ALLs that co-express early myeloid markers, and stem cell markers (CD34 and CD117). These are considered high risk subgroups.…”

Section: Novelties In the New Who Classification Of Mediastinal Tumorsmentioning

confidence: 99%

The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes

Marx

Chan

Coindre

et al. 2015

Journal of Thoracic Oncology

519

420

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This overview of the 4th edition of the WHO Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumour entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1–B3 thymomas and thymic squamous cell carcinoma are given and will hopefully improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery and oncology; by incorporating state-of-the-art PET/CT images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed.

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“…TdT-negative T-ALL/LBL, however, is a rare entity with occasional case reports and series in the literature 5. It progresses at a higher rate and is associated with shorter overall survival 5. We report TdT-negative T-LBL in a 29-year-old man with an aggressive outcome that was associated with loss of CD3 expression on relapse.…”

Section: Introductionmentioning

confidence: 91%

“…Terminal deoxynucleotidyl transferase (TdT) is a marker of immaturity expressed in 90%–95% cases of lymphoblastic lymphoma and useful in differentiating it from other mature lymphomas 3 4. TdT-negative T-ALL/LBL, however, is a rare entity with occasional case reports and series in the literature 5. It progresses at a higher rate and is associated with shorter overall survival 5.…”

Section: Introductionmentioning

confidence: 99%

Terminal deoxynucleotidyl transferase (TdT)-negative T-cell lymphoblastic lymphoma with loss of the T-cell lineage-specific marker CD3 at relapse: a rare entity with an aggressive outcome

Hassan¹,

Abdullah²,

Wahid³

et al. 2018

BMJ Case Reports

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Terminal deoxynucleotidyl transferase (TdT)-negative T-cell lymphoblastic lymphoma is a variant of T-cell lymphoblastic lymphoma/T-cell lymphoblastic leukaemia. TdT is a marker of immaturity expressed in 90%–95% cases of lymphoblastic lymphoma and useful in differentiating it from other mature lymphomas/leukaemias. It has been associated with poorer response to chemotherapy and a more aggressive outcome. Here we present a case of TdT-negative T-cell lymphoblastic lymphoma in a 28-year-old man who presented with superior vena cava syndrome. The patient was treated with hyper-cyclophosphamide,vincristine, Adriamycin, dexamethasone (CVAD), however unfortunately suffered a relapse 1 year later. A unique feature of our case was that on relapse, the patient lost expression of the T-cell lineage-specific marker CD3, which has previously not been reported in association with TdT-negative T-cell lymphoblastic lymphoma. The patient failed to respond to chemotherapy on his relapse and died.

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Absence of terminal deoxynucleotidyl transferase expression identifies a subset of high-risk adult T-lymphoblastic leukemia/lymphoma

Cited by 36 publications

References 33 publications

Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset

Targeting the PIM protein kinases for the treatment of a T-cell acute lymphoblastic leukemia subset

The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes

Terminal deoxynucleotidyl transferase (TdT)-negative T-cell lymphoblastic lymphoma with loss of the T-cell lineage-specific marker CD3 at relapse: a rare entity with an aggressive outcome

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