Download Brief Historical Sketch of Chromosomal

Brief Historical Sketch of Chromosomal Translocations and
Tumors
Michael Potter
The discovery of chromosomes emerged from the cytological analysis of mitosis in the 1870s. At the turn of the 20th century,
cytologists and geneticists established that chromosomes carried the hereditary material. In the early 20th century, Theodore
Boveri, recognizing the nonequivalence of individual chromosomes, began thinking about the biological consequences of imbalances of chromosomal compositions in somatic cells and how these might explain the origin of cancer. Many of his predictions
would have to wait for confirmation until the 1950–1960s, when mammalian cytogenetics became feasible with the use of ascites tumors as sources of metaphases. This advance coupled with the discovery of G banding by Caspersson and his associates
led to finding characteristic recurring chromosomal abnormalities in certain kinds of tumors. Chromosomal translocations that
were associated with promoter deregulations or the formation of novel fusion genes were the prime models. This continuing
progress combined with dramatic advances in DNA structure, transcription, and repair have provided new insights into the role
of this class of mutations in neoplastic development.
J Natl Cancer Inst Monogr 2008;39:2–7
Discovery of Chromosomes in the 1870s
With the availability of much improved microscopes and histological methods, biologists in the 1870s began focusing on the details of
cell division. It was in this period that chromosomes (threads) and
their curious behavior during cell division became the focus of the
science of cytology (see historical review by Henry Harris) (1).
Walther Flemming called the series of changes within the nucleus
as “karyomitosis” (thread-like metamorphosis) and introduced the
term mitosis, a historical landmark in biology (2,3). The period of
1870–1900 was a golden age for cytology (4) and “on its heels” came
the rediscovery of Mendelian Genetics in the early 1900s.
This focused attention again on the nature of the units of heredity.
The realization that chromosomes were the carriers of these units in
1902–1903 is attributed to Walter S. Sutton (5) an American graduate student and the renowned German embryologist Theodore H.
Boveri (6) who early on recognized the nonequivalence of chromosomes and intuitively believed they were the carriers of genetic
information. An early concept of chromosome substructure emerged
from the demonstration of linked genes and crossing over by the
hands and perceptive eyes of the great Drosophila geneticists
Thomas Hunt Morgan, Alfred Sturtevant, Calvin Bridges, and
Herman J. Muller (7,8). The secret of the units of hereditary and
how they were related to the chromosome was much debated (7,9).
Chromosomal Translocations and Other
Manifestations of Chromosomal Instability:
1920-1930s
Implicit in crossing over was the requirement for chromosome
breakage and rejoining but how this happened was not understood.
It was during a later study of linked genes in 1921 that A. H.
Sturtevant noted another example of chromosome breakage when
he found that pieces of chromosomes could not only recombine
with their homologues but occasionally segments of a different
chromosome. “A section, including the peach locus, broke loose
and attached itself near the right-hand end of a normal third
chromosome” (ie, translocation) (10). “Segmental interchanges”
2
was another term for chromosomal translocations (CTs) used by
Belling (11). CTs, insertions, and inversions became the subject of
extensive studies in the late 1920s and 1930s.
Important advances in 1926–1927 were the discoveries of the
mutagenic effects of X-rays in Drosophila by Herman J. Muller (12)
and in Barley and Zea Mays by Lewis J. Stadler (13). This provided a
wealth of new mutations in genetically well-studied species. As
Muller stated “… ionizing radiations … induced point mutations in
abundance also induced structural changes of all known types” (9)
including translocations, inversions, insertions, dicentrics, and deletions. Barbara McClintock who had described the 10 different chromosomes in Zea Mays and could distinguish each by chromomere
patterns was invited by Stadler to come to Missouri and work on the
mutants he had produced. She described the behavior of dicentric
chromosomes in mitosis and the breakage-fusion-bridge cycle
(14,15). These were the beginnings of chromosome (“genome” was
the term she used) instability so provocatively described in her Nobel
lecture: “In the future attention undoubtedly will be centered on the
genome, and with greater appreciation of its significance as a highly
sensitive organ of the cell, monitoring genomic activities and correcting common errors, sensing the unusual and unexpected events,
and responding to them often by restructuring the genome” (16).
Boveri’s Thoughts on Chromosomes in
Cancer in 1914
In the first half of the 20th century, there began serious speculations, hypotheses, and some data about the role of chromosomes
Affiliation of author: Laboratory of Cancer Biology and Genetics, Center for
Cancer Research, National Cancer Institute, National Institutes of Health,
Health and Human Services, Bethesda, MD 20892.
Correspondence to: Michael Potter, MD, Laboratory of Biology and Genetics,
Center for Cancer Research, National Cancer Institute, National Institutes of
Health, Health and Human Services, Bethesda, MD 20892 (e-mail: potter@
helix.nih.gov).
DOI: 10.1093/jncimonographs/lgn013
© The Author 2008. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: [email protected].
Journal of the National Cancer Institute Monographs, No. 39, 2008
in cancer. These thoughts were largely based on observations
made in plant, invertebrate, and amphibian developing cells and
not directly in neoplastic tissues, which were rarely found in these
species. The study of chromosomes in mammals where neoplastic
diseases were abundant was undeveloped. Nonetheless, challenging ideas and speculations were generated about cancer. The
most insightful and indeed prophetic ideas were made by the
outstanding developmental biologist Theodore Boveri based on
experimental observations with developing Sea Urchin eggs in
1902–1903. Essentially, he fertilized haploid egg cells with two
sperms that generated two mitotic spindles with only a triploid
set of chromosomes. The chromosomes were distributed
unequally to the four blastomeres. When a full complement of
chromosomes occurred, the embryo developed normally from a
blastomere, but when there were deficiencies, defects occurred.
From this Boveri had proposed the idea as early as in 1903 that
“different qualities belong to different chromosomes.” He even
proposed that some chromosomes carried “inheritance factors”
that suppressed cell division and that: “cells of tumors with
unlimited growth would arise if these inhibiting chromosomes
were eliminated.” He went on: “… the essence of my theory is not
abnormal mitosis but a certain abnormal chromatin complex not
matter how it arises … This primordial cell of a tumor as I shall
call it in what follows is according to my theory a cell which contains as a result of an abnormal process a definite and wrongly
combined chromosome complex. This above all is the cause of
the tendency to rapid proliferation which is passed on to all the
descendents of the primordial cell” (17). These ideas reflect a
conceptual understanding of a connection of the genetic apparatus embodied in chromosomes to the origins of neoplasia far
ahead of his time.
Cytogenetics in Mammalian Tumor Cells
Begins in Ernest 1950–1976 with Metaphase
Banding Patterns and the Identity of
Individual Chromosomes
This was a period of exciting and revolutionary discoveries in
cytology that began in the laboratory of Torbjorn Caspersson and
opened the door for studying chromosomes in mammalian species where tumors were unfortunately much more prevalent. In
1947, two very talented Hungarian medical students George and
Eva Klein came to Caspersson’s laboratory at the Karolinska
Institute in Stockholm looking for a new home in the world of
science and genetics (18). Caspersson had developed spectrophotometric methods (UV spectrophotometry) to determine the
location and quantity of nucleic acids in cellular organelles. After
some disappointing early attempts to work with fixed mammalian
tissue sections, the Kleins learned about the Ehrlich Ascites
Tumor at a lecture given by Hans Lettré and recognized its
potential for mammalian cytogenetics. The Kleins introduced
this tumor into Caspersson’s laboratory as a source of mammalian
cells in suspension. One can only assume that Caspersson was
impressed with this model and the Kleins as well as he urged them
to develop this project. In 1950, an opportunity opened up for
Caspersson to send two young students to the United States for a
brief fellowship of several months. He selected George Klein
Journal of the National Cancer Institute Monographs, No. 39, 2008
(GK) as one of his choices and sent him to the laboratory of an
old friend and collaborator Jack Schultz at the Institute for
Cancer Research at Fox Chase, Philadelphia. Caspersson and Jack
Schultz had worked together before WWII and formed a great
friendship and correspondence. They even analyzed the bands in
salivary gland polytenic chromosomes using Caspersson’s instruments (19). When GK arrived at Fox Chase, he was introduced to
Theodore S. Hauschka, and these two “enthusiasts” wasted no
time in acquiring every available mouse tumor and converting
each into ascites tumors (20). In turn, Hauschka introduced GK
to tumors in inbred mice and the genetics of tissue transplantation. GK soon returned home loaded down with 200 mice that he
personally escorted from Philadelphia to Stockholm. Hauschka
began studying the chromosome numbers and ploidy in ascites
tumors.
In 1952, the well-established plant cytogeneticist Albert Levan
from Lund became interested in extending his studies to mammalian systems, and this led him to Hauschka’s laboratory in 1952–
1954 at Fox Chase to work on chromosomes in mouse ascites
tumors. One of Levan’s first experiments focused on comparing
the length of chromosomes in mouse spermatagonia with those in
ascites tumor cells, and a remarkable difference was discovered.
Some of the chromosomes in the tumors were longer or shorter
than the longest or shortest chromosomes in spermatagonial cells.
He reasoned that these must have arisen by CTs (21).
Interchromosomal translocations may also lead to recognizable
“types of new chromosomes,” He called these “cryptostructrual
rearrangements” (21,22) and this was confirmed independently by
Hauschka (23). Levan noted “… the structural remodeling of the
chromosome set has played a more important role in the development of a tetraploid tumor idiogram than in diploid.” Levan
recalled that tetraploid plants were more adaptable than their diploid counterparts to environmental changes. The proof that some
of these cryptostructural rearrangements were in fact translocations awaited the development of a method for identifying individual mammalian chromosomes in 1972 and 1973. These were
some of the beginnings of chromosomal instability in mammalian
tumor cells that sparked the remarkable discoveries that
followed.
A major advance in chromosomal disorders in neoplasia in the
1950–1975 period was made by Peter Nowell and David Hungerford
(24). They sought to study the chromosomes in human tumors but
not having the advantages of transplantable ascites tumors began
using human peripheral blood leukemic cells. Short-term cultures
of these cells contained metaphases, but then they discovered that
an available mitogen, phytohemagglutinin, induced an abundance
of mitotic figures (25). This allowed them to survey a great variety
of human leukemic cells and here they discovered a subtle but
highly significant anomaly in the leukemic cells of patients with
chronic myelogenous leukemia (CML), specifically a characteristic
minute chromosome that became known as the Philadelphia chromosome (24). This turned out to be a consistent recurring phenomenon in CML, and a whole new field of investigation was
born. Cytology had entered the practical world of the medical
clinic.
To crown the remarkable achievements of this period from
1950 to 1975 was the discovery of banding patterns in metaphase
3
chromosomes made possible by Torbjorn Caspersson, Lore Zech,
and their colleagues (26). Now, in both humans and mice, it
became possible to identify each of the unique chromosomes in
well-spread metaphase plates. This revolutionized mammalian
cytogenetics and brought it into the world of diagnostic medicine.
The first to develop this was Janet Rowley in 1972 who identified
the Philadelphia chromosome as a one partner in a reciprocal
translocation. Then in 1973, she identified the first recurring CT
in human acute leukemia t(8;21) and this was the beginning of an
exciting series of studies in her laboratory and others that have led
insights into the causes and pathogenesis of acute leukemias in
humans.
1975–2000: Consistent Recurring Breaksites
In 1965, George Klein had become interested in the pathogenesis
of an unusual B cell lymphoma in African children that was associated with disfiguring jaw tumors (18). These dramatic tumors
had been discovered by Denis Burkitt in Africa and bear his name
as Burkitt Lymphomas (BL). Through an extensive series of discoveries, endemic BL became associated with the ubiquitous
human Epstein Barr virus. GK was eager to obtain tissues for his
laboratory in Stockholm to study this fascinating model system.
After numerous enquiries, he located an ENT surgeon in
Nairobi, Peter Clifford, who began sending him specimens on a
weekly basis. GK’s whole laboratory set about culturing and analyzing these tissues that arrived on ice every Tuesday. When
Caspersson developed chromosome banding, cytological studies
were initiated. Two Bulgarian workers Manolov and Manolova at
the Karolinska with the help of Albert Levan found that BL tissues consistently and recurrently contained Chr 14q+. Their
study was discontinued when they had to return home (27). Lore
Zech continued the work and identified that the origin of the
chromosomal fragment attached to 14q+ was from chr8, thus
identifying the t(8;14) CT for the first time in BL (28). GK and
his colleague Francis Wiener then began to search for experimental models and focused first on plasma cell tumors (PCTs) in
mice. Reports by T. H. Yosida (29) and G. Sorenson et al. (30)
had described recurring t(12;15) and t(6;15) CTs in long-term
transplanted PCTs, but GK wished to analyze a consecutive series
of primary or first-generation PCTs. This study showed that these
CTs were consistent and recurrent in pristane-induced PCTs
(31). GK and FW then contacted Hervé Bazin who had developed a spontaneous rat immunocytoma model system and again
found recurring IgH/C-Myc, t(6;7) CTs in each of the tumors
(32–34). The t(6;7) was the rat homologue of t(8;14) and humans
and t(12;15) in mice.
Oncogenes at Breaksites: The Promoter
Insertion Hypothesis 1980–1983
Detailed analysis revealed that the breaksites in these CTs from
three different species occurred in the same bands in each of the
tumors, and the “race was on,” to identify the genes at these
breaksites. Two seminal observations led to their identity. The
first came from a study on the role of the Avian Leukosis Virus
(ALV) in bursal lymphoma development in chickens. ALV did
4
not possess transforming activity, but infection of chickens by
ALV was responsible for epidemics of B cell lymphomas that
decimated flocks of chickens. These occurred after long latent
periods. Because ALV was not associated with a transduced oncogene, its role in lymphoma development was not clearly defined.
Through reverse transcription the RNA genome of the ALV
virus during an active infections was able to insert itself randomly
into the chicken chromosomal genome. William Hayward,
Benjamin Neel, Harriet Robinson, and Susan Astrin postulated
that the insertion of the ALV following an infection might activate a critical oncogene by placing it under the control of ALV
promoters located in the long terminal repeat (LTR) sequences
(35–37). These workers postulated the ALV virus might insert
itself next to a cellular oncogene and take over its regulation.
They systematically tested the known oncogenes in the chicken to
see if LTRs of ALV had inserted into one of these genes and discovered that C-Myc was consistently targeted and driven by ALV
insertion in 28 different bursal lymphomas. This was a stunning
advance because it established the concept of insertional
mutagenesis.
The second turning point observation inspired by the bursal
lymphoma story was made by Grace Shen-Ong and Michael Cole
who looked for rearrangements of c-Myc caused by CTs. They
found consistent myc rearrangements in mouse PCTs (38) and
further identified the genes involved in the breaksites of chr15
and chr12 as c-Myc and IgH, respectively. Riccardo Dalla-Favera
and his colleagues (39) showed independently that IgH and C-Myc
were at the breaksites in the human t(8;14) q32,q24. Similar findings were soon made with the rat immunocytomas. A second type
of Ig/C-Myc–like CT that occurs in both humans and mice
involves the illegitimate recombination of Ig light-chain loci and a
region 3′ of c-Myc (called the plasmacytoma variant [PVT-1] locus)
(see Table 1). Thus, a family of homologous Ig/C-Myc CTs exists
in at least three different mammalian species.
Cytogenetics of Leukemia: Chimeric Genes
and Fusion Proteins 1980–2000
In 1983, the genes at the breaksites in the Philadelphia chromosome were identified as the abl oncogene (chr9) and bcr (chr22)
(40). The v-abl oncogene was first isolated from a mouse lymphosarcoma (41). The genetic study of t(9;22) gene and its protein
products revealed a new and intriguing phenomenon the two
genes at the breaksites had formed a novel chimeric gene with a 5′
segment derived from bcr and the 3′ segment from human abl that
produced a functional protein BCR-ABL. Similar chimeric genes
were discovered in acute leukemias (AML, ALL, APL). These
include de novo leukemias in adults; childhood leukemia where
strong evidence indicates some of these CTs occurred in utero
(42,43) and the leukemias that develop in patients who have
received chemotherapy (44,45). It is important to note that only a
fraction of acute leukemias have a balanced recurring CTs
(rCTs).
In a recent compilation, Zhang and Rowley have listed 129
different rCTs in human leukemias (46). Some reduction in the
complexity of this large number comes from the finding that in
many examples one dominant gene (usually the one controlling
Journal of the National Cancer Institute Monographs, No. 39, 2008
Table 1. Landmarks in the association of CTs in tumors
CTs, inversions, and duplications of linkage groups discovered genetically (1920s)
CTs, inversions, and duplications visualized (1930s) (McClintock, Painter, Bridges, Belling)
Chromosomal abnormalities in somatic tumor cells (1950s) (Levan, Hauschka, Klein, Nowell)
Chromosome metaphase banding (Caspersson, Zech)
Recurrent CTs (1950s) (Klein, Rowley)
Retroviral insertional mutagenesis (Hayward, Noel, Robinson, Astrin)
Retroviral oncogenes Myc and Abl activated at breaksites in CTs (1970s–1980s) (Hayward, Dalla-Favera, Cole, Heisterkamp)
Fusion genes, transcription factors activated at breaksites (1980s–2000s)
Defects in DNA repair (nonhomologous end-joining) and apoptosis (p53, Bcl) augment and accelerate development of tumors with
recurrent CTs (1990–2000s)
CT = chromosomal translocation.
the 3′ segment of the chimera) may have multiple partners (47).
An extreme example are the 47 partners for 11q23 breaksite gene,
which has been identified as mixed lineage leukemia (MLL) gene.
The mutations generated by rCTs comprise a substantial group of
potential oncogenic mutations. Although the promoter insertion
of oncogenes was at first an exciting model, because the original
oncogenes were “transforming genes,” this concept has been
modified. The growing list of new rCTs has uncovered new
classes of genes that participate in gene transcription and may act
as controllers of multiple gene activities and that alter the differentiation and proliferation of hematopoietic cells, eg, MLL, APL
(48–50).
The development of polymerase chain reaction (PCR) technology coupled with the knowledge of the DNA sequences contiguous to the breaksites in rCTs made possible an alternative to the
standard cytological methods for determining the presence of illegitimate recombinations (IRs) between chromosomes (ie, CTs)
(51,52). The sensitivity for detecting the IR was quantitatively
increased. This was not without cautions about artifacts created by
PCR. The exciting experiments of Limpens and Kluin (53) that
the Igh/Bcl-2, t(14;18) CT could be found in healthy individuals
(now estimated to be ~80%) raised many questions about the
biological significance of IRs and the development of neoplasia.
The rCTs provide a clue to the natural history of neoplasia, and
they have a definite probability (though in some examples very
small) of culminating in the formation of an aggressive neoplastic
clone. Each gene with oncogenic potentiality involved in an rCT
must be separately evaluated for how it contributes to neoplastic
development.
by the consequences of abrogating the regulators of apoptosis
through mutations of p53 which activates apoptosis (56,57) or by
the effects of transgenes that code for anti-apoptotic factors (bcl-2,
bcl-xL) (58,59). Both mechanisms dramatically increase and accelerate tumorigenesis.
The immediate response to DNA damage is by patching the
broken ends with Ku70/86, ␥H2AX and interrupting the cell cycle
by ATM, ATR. These actions importantly allow the participation
DNA repair enzymes to find, bind, and religate. The major pathways of repair are by homologous recombination and nonhomologous end-joining. Each one of these pathways involves the
participation of multiple components (see Figure 1). Deficiencies
in many of these components may be associated with increased
chromosomal instability and tumor formation [for review see
(60)].
Factors that Contribute to Chromosomal
Instability a Current and Continuing Insight
Conceptual advances in other related areas have opened up a vastly
complex but interrelated set of mechanisms and responses to DNA
damage that are determinants in CT development (54). Most
important is the extensive science of DNA repair [for history see
(55)]. The DNA double-strand break (DSB) is the critical lesion in
CT development and the responses to this damage are concerned
with how cells immediately control, ultimately repair, and survive.
DSBs may activate cell death by apoptosis or the cells may not
survive the loss of the acentric fragments in successive mitoses.
The importance of apoptosis as the major mechanism for eliminating damaged genomes and the cells that possess them is revealed
Journal of the National Cancer Institute Monographs, No. 39, 2008
Figure 1. B cell lymphoma plasmacytoma.
5
Conclusion
The association of CTs as generators of potential oncogenic
mutations continues to advance into new vistas and provide
insights into the genetic basis of neoplastic development. A brief
sketch of the history of CTs and tumors is subjective and must be
apologetic for its omissions, but most of all indicate that this is a
moving and exciting field.
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