Molecular Insights Into Pathogenesis of Peripheral T Cell Lymphoma: a Review

Lone, Waseem; Alkhiniji, Aisha; Umakanthan, Jayadev Manikkam; Iqbal, Javeed

doi:10.1007/s11899-018-0460-z

Cited by 19 publications

(19 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Their reported incidences range from 10% (e.g., for Sézary syndrome [29]) to 70% (e.g., for intestinal T-cell lymphoma [30]). Compared to those, the cumulative mutation frequency of JAK and STAT genes in T-PLL documented in this meta-analysis is high [31].…”

Section: Discussionmentioning

confidence: 62%

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

Wahnschaffe

Braun

Timonen

et al. 2019

Cancers

View full text Add to dashboard Cite

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. Recent studies detected genomic aberrations affecting JAK and STAT genes in T-PLL. Due to the limited number of primary patient samples available, genomic analyses of the JAK/STAT pathway have been performed in rather small cohorts. Therefore, we conducted-via a primary-data based pipeline-a meta-analysis that re-evaluated the genomic landscape of T-PLL. It included all available data sets with sequence information on JAK or STAT gene loci in 275 T-PLL. We eliminated overlapping cases and determined a cumulative rate of 62.1% of cases with mutated JAK or STAT genes. Most frequently, JAK1 (6.3%), JAK3 (36.4%), and STAT5B (18.8%) carried somatic single-nucleotide variants (SNVs), with missense mutations in the SH2 or pseudokinase domains as most prevalent. Importantly, these lesions were predominantly subclonal. We did not detect any strong association between mutations of a JAK or STAT gene with clinical characteristics. Irrespective of the presence of gain-of-function (GOF) SNVs, basal phosphorylation of STAT5B was elevated in all analyzed T-PLL. Fittingly, a significant proportion of genes encoding for potential negative regulators of STAT5B showed genomic losses (in 71.4% of T-PLL in total, in 68.4% of T-PLL without any JAK or STAT mutations). They included DUSP4, CD45, TCPTP, SHP1, SOCS1, SOCS3, and HDAC9.Overall, considering such losses of negative regulators and the GOF mutations in JAK and STAT genes, a total of 89.8% of T-PLL revealed a genomic aberration potentially explaining enhanced STAT5B activity. In essence, we present a comprehensive meta-analysis on the highly prevalent genomic lesions that affect genes encoding JAK/STAT signaling components. This provides an overview of possible modes of activation of this pathway in a large cohort of T-PLL. In light of new advances in JAK/STAT inhibitor development, we also outline translational contexts for harnessing active JAK/STAT signaling, which has emerged as a 'secondary' hallmark of T-PLL.

show abstract

Section: Discussionmentioning

confidence: 62%

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

Wahnschaffe

Braun

Timonen

et al. 2019

Cancers

View full text Add to dashboard Cite

show abstract

“…2c) 5 . We therefore sought to investigate the transforming and infiltrative capacity of other mature T-cell subsets, since patients with GOF mutations in the JAK1/3-STAT3/5B pathway also suffer from mature γδ or CD4 + T-cell diseases 5,17 . Upon immunohistological analysis of various peripheral organs from STAT5B N642H mice, it was evident that these mice have severe, proliferative T-cell infiltrations into the skin and lung, as previously observed 5 , as well as in the liver and brain (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural and functional consequences of the STAT5BN642H driver mutation

et al. 2019

View full text Add to dashboard Cite

Hyper-activated STAT5B variants are high value oncology targets for pharmacologic intervention. STAT5B N642H , a frequently-occurring oncogenic driver mutation, promotes aggressive T-cell leukemia/lymphoma in patient carriers, although the molecular origins remain unclear. Herein, we emphasize the aggressive nature of STAT5B N642H in driving T-cell neoplasia upon hematopoietic expression in transgenic mice, revealing evidence of multiple T-cell subset organ infiltration. Notably, we demonstrate STAT5B N642H -driven transformation of γδ T-cells in in vivo syngeneic transplant models, comparable to STAT5B N642H patient γδ T-cell entities. Importantly, we present human STAT5B and STAT5B N642H crystal structures, which propose alternative mutation-mediated SH2 domain conformations. Our biophysical data suggests STAT5B N642H can adopt a hyper-activated and hyper-inactivated state with resistance to dephosphorylation. MD simulations support sustained interchain cross-domain interactions in STAT5B N642H , conferring kinetic stability to the mutant anti-parallel dimer. This study provides a molecular explanation for the STAT5B N642H activating potential, and insights into pre-clinical models for targeted intervention of hyper-activated STAT5B.

show abstract

“…The literature often indicates the difficulty of categorizing a specific subtype of TCL. According to Lone et al ., about 30% to 50% of TCL cases remain unspecified.…”

Section: Discussionmentioning

confidence: 99%

“…NHL is common in patients with immunological disorders, such as congenital immunodeficiencies, acquired immunodeficiency syndrome (AIDS), and autoimmune diseases (Sjogren's syndrome and systemic lupus erythematosus), as well as in patients taking immunosuppressive drugs or undergoing organ transplantation . Several viruses may also play an important role in the pathogenesis of NHL, for example, the Epstein‐Barr virus and the human T‐cell lymphotropic virus type I …”

Section: Introductionmentioning

confidence: 99%

“…The analysis of gene expression profiles has contributed to the identification of different oncogenic pathways among T‐cell lymphoma (TCL) subtypes, as well as to elucidate recurrent somatic mutations ( TET2 , IDH2 , RHOA , DNMT3A , and FYN in PTCL) and different molecular signatures, allowing for the clarification of the pathogenic mechanisms of TCL and potential therapeutic targets …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Peripheral T‐cell non‐Hodgkin lymphoma manifesting as a primary lesion on the lip: A rare case report

Santos

Alves

Mattos

et al. 2018

Special Care in Dentistry

View full text Add to dashboard Cite

Primary manifestations of extraganglion non-Hodgkin lymphoma (NHL) from T-cells in the oral cavity are rare and often difficult to diagnose. Herein, we describe a case of T-cell NHL with a primary lesion on the lip diagnosed with a 25-year-old woman. The patient reported the appearance of the initial lesion on the upper lip, which advanced to the hard palate and oral mucosa. Histological examination and immunohistochemistry were compatible with peripheral T-cell NHL without further specifications. The proposed treatment consisted of six cycles of multiagent chemotherapy. The patient died from complications of the disease before the third cycle of chemotherapy. Understanding the clinical signs of lymphoma is important for the early diagnosis of this disease to avoid aggressive and potentially fatal behavior. K E Y W O R D S lymphoma, non-Hodgkin, lip neoplasms, peripheral T-cell lymphoma 438 wileyonlinelibrary.com/journal/scd Spec Care Dentist. 2018;38:438-444.

show abstract

Molecular Insights Into Pathogenesis of Peripheral T Cell Lymphoma: a Review

Cited by 19 publications

References 120 publications

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

Structural and functional consequences of the STAT5BN642H driver mutation

Peripheral T‐cell non‐Hodgkin lymphoma manifesting as a primary lesion on the lip: A rare case report

Contact Info

Product

Resources

About