| During the last few days we have met for
the fourth time here in Wilsede to discuss Modern Trends in Human
Leukemia. The title itself is rather a misnomer becausc there are
no modern trends in leukemia, a discase which does not change from
year to year; our present day civilization probably influences profoundly
leukemia's incidence and course but this aspcct found no place in
our deliberations. It is our approach to understanding the pathogenicity
of leukemia, lymphoma, and rclated diseases which changes, and 1 will
reflect briefly on this. The clinical papers have been summarized
by Dr. Frey and discussed by Dr. M. Feldman. Dr. Frey's statement
that "antibody -drug complexes" might be one of the future approaches
to chemotherapy of leukemia and related diseases was particularly
interesting and reminded me of Albert Coon's early studies on the
combination of antitumor antibodies with chemicals, mostly dyes, with
the goal of concentrating cytostatic or cytotoxic substances in tumors.
This idea did not work then but it brought about the development of
the fluorescent antibody techniques. Maybe today the time has come
when the combination of more highly specific antibodies, i.e., monoclonal
antibodies, with more potent chemotherapeutics would be successful.
During the other sessions of the conference I looked for indications
of trends, for those .'red threads" which may be a guide for future
work. In the virology section the long arguments of the past on the
specificity of molecular hybridization and the stringency needed for
obtaining significant results have disappeared, and in comparison
to past conferences, there were few reports on virus isolations or
detection of viral antigens or antibodies in man. The Haematology
and Blood Transfusion Vol26 Modern Trends in Human Leukemia IV Edited
by Neth, Gallo, Graf, Mannweiler, Winkler c Springer- Verlag Berlin
Heidelberg 1981 retroviruses supposedly isolated from man, all of
which shared genetic information with nonhuman primate viruses, receivcd
relatively little attention, but the riddle of these isolations has
not been solved nor has the question whether they were all laboratory
contaminations been answered. Much more work is needed before further
discussion of these agents would be fruitful, but most of these isolates
can probably be declassified from their human status, and the significance
of the indirect evidence for human retroviruses by demonstration in
man of antigens or antibodies which werc related or identical to simian
viruses is at least questionable. Even so, as I am tempted to announce
that "Thc king is dead", Dr. Gallo is proclaiming "Long live the king"
as he presented us with a new candidate for a human leukemia virus,
a report which is certain to stimulate a new wave of research in this
area. In contrast, we heard a great deal (perhaps too much and in
too much technical dctail) about gag, env, pol, onc, sarc, leuk, and
other gcnes of animal and particularly avian retroviruses, their characteristic
gene products, and their functions. The relevance of these studies
of experimental, artificially produced diseases created under laboratory
conditions for the natural genesis of leukemia is questionable. Nevertheless,
dissection of the genomes of these retroviruscs with endonucleases
and the cloning of specific parts of the genomes in bacterial plasmids
with subsequent evaluation of the function of the various regions
of the genes and of the gene products, both in in vitro translation
systems and in their normal eukaryotic target cells, may improve our
understanding of the basic mechanisms of cell transformation in vitro
and possibly also of tumor induction in vivo by the RNA retroviruses.
It is still a major puzzle that similar or identical genomes can induce
quite different malignancies, as observed for example in the induction
of tumors as different as fibrosarcomas, melanomas, and glioblastomas
by a single strain of Rous sarcoma virus, and that the same malignancy
can be initiated by different viral genomes. I am sure that the pathogenicity
of these diseases will be understood much better during the coming
years, although this understanding will be achieved not only by analysis
of the genomes down to the last base pair but more by examination
of the total process of transformation, i.e., the virus, the route
of infection, the type and physiologic state of the infected cells,
and the response of the total organism to the emergence of transformed
cell clones. There was relatively little discussion of DNA tumor viruses,
except for an overview of the structure of the primate Iymphotropic
herpesviruses and discussions of the pathogenesis of Epstein -Barr
virus (EBV) infections. The pathogenic events leading from primary
lymphoproliferative EBV infections to comp]ete recovery with a lifelong
carrier state and the development later of monoclonal malignancies
or an immediate progression of an acute monucleosis into a malignant
fatal Iymphoproliferative disease are particularly interesting and
deserve intensive study. The report of lytic activity of EBV is important
for two reasons: it allows better study in vitro of EBV and it may
explain the infection of epithelial cells in vivo. Of importance also
is the demonstration of EBV genomes in normal parotic cells which
may answer the old question of where EBV multiplies during the long
periods of oral excretion. On reflecting generally on the viral studies
I want to repeat a caution sounded often before: We must not ignore
the fact that some of our virus models, and I am referring particularly
to the avian and murine retroviruses, are highly artificial, using
inbred selected animals and laboratory-propagated and perhaps laboratory-created
viruses, whose relevance to naturally occurring disease is at least
in part questionable, although their value for a basic understanding
of cell function and regulation is undisputed. Studies in outbred
animal populations, such as cats and cattle, may be more comparable
to real life. Particularly intriguing is the situation of "virus-free"
cat leukemias in which the virus might have acted as a "hit and run"
villain, lcaving either only a small part of itself behind or changing
only the genes responsible for cell regulatory mechanisms without
a need for persistence of any part of the viral genome, a mechanism
which has also been considered for the transformation of cells by
some DNA viruses, particularly the herpesviruses. In yesterday's sessions
we heard about vcry exciting developments in cell biology and immunology.
The differentiation of the cells of the hematopoietic and the immune
systems into many highly specialized cell subpopulations has been
analyzed in detail, thus allowing a much finer and detailed analysis
of the immune mechanisms which playa role in the emergence of tumors
and the defense of the organism against them. Use of monoclonal antibodies
has almost revolutionized this field, and it will be most interesting
to study not only the physiologic and immunologic functions and antigenic
identities of the various cell types but also their susceptibility
to exogenous viral infection, to activation of endogenous viral genes,
and to chemical or physical carcinogens. The development of cell culture
techniques and separation of various cell populations have progressed
rapidly and already have improved our understanding of normal differentiation
and of regulatory disturbances leading to malignant transformation,
although this is another area in which we must remember that isolated
cells in vitro may behave quite differently from cells in the intact
organism with its multiple cell interactions and regulatory mechanisms,
to which we should add Dr. Moore's newly defined "oncgene"-mediated
"pericrine " controls as well as still unidentified influences. The
report of thymic nurse cells within which differentiation of other
cells seems to occur is an intriguing observation, the general significance
of which needs further exploration. In addition the nude thymusless,
the spleenless, and the very special mice lacking both of thesc organs
are now joined by the "beige mouse," a strain which is deficient for
natural killer cells and which will permit a further dissection of
the immune defenses against tumor development. The new perspective
of the various, specific chromosomal aberrations in different diseases
should stimulate further research to relate specific chromosomal to
specific pathologic changes, and in this respect the studies on the
X-Iinked Iymphoproliferative syndrome (Duncan's disease) which is
associated with immunodeficiency, multiclonal lymphoproliferation,
and finally lymphoma or lymphosarcoma are particular interesting.
Better tools will be needed for a finer analysis of the human genetic
material before we can understand the genetic influences on leukemias
and lymphomas, as our current methods of chromosomal analysis are
at best very crude. Another significant observation was the identification
of la antigens on various tumor cells and the implication that they
have not only immunologic functions but also play some role in differentiation
and cell regulation. In closing, it must be said that we are still
far from understanding the pathogenicity of leukemia, lymphoma, and
related diseases but that our knowledge has rapidly increased and
will continne to do so with the help of modern molecular, virologic,
and immunologic techniques developed during the last years. I must,
however, remind you that in the clinical arena the battle against
leukemia needs abetter exchange and co-ordination between clinicians,
immunologists, molecular biologists, geneticists, and virologists.
Only then can our potential be realized. |
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