Targeted Deep Sequencing of Mycosis Fungoides Reveals Intracellular Signaling Pathways Associated with Aggressiveness and Large Cell Transformation

Wobser, Marion; Roth, Sabine; Appenzeller, Silke; Houben, Roland; Schrama, David; Goebeler, Matthias; Geissinger, Eva; Rosenwald, Andreas; Maurus, Katja

doi:10.3390/cancers13215512

Cited by 8 publications

(3 citation statements)

References 58 publications

(81 reference statements)

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“…tMF was shown to have recurrent activating RAS mutations ( KRAS and NRAS ), mutations in JAK/STAT pathway, and epigenetic regulation genes ( TET2 , DNMT3A, KMT2D , EP300 , EZH2 , and CREBBP ). 9 Another common molecular finding associated with tMF is CDKN2A/CDKN2B deletions, which also serve as an independent predictor of reduced survival, and which might be a useful diagnostic tool in the differentiation of tMF and pcALCL. 10 Although our case did not show similar molecular findings, the NGS study of the lymph node showed mutations in genes commonly altered in MF, including SOCS1 , TP53 , and RB1 , and we believe that these findings support the diagnosis of tMF.…”

Section: Discussionmentioning

confidence: 99%

Anaplastic Large Cell Transformation of Mycosis Fungoides: Case Report and Review of the Literature

Flerova,

Alpdogan,

Bhatti

et al. 2023

The American Journal of Dermatopathology

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We report a 48-year-old man with CD30+ large cell transformation of mycosis fungoides (tMF) with distinctive anaplastic morphology. The patient initially presented with folliculotropic and syringotropic mycosis fungoides (MF) manifested as occipital scalp plaque and trunk and extremities patches. Six years later, he progressed to the tumor stage from his scalp lesion and developed cervical lymphadenopathy. Lymph node and scalp biopsies showed diffuse infiltration of CD30+ anaplastic cells with multinucleated, hallmark-like, Hodgkin–Reed–Sternberg-like, histiocytoid forms, indistinguishable from anaplastic large cell lymphoma (ALCL). T-cell receptor gamma gene (TCRg) rearrangement studies revealed identical clones in the initial MF scalp lesion and nodal anaplastic lesion, confirming the transformation. Ancillary studies showed absence of IRF4/DUSP22 and ALK rearrangements and positive RB1, SMARCA4, SOCS1, and TP53 mutations. The patient achieved partial response with systemic chemotherapy. Our case is an example of tMF presenting as the morphology and phenotype of ALCL. Because clinical behavior and therapeutic options of tMF and primary cutaneous ALCL may be different, it is clinically relevant to differentiate these 2 entities. The proof of clonal relationship may be useful in diagnostically challenging cases with features overlapping between tMF and primary cutaneous ALCL.

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Section: Discussionmentioning

confidence: 99%

Anaplastic Large Cell Transformation of Mycosis Fungoides: Case Report and Review of the Literature

Flerova,

Alpdogan,

Bhatti

et al. 2023

The American Journal of Dermatopathology

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“…The overexpression of downstream signaling components like MAPK of cytokine receptors is due to gain-of-function mutation in B-Raf (p. Asp594Asn) and ERK-1 (p. Glu322Ala, p. Glu322lys) in MF subjects (74). In stage IV subjects of MF, mutations were identified in KRAS (Kristen Rat Sarcoma Viral oncogene homolog) and NRAS (Neuroblastoma RAS Viral oncogene homolog) genes (74)(75)(76). Immunohistochemistry studies revealed that in the nucleus of 53% cells of MF lesion, ERK1/2 gets phosphorylated, which has been associated with phospho-4E-BP1 (Eukaryotic Translation Initiation Factor 4E Binding Protein 1) (p-4E-BP1) upregulation.…”

Section: Cytokine and Cell Signaling In The Tumor Microenvironment Of...mentioning

confidence: 99%

Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment

Yadav,

Uikey,

Rathore

et al. 2023

Front. Oncol.

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T cells are an important component of adaptive immunity and T-cell-derived lymphomas are very complex due to many functional sub-types and functional elasticity of T-cells. As with other tumors, tissues specific factors are crucial in the development of T-cell lymphomas. In addition to neoplastic cells, T- cell lymphomas consist of a tumor micro-environment composed of normal cells and stroma. Numerous studies established the qualitative and quantitative differences between the tumor microenvironment and normal cell surroundings. Interaction between the various component of the tumor microenvironment is crucial since tumor cells can change the microenvironment and vice versa. In normal T-cell development, T-cells must respond to various stimulants deferentially and during these courses of adaptation. T-cells undergo various metabolic alterations. From the stage of quiescence to attention of fully active form T-cells undergoes various stage in terms of metabolic activity. Predominantly quiescent T-cells have ATP-generating metabolism while during the proliferative stage, their metabolism tilted towards the growth-promoting pathways. In addition to this, a functionally different subset of T-cells requires to activate the different metabolic pathways, and consequently, this regulation of the metabolic pathway control activation and function of T-cells. So, it is obvious that dynamic, and well-regulated metabolic pathways are important for the normal functioning of T-cells and their interaction with the microenvironment. There are various cell signaling mechanisms of metabolism are involved in this regulation and more and more studies have suggested the involvement of additional signaling in the development of the overall metabolic phenotype of T cells. These important signaling mediators include cytokines and hormones. The impact and role of these mediators especially the cytokines on the interplay between T-cell metabolism and the interaction of T-cells with their micro-environments in the context of T-cells lymphomas are discussed in this review article.

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“…MF/SS pathogenesis and the mechanisms involved in their progression from early to advanced phases are far from being fully understood [10][11][12]. Different players are involved in MF/SS, such as gene alterations, changes in the microenvironment composition, cytokine balance changes, and transcriptional pathways [10][11][12][13][14][15][16]. All these players are intrinsically linked.…”

Section: Introductionmentioning

confidence: 99%

The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets

Guglielmo,

Zengarini,

Agostinelli

et al. 2024

Cells

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Cutaneous T cell lymphomas (CTCLs), encompassing mycosis fungoides (MF) and Sézary syndrome (SS), present a complex landscape influenced by cytokines and cellular responses. In this work, the intricate relationship between these inflammatory proteins and disease pathogenesis is examined, focusing on what is known at the clinical and therapeutic levels regarding the most well-known inflammatory mediators. An in-depth look is given to their possible alterations caused by novel immunomodulatory drugs and how they may alter disease progression. From this narrative review of the actual scientific landscape, Interferon-gamma (IFN-γ) emerges as a central player, demonstrating a dual role in both promoting and inhibiting cancer immunity, but the work navigates through all the major interleukins known in inflammatory environments. Immunotherapeutic perspectives are elucidated, highlighting the crucial role of the cutaneous microenvironment in shaping dysfunctional cell trafficking, antitumor immunity, and angiogenesis in MF, showcasing advancements in understanding and targeting the immune phenotype in CTCL. In summary, this manuscript aims to comprehensively explore the multifaceted aspects of CTCL, from the immunopathogenesis and cytokine dynamics centred around TNF-α and IFN-γ to evolving therapeutic modalities. Including all the major known and studied cytokines in this analysis broadens our understanding of the intricate interplay influencing CTCL, paving the way for improved management of this complex lymphoma.

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Targeted Deep Sequencing of Mycosis Fungoides Reveals Intracellular Signaling Pathways Associated with Aggressiveness and Large Cell Transformation

Cited by 8 publications

References 58 publications

Anaplastic Large Cell Transformation of Mycosis Fungoides: Case Report and Review of the Literature

Anaplastic Large Cell Transformation of Mycosis Fungoides: Case Report and Review of the Literature

Role of cytokine in malignant T-cell metabolism and subsequent alternation in T-cell tumor microenvironment

The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets

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