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Ferrata Storti Foundation
Haematologica 2021 Volume 106(8):2076-2085
Acute Lymphoblastic Leukemia
Dual cytoplasmic and nuclear localization of HTLV-1-encoded HBZ protein is a unique feature of adult T-cell leukemia
Greta Forlani,1 Mariam Shallak,1 Alessandra Tedeschi,1 Ilaria Cavallari,2 Ambroise Marçais,3 Olivier Hermine3 and Roberto S. Accolla1
1Laboratories of General Pathology and Immunology “Giovanna Tosi”, Department of Medicine and Surgery, University of Insubria, Varese, Italy; 2Istituto Oncologico Veneto IOV - IRCCS, Padua, Italy and 3Department of Hematology, Necker-Enfants Malades, University Hospital, Assistance Publique Hopitaux de Paris, Paris Descartes University, Paris, France
ABSTRACT
Adult T-cell leukemia-lymphoma (ATL), is a highly malignant T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), characterized by poor prognosis. Two viral proteins, Tax-1 and HTLV-1 basic-zipper factor (HBZ) play important roles in the pathogenesis of ATL. While Tax-1 can be found in both the cytoplasm and nucleus of HTLV-1 infected patients, HBZ is exclusively localized in the cytoplasm of HTLV-1 asymptomatic carriers and in patients with the chronic neurologic disease HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HBZ is only localized in the nucleus of ATL cell lines, suggest- ing that the nuclear localization of HBZ can be a hallmark of neoplastic transformation. In order to clarify this crucial point, we investigated in detail the pattern of HBZ expression in ATL patients. We made use of our mono- clonal antibody 4D4-F3, that at present is the only reported reagent, among the few described, able to detect endogenous HBZ by immunofluorescence and confocal microscopy in cells from asymptomatic carriers, HAM/TSP and ATL patients. We found that HBZ is localized both in the cytoplasm and nucleus of cells of ATL patients irrespective of their clinical status, with a strong preference for the cytoplasmic localization. Also Tax-1 is localized in both compartments. As HBZ is exclusively localized in the cytoplasm in asymptomatic carriers and in non-neoplastic pathologies, this finding shows that neoplastic transformation consequent to HTLV-1 infection is accompa- nied and associated with the capacity of HBZ to translocate to the nucleus, which suggests a role of cytoplasmic-to-nuclear translocation in HTLV-1- mediated oncogenesis.
Introduction
Human T-cell leukemia virus type 1 (HTLV-1), the first identified human onco- genic retrovirus, is the etiological agent of a severe form of adult T-cell leukemia/lymphoma (ATL)1 and of HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neurological disease.2,3 10-20 million people are infected by HTLV-1 worldwide with a preferential localization in the Southwestern region of Japan, Australasia region, North and Central Africa, the Middle East, Central and South America and the Caribbean.4 Virus transmission occurs via cell-to-cell contact through breastfeeding, sexual intercourse, blood transfusions, and drug use with contaminated needles.5
Pathologies associated to HTLV-1 infections usually manifest after a long period of incubation that, in the case of ATL, may be of decades.6 ATL are divided into four clinical subtypes: acute, lymphoma, chronic, and smoldering, depending upon the relative lymphocytosis and lymphocyte abnormalities,7 the presence or absence of hypercalcemia, lactate dehydrogenase (LDH) serum concentration, and involve- ment of other organs.8
Although progress has been made in the pathophysiology and clinical treatment
Correspondence:
ROBERTO S. ACCOLLA
roberto.accolla@uninsubria.it
Received: September 16, 2020. Accepted: January 19, 2021. Pre-published: February 25, 2021.
https://doi.org/10.3324/haematol.2020.272468
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