Abstract
HTLV-1 is estimated to affect ~20 million people worldwide and in ~5% of carriers it produces Adult T-Cell Leukemia/Lymphoma (ATLL), which can often masquerade and present with classic erythematous pruritic patches and plaques that are typically seen in Mycosis Fungoides (MF) and Sézary Syndrome (SS), the most recognized variants of Cutaneous T-Cell Lymphomas (CTCL). For many years the role of HTLV-1 in the pathogenesis of MF/SS has been hotly debated. In this study we analyzed CTCL vs. HTLV-1+ leukemic cells. We performed G-banding/spectral karyotyping, extensive gene expression analysis, TP53 sequencing in the 11 patient-derived HTLV-1+ (MJ and Hut102) vs. HTLV-1- (Myla, Mac2a, PB2B, HH, H9, Hut78, SZ4, Sez4 and SeAx) CTCL cell lines. We further tested drug sensitivities to commonly used CTCL therapies and studied the ability of these cells to produce subcutaneous xenograft tumors in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice. Our work demonstrates that unlike classic advanced MF/SS cells that acquire many ongoing balanced and unbalanced chromosomal translocations, HTLV-1+ CTCL leukemia cells are diploid and exhibit only a minimal number of non-specific chromosomal alterations. Our results indicate that HTLV-1 virus is likely not involved in the pathogenesis of classic MF/SS since it drives a very different pathway of lymphomagenesis based on our findings in these cells. This study also provides for the first time a comprehensive characterization of the CTCL cells with respect to gene expression profiling, TP53 mutation status, ability to produce tumors in mice and response to commonly used therapies.
Highlights
Viruses are known to cause a number of human cancers, where Human Papilloma Virus (HPV), Human Herpesvirus 8 (HHV8) and Merkel Cell Polyomavirus were shown to cause Squamous Cell, Kaposi Sarcomas and Merkel Cell cancers, respectively
Human T-Cell Lymphotropic Virus Type 1 (HTLV-1) is estimated to affect ~20 million people worldwide and in ~5% of carriers it produces Adult T-Cell Leukemia/Lymphoma (ATLL), which can often masquerade and present with classic erythematous pruritic patches and plaques that are typically seen in Mycosis Fungoides (MF) and Sézary Syndrome (SS), the most recognized variants of Cutaneous T-Cell Lymphomas (CTCL)
Our results indicate that HTLV-1 virus is likely not involved in the pathogenesis of classic MF/SS since it drives a very different pathway of lymphomagenesis based on our findings in these cells
Summary
Viruses are known to cause a number of human cancers, where Human Papilloma Virus (HPV), Human Herpesvirus 8 (HHV8) and Merkel Cell Polyomavirus were shown to cause Squamous Cell, Kaposi Sarcomas and Merkel Cell cancers, respectively. EpsteinBarr Virus (EBV) and Human T-Cell Lymphotropic Virus Type 1 (HTLV-1) were implicated as causes for a number of hematologic malignancies [1,2,3], where HTLV-1 is known to cause Adult T-Cell Leukemia/ Lymphoma (ATLL), a WHO recognized variant of Cutaneous T-Cell Lymphoma (CTCL)[4, 5]. It is estimated that ~20 million people are infected with HTLV-1 around the world. This virus is prevalent in Central and West Africa, in the Caribbean, in Central and South America, in native populations in Canada, and among intravenous drug users in the United States [6]. Mycosis Fungoides (MF), its leukemic form, Sézary Syndrome (SS), and primary cutaneous anaplastic large cell lymphoma (cALCL) are the most common forms and account for ~80% of all CTCL [10]
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