* Leukemia/lymphoma:
ATL (Adult T-cell leukemia/lymphoma)
Burkitt's lymphoma, B-cell, T-cell,
T/NK-cell, Hodgkin’s disease
* Carcinogenesis (transformation)
A. Acutely transforming retroviruses (e.g., RSV) incorporate and exert control over
cellular growth-related genes (protooncogene capture) and subsequently transfer
these deregulated genes into new cells. (v-src)
B. Slowly transforming viruses (e.g., ALV) alter cellular gene expression by chance
insertion of cis-acting viral regulatory sequences adjacent to these genes
(insertional mutagenesis). (LTR)
( ORF III )
ORF I ( p12I )
Host #2
Inverse PCR
Host DNA
PCR
Causal association of HTLV-1 with ATL
* Identical geographic distributions.
* Almost 100% HTLV-1 infection in ATL patients.
* All leukemia cells are HTLV-1 positive and contain monoclonal proviral DNA.
* HTLV-1 immortalizes CD4-positive T cells.
Interesting observations
* HTLV-1 infection through transfusion HAM/TSP (but not ATL).
HAM/TSP (HTLV-1-Associated Myelopathy / Tropical Spastic Paraparesis)
( 神經性脊髓疾病 / 熱帶痙攣性下肢癱瘓 )
HTLV-1-infected T cells infiltrate into cerebrospinal fluid and spinal cord.
* HTLV-1 transmitted sexually in adulthood does NOT result in ATL.
( ORF IV )
Cellular factors
ORF I
Cellular
p12I
* When such cells are cultured in vitro with FCS HTLV-1 expression
Presence of suppressive factor(s) in the blood (other than antibody).
* ATL cells do not replicate in peripheral blood but in lymph nodes, spleen, skin.
Models of disease progression: pathways to ATL
( Decades )
Models of disease progression: pathways to HAM/TSP
APCs
strong
Control of Infection and Clinical Management:
* Primary prevention: avoid viral infection.
(a) Breast feeding (major) (Mother Child: Vertical transmission)
30% childhood infection Just a few% (by avoiding BF)
(b) Sexual activities (Husband Wife : Horizontal transmission)
(c) Blood transfusion (2/3 chance of infection from a HTLV-1+ blood )
HTLV-1 screening in blood banks Transmission reduced ( 日本 )
Requirement of the HTLV-1 tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes.
Waldele et al., Blood. 2006 Jun 1;107(11):4491-9.
HTLV-1 Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-inhibitory
protein (c-FLIP). Krueger et al., Blood. 2006, 107(10):3933-9.
HTLV-1 oncoprotein tax inhibits Fas-mediated apoptosis by inducing cellular FLIP through activation of
NF-kappaB. Okamoto et al., Genes Cells. 2006 Feb;11(2):177-91.
HTLV-1 Tax Protein Down-regulates the Pre-TCR-α Gene Transcription in Human Immature
Thymocytes. Wencker et al., J Virol. 2006 Oct 18; [Epub]
Overexpression of TGF-β in transgenic mice carrying the HTLV-1 tax gene. Kim et al., Mol Cell Biol. 1991
Oct;11(10):5222-8.
Transactivation of the TGF-β1 gene by HTLV-1 tax: a potential mechanism for the increased production
of TGF-β1 in adult T cell leukemia. Kim et al., J Exp Med. 1990 Jul 1;172(1):121-9.
HHV-1 (Alpha) Herpes simplex Orofacial herpes (cold sores), ocular lesions, erythema
virus 1 (HSV-1) multiforme, genital herpes
HHV-4 (Gamma) Epstein Barr virus Infectious mononucleosis (glandular fever), Burkitt’s
(EBV) lymphoma, nasopharyngeal carcinoma
Copies of
Tandem
Repeats
Indicate
Clonality
Immuno-
compromised
BL
↗
Further
c-myc
Activation
TPA
(Zta/Zebra)
(Bcl-2 family)
EBV-associated malignancies:
Long after primary infection,
many malignancies may occur:
(EBV association)
Burkitts’s lymphoma (100%, 15~88%, 30~40%)
Hodgkin’s disease (lymphoma) (40~60%)
Nasal T/NK-lymphoma (>90%) Asians, Peruvians
Post-transplantation lymphoma (>95%)
NPC (>95%) …
◆
Burkitt’s lymphoma
* Endemic: 10/105, ~100% EBV+ (Central Africa, Papua New Guinea)
Sporadic: 0.1/105, 15~88% EBV+
AIDS-related: 608/105, 30~40% EBV+
* All contains translocations between immunoglobulin gene and c-myc.
t(8:14) ---- Ig heavy chain gene + c-myc
t(2:8) ---- Ig light chain gene κ + c-myc
t(8:22) ---- Ig light chain gene λ + c-myc
Endemic BL:
* All BL cells are EBV positive.
EBV-negative BL cell lines are difficult to infect with the virus.
* Uniclonality of EBV in tumors.
* Holoendemic malaria infection
Malaria infection stimulates B-cell proliferation and depresses cytotoxic T-cells.
* Familial aggregation (HLA types/Genetics, Environments)
* Euphorbia plants. ( 綠珊瑚 )
Endemic BL
Sporadic BL
? 鹿角草 ?
H9
RHEK1 or
BJAB
Epithelial T or B lymphoid
The drug sensitivity of LMP1-transfected stable clones.
100 80 80
80 60 60
60 Mock Mock
40 Mock 40
40 pLMP1-low pLMP1
pLMP1-high 20 pLMP1 20
20
0 0 0
0 0.01 0.1 1 0 0.01 0.1 1 0 0.01 0.1 1
Dosage (uM) Dosage (uM) Dosage (uM)
Prognostic role of EBV LMP-1 and IL-10 expression in patients with NPC. Ozyar
et al., Cancer Invest. 2004;22(4):483-91. (immune suppression)
EBV LMP-1 induces IL-8 through the NF-kB signaling pathway in EBV-infected
NPC cell line. Ren et al., Laryngoscope. 2004 May;114(5):855-9.
Hong Kong
Chinese
25
Male
Female
30
California
Chinese
7
1.8
Whites
0.7
B-cells in
Pharyngeal ?
Type II
Type III
Type II
Type III
Type I
Type I
Type II
Type II Type I
Type I
Immune Immune
normal suppression
Type III
EBNA-1 and EBERs are expressed in all types
Enhanced transforming potential?
Table 52.1-6: Risks of Transfusion-Transmitted Disease
HBsAg, hepatitis B surface antigen; anti-HBc, hepatitis B core antibody; vCJD, variant Creutzfeldt-Jacob disease.
Table 7.2-1: Human Viruses with Oncogenic Properties
Virus Family Type Human Tumor Cofactors
Adenoviruses Types 2, 5, 12 None —
Flaviviruses HCV Hepatocellular carcinoma —
Hepadnavirus HBV Hepatocellular carcinoma Aflatoxin, alcohol, smoking
Herpesviruses EBV Burkitt's lymphoma Malaria
Immunoblastic lymphoma Immunodeficiency
Nasopharyngeal carcinoma Nitrosamines, HLA genotype
Hodgkin's disease —
Leiomyosarcomas —
Gastric cancers —
HHV-8 Kaposi's sarcoma HIV infection
Body cavity–based lymphoma HIV infection
Castleman's disease HIV infection
Papillomaviruses HPV-16, -18, -33, -39 Anogenital cancers and some upper airway cancers Smoking, ? other factors
HPV-5, -8, -17 Skin cancer EV, sunlight, immune suppression
EBV, Epstein-Barr virus; EV, epidermodysplasia verruciformis; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV,
human herpesvirus; HIV, human immunodeficiency virus; HPV, human papillomavirus; HTLV, human T-cell leukemia
virus; SV40, simian vacuolating virus 40.
Table 41.2-4: Revised European-American Lymphoma/World Health Organization Classification of Lymphoid Neoplasms
B-cell neoplasms
Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)
Mature (peripheral) B-cell neoplasmsa
Chronic lymphocytic leukemia/B-cell small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Splenic marginal zone B-cell lymphoma (splenic lymphoma with villous lymphocytes)
Hairy cell leukemia
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B-cell lymphoma (MALT lymphoma)
Nodal marginal zone B-cell lymphoma
Follicular lymphoma
Mantle cell lymphoma
Diffuse large B-cell lymphomas
Burkitt's lymphoma/leukemia (EBV)
T- and NK-cell neoplasms
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma (precursor T-cell acute lymphoblastic leukemia)
Blastoid NK cell lymphoma
Mature (peripheral) T-cell neoplasms
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Aggressive NK cell leukemia
Adult T-cell lymphoma/leukemia (HTLV-1+)
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides/Sézary syndrome
Primary cutaneous anaplastic large cell lymphoma
Peripheral T-cell lymphoma, not otherwise specified
Angioimmunoblastic T-cell lymphoma
Primary systemic anaplastic large cell lymphoma
HTLV, human T-cell lymphotropic virus; MALT, mucosa-associated lymphoid tissue; NK, natural killer.
a
B- and T/NK-cell neoplasms are grouped according to major clinical presentations (predominantly disseminated/leukemic, primary extranodal, predominantly nodal).
Multiple mechanisms were identified that may contribute to its
constitutive activation. Among them, mutations (inactivation) of the
IkBa gene (in EBV-negative HD) and expression of EBV-encoded
latent gene products appear to give feasible explanations for this
phenotype. Both leads to NFkB activation.
Involvement of HTLV-1 Tax and CREB in aneuploidy: a bioinformatics approach.
Retrovirology. 2006, 3:43
de la Fuente C, Gupta MV, Klase Z, Strouss K, Cahan P, McCaffery T, Galante A, Soteropoulos P, Pumfery A, Fujii M, Kashanchi F.
Background
Adult T-cell leukemia (ATL) is a complex and multifaceted disease associated with human T-cell leukemia
virus type 1 (HTLV-1) infection. Tax, the viral oncoprotein, is considered a major contributor to cell cycle
deregulation in HTLV-1 transformed cells by either directly disrupting cellular factors (protein-protein
interactions) or altering their transcription profile. Tax transactivates these cellular promoters by interacting
with transcription factors such as CREB/ATF, NF-κB, and SRF. Therefore by examining which factors
upregulate a particular set of promoters we may begin to understand how Tax orchestrates leukemia
development.
Results
We observed that CTLL cells stably expressing wild-type Tax (CTLL/WT) exhibited aneuploidy as
compared to a Tax clone deficient for CREB transactivation (CTLL/703). To better understand the
contribution of Tax transactivation through the CREB/ATF pathway to the aneuploid phenotype, we
performed microarray analysis comparing CTLL/WT to CTLL/703 cells. Promoter analysis of altered
genes revealed that a subset of these genes contain CREB/ATF consensus sequences. While these genes
had diverse functions, smaller subsets of genes were found to be involved in G2/M phase regulation, in
particular kinetochore assembly. Furthermore, we confirmed the presence of CREB, Tax and RNA
Polymerase II at the p97Vcp and Sgt1 promoters in vivo through chromatin immunoprecipitation in
CTLL/WT cells.
Conclusion
These results indicate that the development of aneuploidy in Tax-expressing cells may occur in response to
an alteration in the transcription profile, in addition to direct protein interactions.
Oncogene. 2005 Sep 5;24(39):5976-85.
The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation
leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since
it transforms and immortalizes rodent fibroblasts and human T-lymphocytes. Through CREB,
NF-kappaB and SRF pathways Tax transactivates cellular promoters including those of cytokines
(IL-13, IL-15), cytokine receptors (IL-2Ralpha) and costimulatory surface receptors
(OX40/OX40L) leading to upregulated protein expression and activated signaling cascades (e.g.
Jak/STAT, PI3Kinase, JNK). Tax also stimulates cell growth by direct binding to cyclin-
dependent kinase holenzymes and/or inactivating tumor suppressors (e.g. p53, DLG). Moreover,
Tax silences cellular checkpoints, which guard against DNA structural damage and chromosomal
missegregation, thereby favoring the manifestation of a mutator phenotype in cells.
Lancet Oncol. 2004 Dec;5(12):738-46.
Is endemic Burkitt's lymphoma an alliance between three infections and a tumour promoter?
Communicable Disease Control, Surrey Health Protection Unit, Wolfson Institute of Preventive
Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, London, UK.
cavandenbosch@yahoo.co.uk
Malaria and Epstein-Barr virus (EBV), recognised cofactors for endemic Burkitt's lymphoma, are
ubiquitous within the lymphoma belt of Africa, and, unless other cofactors are involved, the tumour
should be much more common than it is. Malaria and EBV alone cannot account for the
occasional shifting foci and space-time case clusters of endemic Burkitt's lymphoma. Arboviruses
and plant tumour promoters are other possible local cofactors that could explain such
characteristics. The geographical and age distributions of endemic Burkitt's lymphoma parallel
those of potentially oncogenic, mosquito-borne arboviruses. Arboviruses seem to be associated
with case clusters of endemic Burkitt's lymphoma, and symptoms compatible with arbovirus
infection have been seen immediately before the onset of the tumour. RNA and DNA viruses,
including EBV, are promoted by extracts of a commonly used plant, Euphorbia tirucalli, the
distribution of which coincides with the boundaries of the lymphoma belt. Extracts of E tirucalli are
tumour promoters and can induce the characteristic 8;14 translocation of endemic Burkitt's
lymphoma in EBV-infected cell-lines. They also activate latent EBV in infected cells, enhance
EBV-mediated cell transformation, and modulate EBV-specific immunity.
Nat Rev Cancer. 2004 Oct;4(10):757-68.
Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, B15
2TT, UK. l.s.young@bham.ac.uk
Epstein-Barr virus (EBV) was discovered 40 years ago (1964) from examining electron
micrographs of cells cultured from Burkitt's lymphoma, a childhood tumour that is common in
sub-Saharan Africa, where its unusual geographical distribution - which matches that of
holoendemic malaria -indicated a viral aetiology. However, far from showing a restricted
distribution, EBV - a gamma-herpesvirus - was found to be widespread in all human populations
and to persist in the vast majority of individuals as a lifelong, asymptomatic infection of the B-
lymphocyte pool. Despite such ubiquity, the link between EBV and 'endemic' Burkitt's lymphoma
proved consistent and became the first of an unexpectedly wide range of associations discovered
between this virus and tumours.
Semin Cancer Biol. 2004 Dec;14(6):453-71.
Lineberger Comprehensive Cancer Center and Departments of Medicine and Microbiology, University of North
Carolina at Chapel Hill, Campus Box 7295, Mason Farm Road, Chapel Hill, NC 27599-7295, USA.
joseph_pagano@med.unc.edu
Infectious agents, mainly viruses, are among the few known causes of cancer and contribute to a variety of
malignancies worldwide. The agents and cancers considered here are human papillomaviruses (cervical carcinoma);
human polyomaviruses (mesotheliomas, brain tumors); Epstein-Barr virus (B-cell lymphoproliferative diseases and
nasopharyngeal carcinoma); Kaposi's Sarcoma Herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas);
hepatitis B and hepatitis C viruses (hepatocellular carcinoma); Human T-cell Leukemia Virus-1 (T-cell leukemias);
and helicobacter pylori (gastric carcinoma), which account for up to 20% of malignancies around the globe. The
criteria most often used in determining causality are consistency of the association, either epidemiologic or on the
molecular level, and oncogenicity of the agent in animal models or cell cultures. However use of these generally
applied criteria in deciding on causality is selective, and the criteria may be weighted differently. Whereas for most of
the tumor viruses the viral genome persists in an integrated or episomal form with a subset of viral genes expressed in
the tumor cells, some agents (HBV, HCV, helicobacter) are not inherently oncogenic, but infection leads to
transformation of cells by indirect means. For some malignancies the viral agent appears to serve as a cofactor
(Burkitt's lymphoma-EBV; mesothelioma - SV(40)). For others the association is inconsistent (Hodgkin's Disease,
gastric carcinomas, breast cancer-EBV) and may either define subsets of these malignancies, or the virus may act to
modify phenotype of an established tumor, contributing to tumor progression rather than causing the tumor. In these
cases and for the human polyomaviruses the association with malignancy is less consistent or still emerging. In
contrast despite the potent oncogenic properties of some strains of human adenovirus in tissue culture and animals the
virus has not been linked with any human cancers. Finally it is likely that more agents, most likely viruses, both
known and unidentified, have yet to be implicated in human cancer. In the meantime study of tumorigenic infectious
agents will continue to illuminate molecular oncogenic processes.
Br J Haematol. 2004 May;125(3):267-81.
Survivors of Hodgkin's lymphoma (HL) frequently have many years to experience the long-term
toxicities of combined modality therapies. Also, a significant proportion of HL patients will
relapse or have refractory disease, and less than half of these patients will respond to current
salvage strategies. 30-50% of HL cases are Epstein-Barr virus associated (EBV-positive HL). The
virus is localized to the malignant cells and is clonal. EBV-positive HL is more frequent in
childhood, in older adults (>45 years) and in mixed cellularity cases. The survival of EBV-positive
HL in the elderly and the immunosuppressed is particularly poor. Despite improvements in our
understanding of EBV-positive HL, the true contribution of EBV to the pathogenesis of HL
remains unknown. Increased knowledge of the virus' role in the basic biology of HL may generate
novel therapeutic strategies for EBV-positive HL and the presence of EBV-latent antigens in the
malignant HL cells may represent a target for cellular immunotherapy.
Clin Cancer Res. 2004 Feb 1;10(3):803-21.
EBV was the first human virus to be directly implicated in carcinogenesis. It infects >90% of the
world's population. Although most humans coexist with the virus without serious sequelae, a small
proportion will develop tumors. Normal host populations can have vastly different susceptibility to
EBV-related tumors as demonstrated by geographical and immunological variations in the
prevalence of these cancers. EBV has been implicated in the pathogenesis of Burkitt's lymphoma,
Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and lymphomas, as well
as leiomyosarcomas arising in immunocompromised individuals. The presence of this virus has
also been associated with epithelial malignancies arising in the gastric region and the breast,
although some of this work remains in dispute. EBV uses its viral proteins, the actions of which
mimic several growth factors, transcription factors, and antiapoptotic factors, to usurp control of
the cellular pathways that regulate diverse homeostatic cellular functions. Recent advances in
antiviral therapeutics, application of monoclonal antibodies, and generation of EBV-specific CTLs
are beginning to show promise in the treatment of EBV-related disorders.
Oncogene. 2005 Sep 5;24(39):6047-57.
Department of GU Medicine & Communicable Diseases, Faculty of Medicine, Imperial College, Norfolk Place,
London W2 1PG, UK.
After cell-to-cell transmission, HTLV-1 increases its viral genome by de novo infection and proliferation of
infected cells. Proliferation of infected cells is clonal and persistent in vivo. During the carrier state, infected
cells are selected in vivo by the host's immune system, the genetic and epigenetic environment of proviral
integration sites, and other factors. In leukemic cells, tax gene expression is frequently impaired by genetic and
epigenetic mechanisms. Such loss of Tax expression enables ATL cells to escape the host immune system. On
the other hand, ATL cells acquire the ability to proliferate without Tax by intracellular genetic and epigenetic
changes. Despite advances in support and the development of novel treatment agents, the prognosis for ATLL
remains poor. A number of therapies, however, do appear to improve prognosis compared to CHOP (VEPA).
These include interferon-alpha plus zidovudine (probably after 1-2 cycles of CHOP), intensive chemotherapy as
in LSG-15 with G-CSF support and Allo-SCT (which includes the potential for cure). Emerging novel
approaches include HDAC inhibitors, monoclonal antibodies, and proteasome inhibitors. Comparison between
different therapeutic approaches is complicated by the range of natural history of ATLL, different recruitments
of naive-to-therapy, refractory or relapsed patients, and variations in the reporting of outcome that frequently
excludes difficult-to-evaluate patients. Moreover, results from relatively small proof-of-principle studies have
not been extended with randomized, controlled trials. As a result, currently, there is no clear evidence to support
the value of any particular treatment approach over others. To avoid further unnecessary patient suffering and to
identify optimal therapy as rapidly as possible, large randomized, controlled trials encompassing multicenter,
international collaborations will be necessary.
In the early 1950s, Ludwik Gross found that a virus could transmit leukaemia: ground-up,
filtered leukaemia cells induced a malignancy when injected into infant mice (Gross,
1951). This finding was anathema to the biological establishment—Gross commented that
some oncologists "even doubted my integrity; one of the well-known pathologists [...]
refused to shake my hand when I greeted him before one of my lectures" (Kevles, 1997).
Gross, who later won the Lasker prize, might today have found himself hauled up on a
charge of scientific misconduct or even fraud for announcing such a controversial
discovery (Kevles, 1997). In the 1960s, Howard Temin faced resistance—even ridicule—
when he suggested that viral RNA could generate complementary DNA. "I'll give
Howard's idea the amount of time it's worth—none," said a leading virologist during a
meeting at the time. About a decade later, Temin was awarded the 1975 Nobel Prize in
Physiology or Medicine for his discovery. In the 1970s, J. Michael Bishop and Harold
Varmus faced similar problems when they proposed the oncogene theory of
carcinogenesis, which won them the Nobel Prize in 1989 (Kevles, 1997).
More than 50 years ago, a young woman named Henrietta Lacks was diagnosed with cervical cancer. Despite surgery
and aggressive radiation therapy, the cancer soon spread throughout her body, and on October 4, 1951, she died.
It was a cruel death for the 31-year-old mother of five, but Lacks’ story didn’t end there. George O. Gey, M.D., head of
tissue culture at Johns Hopkins University, where Lacks was treated, had been searching, for research purposes, for a
line of human cells that could live indefinitely outside the body. He got his wish when cells from Lacks’ cancerous
tumor were cultured. Just as they had done in her body, the cells multiplied ferociously in the lab, crawling up the sides
of test tubes and consuming the medium around them. An entire generation of the cells reproduced every 24 hours.
Referring to Lacks’ cells, Gey declared at the time, “It is possible that, from a fundamental study such as this, we will be
able to learn a way by which cancer can be completely wiped out.” To this day, Lacks’ cells, known as the HeLa cell
line, are some of the most robust and rapidly growing cells known to science. They are still used by thousands of
researchers around the world to decipher the complexities of cell biology, particularly as they apply to cancer.
At Yale, scientists are using the HeLa cell line to study, among other things, the human papillomavirus (HPV) that
causes the cervical cancer that killed Lacks. “Her legacy,” says Daniel C. DiMaio, M.D., Ph.D., the Waldemar Von
Zedtwitz Professor of Genetics and professor of therapeutic radiology, “is that her cells are helping us unravel the
pathogenesis of cervical cancer, so that some day we might be able to prevent and treat it. It’s rather remarkable.”
More recently, DiMaio’s lab demonstrated that cervical cancer cells need the viral proteins to grow, thus raising
the possibility that the cancers can be treated with antiviral drugs. DiMaio, Janet L. Brandsma, Ph.D. ’81, and
others are currently working on a vaccine to treat patients with cervical cancer.
HPV is the best-understood example of how a virus leads to cancer. Two things have to happen: First, viral gene
products cause the cells to become genetically unstable and accumulate mutations that render cells unresponsive
to aspects of growth control and the immune response. Second, the viral oncogenes provide a sustained stimulus
to cell growth.
Tight corsets and HPV
Early thinking on cervical cancer and what causes it would hardly suggest such a rosy
scenario. In 1842 an Italian physician in Florence observed that married women in the
city were getting cervical cancer, but nuns in nearby convents weren’t. Although this
observation would seem to point to a link between sexual activity and cervical cancer, the
physician did not make this connection. He also observed that nuns had higher rates of
breast cancer, and suggested that the nuns’ corsets were too tight. “Clearly they had no
clue,” DiMaio says, “but the observation was significant.”
Beginning in 1975, the virologist Harald zur Hausen, M.D., D.Sc., figured out what had
eluded the Florentine physician. Zur Hausen, who for 20 years headed the German Cancer
Research Center in Heidelberg, showed that HPV, a common infection spread through skin-
to-skin contact and sex, could lead to cervical cancer. He and his research team successfully
isolated several genotypes of the virus, some of which they linked to genital warts and others
to cervical cancer.
Today, cervical cancer is responsible for 250,000 deaths each year worldwide, according
to Charles J. Lockwood, M.D., the Anita O’Keefe Young Professor of Women’s Health and
chair of the Department of Obstetrics, Gynecology and Reproductive Sciences. In the United
States, where early screening has greatly reduced the mortality rate due to cervical cancer,
about 5,000 women a year still die of the disease.
HTLV-1 Tax: centrosome amplification and cancer.
Pumfery et al., 2006 Aug 9;3:50.
Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for
the survival of transformed lymphocytes. Waldele et al., Blood. 2006 Jun 1;107(11):4491-9.
HTLV-1 Tax protects against CD95-mediated apoptosis by induction of the cellular FLICE-
inhibitory protein (c-FLIP). Krueger et al., Blood. 2006, 107(10):3933-9.
HTLV-1 Tax transgenic mice develop spontaneous osteolytic bone metastases prevented by
osteoclast inhibition. Gao et al., Blood. 2005, 106:4294-302.