current views in htlv-i-associated adult t-cell leukemia/lymphoma

Current Views in HTLV-I-Associated Adult T-CellLeukemia/Lymphoma

Christophe NicotDepartment of Microbiology, Immunology and Molecular Genetics, University of Kansas Medical Center, Kansas City, Kansas

Epidemiological studies have demonstrated that the relative percentage of malignant lym-

phoid proliferations varies widely according to geographical location and ethnic popula-

tions. HTLV-I is the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and is also

associated with cutaneous T-cell lymphoma (CTCL). However, a definite role of HTLV-I in

mycosis fungoides (MF) and/or Sezary syndrome (SS) remains controversial. While most

HTLV-I-infected individuals remain asymptomatic carriers, 1–5%will developATLL, an invari-

ably fatal expansion of virus-infected CD4+ T cells. This low incidence and the long latency

period preceding occurrence of the disease suggest that additional factors are involved in

development of ATLL. In this review, diagnosis, clinical features, and molecular patho-

genesis of HTLV-I are discussed. Am. J. Hematol. 78:232–239, 2005. ª 2005Wiley-Liss, Inc.

DISCOVERY AND EPIDEMIOLOGY

In 1977, epidemiological studies revealed the pres-ence of unusual clusters of adult T-cell leukemia/lymphoma (ATLL) in some areas of Japan, suggestinga transmissible agent may be involved in the disease [1].The first description of HTLV-I came after the discov-ery of the human T-cell growth factor (interleukin-2;IL-2) [2], allowing long-term in vitro culture of T cellsand establishment of T-cell lines from a patient with acutaneous T-cell lymphoma (CTCL) [3]. Soon after,this virus was identified as the etiological agent ofATLL [4], and the term ‘‘HTLV-I’’ was adopted.The relative percentage of malignant lymphoid

proliferations varies widely according to geographicallocation, probably reflecting exposure to differentetiological factors, including viruses. Peripheral T-celllymphoma (PTCL) is relatively uncommon in Cauca-sian populations. For patients with non-Hodgkin lym-phoma (NHL), the proportion of PTCL is only around10% in Western countries [5] while the incidence ofPTCL is as high as 70% in southwestern Japan, whereHTLV-I infection is endemic. A recent survey oflymphoid malignancies in Japan showed that 50%were B-cell lymphoma and 42% were T/natural killer(NK)-cell lymphoma, among which 58%were HTLV-Iinfected while only 4% were Hodgkin lymphoma(HL) [6].

All routes of HTLV-1 virus transmission requireclose contact with infected T-lymphocytes. Mother-to-child transmission is associated with prolongedbreast-feeding in the postnatal period [7–10] and hasbeen associated with an increased risk of developingATLL. HTLV-1 can be sexually transmitted with ahigher transmission efficiency from male to femalethan from female to male [11,12]. The intravenousroute of infection, mainly by blood transfusion,appears to be the most efficient mode for HTLV-1transmission [13]. The intravenous route of con-tamination is associated with a higher risk of devel-oping tropical spastic paraparesis/HTLV-1 associated

Contract grant sponsor: National Institutes of Health; Contractgrant number: RR016443 (NIH) from the COBRE Program of theNational Center for Research Resources; Contract grant sponsor:Lied Basic Science Research Grant of the University of KansasMedical Center Research Institute.

*Correspondence to: C. Nicot, University of Kansas MedicalCenter, Department of Microbiology, Immunology andMolecular Genetics, 3025 Wahl Hall West, 3901 RainbowBoulevard, Kansas City, KS 66160. E-mail: [email protected]

Received for publication 28 May 2004; Accepted 29 September2004

Published online inWiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ajh.20307

American Journal of Hematology 78:232–239 (2005)

ª 2005 Wiley-Liss, Inc.

myelopathy (TSP/HAM). Transmission of HTLV-Iby blood transfusion occurs with transfusion of cel-lular blood products (whole blood, red blood cells,and platelets) but not with the plasma fraction orplasma derivatives from HTLV-I-infected blood. Sero-conversion rates of 44–63% have been reported inrecipients of HTLV-I-infected cellular components inHTLV-I endemic areas.In 1988, the Food and Drug Administration (FDA)

recommended all blood donation centers screen theU.S. blood supply for HTLV-I. In 2001, data relatingto all blood donations to the American Red Crossindicated the rates per 100,000 were 9.7 for HIV and9.6 for HTLV. Incidences of new infection amongdonors were 1.554 and 0.239 for HIV and HTLV,respectively. Current estimations indicate 20–30 mil-lion people worldwide are infected with HTLV-I.Endemic areas are mainly found in Japan, Africa,South America, Caribbean basin, Southern parts ofNorth America, and Eastern Europe. While mostHTLV-I-infected individuals remain asymptomaticcarriers, 1–5% (lifelong risk) will develop ATLL, aninvariably fatal expansion of virus-infected CD4+

T cells. The human T-cell lymphotropic virus type II(HTLV-II) resembles HTLV-I in provirus organiza-tion and exerts less lymphoproliferative effects on thehost’s infected cells. To date, a clear association ofHTLV-II with a specific human disease has not beenestablished.

DIAGNOSIS CRITERIA

The diagnosis of ATL is usually made on morpholo-gical analysis. Cytological examination may revealinfiltration by ‘‘cerebriform’’ or ‘‘flower cells’’ (activatedlymphocytes with convoluted nuclei and basophiliccytoplasm), indicators of acute or lymphoma typeATL. This must be confirmed by clonal integration ofHTLV-I provirus in the host genome. The predominantimmunological phenotype of neoplastic cells is helperT-cell, CD3+, CD4+, L-selectin+, CD25+, CD45RA+,HLA-DR+, CD29�, and CD45RO� in peripheralblood, or CD3+, CD4+, L-selectin+, CD29+,CD45RO+, HLA-DR+, and CD45RA� in the skinand lymph nodes [14,15]. Phenotypic as well as mor-phological heterogeneity of ATL cells and heterogene-ity of CD45R isoform expression on ATL cells can befound in different organs. The CD7 and CD8 antigensare usually absent. Factors signifying a poor prognosisinclude high serum thymidine kinase levels [16,17], highserum soluble interleukin-2 receptor levels [18], highserum b2-microglobulin levels [19], high expressionof the Ki67 antigen, and high serum parathyroidhormone-related protein levels. The serum neuron-specific enolase (NSE) value positively correlated with

serum thymidine kinase activity and serum solubleinterleukin-2 receptor levels. Because ATL cells pro-duce significantly more NSE than other NHL cells,serum NSE may serve as a marker of disease aggres-siveness as well as a prognostic factor for ATL [20].Whether HTLV-1-associated malignancies are referredto as leukemias or lymphomas depends on specificcriteria found in the peripheral blood. Acute ATL ischaracterized by a massive infiltration of the peripheralblood by ATL cells, while the ATL lymphoma is char-acterized by the presence of less than 1% of leukemiccells on a blood smear and major involvement of lym-phoid organs.The T-cell receptor expressed on leukemic cells is

usually a heterodimer of a and b chains. There are noreports showing that particular variable segments ofthe b chain genes are preferentially expressed in theleukemic cells of ATLL patients, indicating leukemiccells are not derived from particular antigen-specificT-cell clones. According to the Revised European–American Lymphoma (REAL) classification of non-Hodgkin lymphomas (NHL), with emphasis onimmunophenotypic analysis along with clinical fea-tures, ATLL belongs to the category of peripheralT-cell lymphoma (PTCL) and natural killer-cell neo-plasms. Shirono et al. proposed that ATL is charac-terized as acute when more than 18% of PBMCs arefound to be Ki-67 antigen-positive [21].No specific karyotypic abnormalities have been

associated with the development of ATLL, but cyto-genetic analyses of leukemic cells revealed multipleabnormalities such as trisomy 3, 7, and 21, involve-ment of chromosomes 6 and 14, and loss of chromo-some Y [22–25]. Recently, loss of heterozygosity onchromosome 6q [region (6q15–21)] was reported inapproximately 50% of acute/lymphoma ATL, sug-gesting the presence in this location of a putativetumor-suppressor gene involved in ATLL pathogen-esis [26]. The cytogenetic abnormalities found inATLL are more frequent in the acute and lymphomatypes than in the chronic or the smoldering types.Whether or not these genetic alterations are thecause or the result of ATL is unknown.

HTLV-I-Associated Cutaneous T-Cell Lymphoma(CTCL)

ATLL prevalence is often underestimated due to theseverity and the rapid evolution of this disease, and theconfusion of ATLL with Sezary syndrome (SS), myco-sis fungoides (MF), or other types of T-cell NHL.There are marked similarities between the clinical andhistopathological features of the lymphoma type ofATLL and other types of cutaneous T-cell lymphoma(CTCL) including SS, MF, and CD30 anaplastic large

Concise Review: Current Views in HTLV-I-Associated Adult T-Cell Leukemia/Lymphoma 233

cell CTCL. Importantly, liver invasion by ATLL cellsand impaired hepatic functions are frequent in HTLV-I-infected individuals as opposed to NHL that are notassociated with HTLV-I infection. Most patients withCTCL are negative for antibodies to the structuralproteins of HTLV-I, and thus a causative role for thisvirus is usually dismissed. However, numerous studieshave found HTLV-I-related proviral tax sequence ordeleted proviruses in tumor samples from CTCLpatients [27–34]. Recently a study on the northeasterncoast of Brazil found HTLV-I integrated proviralsequences by southern blot in several mycosis fun-goides-like cutaneous lymphomas, and CD30+ large-cell anaplastic lymphomas [35]. However, other studiescould not identify any HTLV-I sequences in MF or SSpatients, and therefore a causative role for HTLV-Iremains controversial [36–40].It is well accepted that HTLV-I is associated with a

cutaneous-lymphoma type of ATL, in which detectionof monoclonal integration of HTLV-I and T-cellmonoclonality can be detected in the skin, but usuallynot in the peripheral lymphocytes of ATL patients[41–44]. Various cutaneous lesions have been describedinATL lymphoma, including papules, nodules, erythro-derma, plaques, tumors, and ulcerative lesions. Thefrequent expression of the chemokine (C-C motif)receptor 4 (CCR4) on the surface of tumor cells mayin part explain skin involvement [45,46]. Other factorssuch as expression of cutaneous lymphocyte antigen(CLA) [47,48], expression of lymphocyte chemoattrac-tant chemokine, stromal cell-derived factor/pre-B-cellgrowth-stimulating factor (SDF-1/PBSF) [45], as wellas inflammatory responses may lead to chemotaxis ofinfected lymphocytes [49] and contribute to skin infil-tration by ATL cells. Virus-infected cells can remain inthe skin for several months or years before their dis-semination to the peripheral blood and organs.

Clinical Features of HTLV-I-Associated ATLand ATL Lymphoma

In addition to ATLL, HTLV-I is also the etiologicalagent of an inflammatory neurodegenerative disordercalled tropical spastic paraparesis/HTLV-I-associatedmyelopathy (TSP/HAM), as well as HTLV-I-asso-ciated arthropathy (HAAP), HTLV-I-associated uvei-tis (HAU), infective dermatitis, and polymyositis. Therole of HTLV-I in TSP/HAM pathogenesis hasrecently been reviewed [50–52].ATLL has a broad clinical spectrum divided into four

clinically distinct entities (acute, chronic, smoldering,and lymphoma) that differ in their presentation, pro-gression and response to treatment [53].Acute ATLL is characterized by fever, cough, lym-

phoadenopathy, skin lesions, hepatosplenomegaly,

marked leukocytosis, and hypercalcemia frequentlyassociated with lytic bone lesions and generalizedbone resorbtion. About 70% of ATL patients develophigh serum calcium levels during the clinical course ofthe disease, particularly during the aggressive stage[54,55]. High serum levels of lactate dehydrogenase, asoluble form of the interleukin-2 receptor a chain,and atypical lymphocytes with characteristic convo-luted or lobulated nuclei and basophilic cytoplasm,are also characteristic of the acute type of ATL. Themean survival time is 6 months with a poor responseto chemo- or radiotherapy.Chronic-type ATL is characterized by milder clin-

ical symptoms and signs and a longer clinical course.Serum calcium levels are normal and there is noorgan involvement other than lymphadenopathy,cutaneous or pulmonary lesions, and hepatospleno-megaly. Chronic lymphocytosis, with more than 10%circulating leukemia cells and a tendency to be lesscytologically atypical than in the acute type, is also anindicator of chronic type ATL. The mean survivaltime is 24 months.The smoldering type is characterized by few leukemia

cells in the peripheral blood (less than 5%) and maypresent with skin lesions such as papules, nodules, anderythema. Lymph node enlargement and splenomegalyare minimal, and serum lactate dehydrogenase levelsare either slightly elevated or normal; hypercalcemia isusually not detected. Survival is quite long. Bothchronic and smoldering types can progress into anacute form of leukemia or lymphoma following a pro-gressive aggravation of the clinical picture. Progressionappears to be linked with an increase from low to highproviral loads, possibly through exposure to chronicantigen stimulation.Lymphoma type ATLL is predominantly charac-

terized by lymph node enlargement without manifest-ations of leukemia. Peripheral blood lacks absolutelymphocytosis, but sporadic circulating leukemia cellsmay be seen (<1%); hypercalcemia is absent. Meansurvival time for this group of patients is 10 months,and response to chemotherapy is generally poor. The4-year survival rates are 5.0% for the acute type,5.7% for the lymphoma type, 26.9% for the chronictype, and 62.8% for the smoldering type.A major complication of ATLL is the immunodefi-

ciency of patients that leads to serious infections withbacteria, fungi, protozoa, and viruses. Common infec-tions include Pneumocystis carinii, aspergillosis, candi-diasis, cytomegalovirus pneumonia, and Strongyloidesstercoralis [56–61]. Opportunistic malignancies, such asKaposi sarcoma [62] and Epstein-Barr virus (EBV)-associated lymphoma have been reported in patientswith ATL [63]. Although in the last 20 years consider-able progress has been made regarding the biology of

234 Concise Review: Nicot

HTLV-I, treatment of ATL patients’ remains unsatis-factory. ATL generally has a very poor prognosis and,in leukemic or lymphomatous presentation, life expec-tancy does not exceed 1 year. High-dose radiotherapyor chemotherapy regimens, by themselves or in combi-nation, including those designed for the treatment ofaggressive non-Hodgkin lymphomas or acute lympho-blastic leukemia, are ineffective in ATL patients.Although initial treatments often result in completeremissions (40% CR), all patients relapse and die,usually in less than a year. The poor prognosis ofATL results from a combination of several factors.Immune deficiency often results in opportunistic infec-tions, and failure of hepatic functions prevents admin-istration of intensive induction treatments. Othernegative factors include the intrinsic resistance ofATL cells to apoptotic stimuli, often facilitated bymutations in the p53 gene [64] and p16ink [65], over-expression of multidrug resistance [66], and the ATL-derived factor (ADF), a thioredoxin analogue [67,68].Many polychemotherapy clinical trials were carried outin Japan between 1978 and 1983 [69], and although theCR rate was usually higher in the lymphoma type ascompared to acute ATL, the long-term survival wasidentical. Despite these obstacles recent encouragingresults were obtained by allogeneic bone marrow trans-plantation (alloBMT) [70], combinations of AZT anda-IFN [71–74], arsenic trioxide and a-IFN [75,76], all-trans-retinoic acid (ATRA) therapy [77–79], and theuse of radiolabeled anti IL-2R (CD25) antibodies[80,81]. Current therapeutic strategies for the treatmentof ATLL have recently been reviewed [82].

Molecular Pathogenesis

The low incidence and the long latency of HTLV-I-associated ATLL suggest, in addition to viral infec-tion, accumulations of genetic mutations are requiredfor cellular transformation in vivo. HTLV-I-mediatedT-cell transformation presumably arises from a multi-step oncogenic process [83], in which the virus orenvironmental factors induce chronic T-cell prolifera-tion resulting in an accumulation of genetic defectsand the deregulated growth of infected cells. There isa recognized discrepancy between the number of cellscarrying the provirus and the expression of viralmRNA, even in the early stages of the disease [84].Two possible models may explain this observation:either cells are latently infected or cells expressingviral antigens are rapidly eliminated by immuneresponses. The higher viral load and polyclonal expan-sion of infected cells observed in TSP/HAM patho-genesis, suggest it may result from chronic virusexpression and a state of balance with the immunesystem. However, to achieve the monoclonal expansion

that characterizes ATL [85], the virus has to establish alatent reservoir that can be amplified by cellular repli-cation. In fact, studies of clonal expansion of HTLV-I-infected cells in HTLV-I carriers, demonstrate someclones persist for over 7 years in the same individual[86,87]. We have recently found that the virally encodedp30 protein prevents nuclear export of the tax/rexRNA and suppresses viral gene expression in vitro[88]. Whether or not p30 may act as latency factor invivo remains to be investigated.While it is not yet fully understood how HTLV-I

engenders ATLL, several lines of evidence have estab-lished that the viral oncoprotein Tax plays a centralrole, at least in the early stages of the disease [89]. Taxusurps signaling pathways, including NF-kappa B[90], leading to the up-regulation of numerous cyto-kines and cytokine receptors. Remarkably, Tax hasbeen shown to up-regulate expression of IL-2 andIL-2Ra chain [91,92] as well as IL-15 and IL-15Rachain [93,94], suggesting that an autocrine/paracrinemechanism could be involved in proliferation ofATL cells in early stages of infection [95]. Of note,recent studies have found that the viral protein p12stimulates production of IL-2 in activated T-cells [96],interacts with the IL-2 receptor b chain, and stimu-lates the Jak/STAT5 pathway and T-cell proliferation[97]. A more detailed role of p12 in HTLV-I patho-genesis has recently been reviewed [98]. A commonand striking feature of ATL cells in late stages of thedisease is the absence of detectable Tax expression,suggesting that Tax expression may no longer berequired [99]. However, ATL cells appear to haveacquired a ‘‘Tax phenotype’’: NF-kB and AP-1 areconstitutively activated [100,101], p53 is stabilizedand functionally impaired in the absence of mutations[102], and expression of p21waf, survivin, and Bcl-xLis increased [103–106].During the transformation process, Tax is also

involved in deregulation of cell growth [107] and apop-tosis pathways [108,109], repression of the b-polymer-ase [110], the host DNA repair machinery [111], theanaphase promoting complex [112], and inactivationof the mitotic arrest defective (MAD1) protein [113].These effects increase the occurrence and accumulationof somatic mutations and predispose HTLV-I infectedcells to chromosome instability. As expected, reactiva-tion of the human telomerase gene catalytic subunit(hTERT) and increased telomerase activity is com-monly found in HTLV-I infected cell lines in vitroand in ex vivo ATL cells [114–118]. Recent studiesdemonstrate Tax, through its NF-kB inducing activity,stimulates hTERT expression in HTLV-I-infected cells,allowing maintenance of long telomeres and avoidanceof replicative senescence [118]. However, in thepresence of antigenic stimulation of T-lymphocytes


bearing Tax, hTERT mRNA induction is diminished[118,119]. hTERT is highly inducible in lymphocytesfollowing activation through CD3, possibly to main-tain genetic stability of actively dividing cells. We pro-pose the following model: in HTLV-I-infected T-cells,Tax-mediated down-regulation of Lck, TCR, CD45,and Syk/Zap-70 kinase expression results in attenua-tions of CD3 responses [120,121] and prevents thefull induction of hTERT expression following TCRengagement. In turn, active cellular proliferation inthe presence of limiting amounts of telomerase mayresult in a transient state of genetic instability. Oncethe mitogenic effect has vanished, Tax-mediated activa-tion of hTERT may stabilize and, thereafter, promotethe long-term expansion of potential tumor cellsthat have acquired chromosomal abnormalities. Sev-eral cycles of transient active proliferation combinedwith chromosomal instability may be required for aclonal selection and the development of adult T-cellleukemia. In support of such a model, a high frequencyof T-cell clonal expansion has been associatedwith chronic antigenic stimulation in carriers ofS. stercoralis [122,123], and a higher frequency of leu-kemia has been reported in individuals carrying thisparasite [124–126].

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current views in htlv-i-associated adult t-cell leukemia/lymphoma

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