Understanding Cell Lines, Patient-Derived Xenograft and Genetically Engineered Mouse Models Used to Study Cutaneous T-Cell Lymphoma

Abstract

Cutaneous T cell lymphoma (CTCL) is a spectrum of lymphoproliferative disorders caused by the infiltration of malignant T cells into the skin. The most common variants of CTCL include mycosis fungoides (MF), Sézary syndrome (SS) and CD30+ Lymphoproliferative disorders (CD30+ LPDs). CD30+ LPDs include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP) and borderline CD30+ LPD. The frequency of MF, SS and CD30+ LPDs is ~40–50%, <5% and ~10–25%, respectively. Despite recent advances, CTCL remains challenging to diagnose. The mechanism of CTCL carcinogenesis still remains to be fully elucidated. Hence, experiments in patient-derived cell lines and xenografts/genetically engineered mouse models (GEMMs) are critical to advance our understanding of disease pathogenesis. To enable this, understanding the intricacies and limitations of each individual model system is highly important. Presently, 11 immortalized patient-derived cell lines and different xenograft/GEMMs are being used to study the pathogenesis of CTCL and evaluate the therapeutic efficacy of various treatment modalities prior to clinical trials. Gene expression studies, and the karyotyping analyses of cell lines demonstrated that the molecular profile of SeAx, Sez4, SZ4, H9 and Hut78 is consistent with SS origin; MyLa and HH resemble the molecular profile of advanced MF, while Mac2A and PB2B represent CD30+ LPDs. Molecular analysis of the other two frequently used Human T-Cell Lymphotropic Virus-1 (HTLV-1)+ cell lines, MJ and Hut102, were found to have characteristics of Adult T-cell Leukemia/Lymphoma (ATLL). Studies in mouse models demonstrated that xenograft tumors could be grown using MyLa, HH, H9, Hut78, PB2B and SZ4 cells in NSG (NOD Scid gamma mouse) mice, while several additional experimental GEMMs were established to study the pathogenesis, effect of drugs and inflammatory cytokines in CTCL. The current review summarizes cell lines and xenograft/GEMMs used to study and understand the etiology and heterogeneity of CTCL.

In vivo modelling of cutaneous T-cell lymphoma: The role of SOCS1

“…To elaborate on the function of SOCS1 and other identified genes in mycosis fungoides, in particular in the initiating events, we aim to use mouse models. The currently available mouse models ( 12 ) are nearly all based on cell lines and xenografts in immune compromised mice and models that represent early stages of MF are lacking. Here we describe the development of a genetically engineered mouse model that aims to represent autochthonous CTCLs, permitting the necessary next steps in dissecting the precise role(s) of identified genes in the pathogenesis starting with SOCS1.…”

“Next top” mouse models advancing CTCL research

“…Among the cell lines utilized to study CTCL, SeAx, Sez4, SZ4, H9, and Hut78 correspond to SS origin, providing insight into this subtype. Similarly, Myla and HH cell lines reflect advanced MF, while Mac2A and PB2B are indicative of CD30 + LPDs, and MJ and Hut102 lines are associated with Adult T-cell Leukemia/Lymphoma (ATLL), demonstrating the broad spectrum of CTCL manifestations ( Gill et al, 2022 ). The recipient mice for the PDX and CDX model, due to targeted genetic modifications that eliminate certain crucial immune functions, do not reject the transplanted cells or samples ( Mosier, 1990 ).…”

Dclre1c-Mutation-Induced Immunocompromised Mice Are a Novel Model for Human Xenograft Research

“…The developmental aberrations observed in T and B cell lineages affirm the classification of the dclre1c knockout mouse as a novel SCID phenotype. Preceding studies have established the utility of SCID mouse models, such as NOD-SCID, C.B17-SCID and SCID beige, in human xenograft research [21][22][23]. In this vein, we explored the aptitude of dclre1c-knockout-mediated SCID mice to serve as hosts for human xenografts.…”