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A Story of Swapped Ends
Janet D. Rowley
Science 340, 1412 (2013);
DOI: 10.1126/science.1241318
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PERSPECTIVES
GENETICS
A Story of Swapped Ends
Forty years ago, a chromosomal translocation
was discovered to cause leukemia and revealed
cancer as a genetic disease.
Online
Department of Medicine, University of Chicago, 5841
S. Maryland Avenue, Chicago, IL 60637, USA. E-mail:
[email protected]
1412
Distinguishing chromosomes. New staining techniques developed in the 1970s allowed the visualization of characteristic banding patterns on chromosomes. Janet Rowley (shown) used images of banded
chromosomes (white on black background) to show
that the Philadelphia chromosome in CML was a
translocation between chromosomes 9 and 22.
Among these patients were two with acute
myeloid leukemia (AML), where banding
revealed that a piece of chromosome 8 had
broken off and joined chromosome 21. This
was the first recurring chromosomal translocation [t(8;21)] to be identified (5). Were
chromosomal changes consistent in other
leukemias? It was already known that CML
patients in terminal blast crisis showed a gain
in middle-size chromosomes; these, I discovered, all turned out to be chromosome 8. What
was even more startling was that chromosome
9 had an extra piece of material whose staining resembled that of the missing piece of
the Ph chromosome (by then, known to be
chromosome 22). This suggested that the
Ph chromosome could be the result of a
translocation involving the swapped ends of
chromosome 9 and chromosome 22. Leukemia cells from the same patients in the
chronic phase of CML showed the same
(9;22) translocation, whereas nonleukemia
cells from their peripheral blood had a normal karyotype. It seemed quite likely that the
Ph chromosome was an acquired translocation, a finding I reported 40 years ago (6).
There the matter stood for a decade. In
the meantime, Herbert Abelson had isolated a virus that induced B cell leukemia.
The “Abelson” virus could transform normal murine lymphocytes and fibroblasts, and
the causative viral factor was a protein with
tyrosine kinase activity (v-Abl). The human
counterpart of the Abelson viral gene, ABL,
was mapped to chromosome 9 (7). Moreover, the only additional DNA found in the
Ph chromosome was from chromosome 9
(8).The laborious task of cloning the chromosomal breakpoint in CML revealed that the
ABL gene on chromosome 9 was translocated
into part of a gene called the breakpoint cluster region (BCR) in chromosome 22, creating
a BCR-ABL gene fusion (9–11).
The only previously cloned translocation
breakpoints, namely the t(8;14) in Burkitt
lymphoma (B cells), had involved an oncogene called MYC (the human counterpart of
the viral oncogene v-myc), and the immunoglobulin gene on chromosome 14 (12, 13).
The discovery that oncogenes were involved
in translocation breakpoints proved to be a
remarkable validation of virology and of
cytogenetics, fields that were struggling
to show their relevance to human cancer.
That CML involved the human oncogene
ABL was welcome corroboration. Additional translocations were found to involve
oncogenes as well, a few of which encoded
tyrosine kinases like ABL; others involved
genes that activate transcription factors that
function in cell growth, differentiation, and
even cell death. It was fortuitous that at the
same time, drug companies were developing
tyrosine kinase inhibitors. From this focus
emerged imatinib (marketed as Gleevec),
the compound eventually approved in 2001
to treat CML (and later, for other cancers).
Like all tyrosine kinase inhibitors, imatinib
prevents the protein (BCR-ABL, in the case
of CML) from phosphorylating proteins
that promote cancer development (14). This
pharmaceutical breakthrough came almost
50 years after the discovery of the Ph chromosome. Imatinib changed CML from a disease with a 3- to 5-year average life span to
one where patients have an almost normal
life expectancy, especially with the advent
of new second- and third-generation tyrosine
kinase inhibitors. These later drugs, especially ponatinib, have been designed to be
21 JUNE 2013 VOL 340 SCIENCE www.sciencemag.org
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CREDIT: UNIVERSITY OF CHICAGO MEDICAL CENTER
I
t was dubbed the “Philadelphia chromosome,” named after the city where
the abnormal chromosome was first
described in 1960 ( 1). Peter Nowell, of
the University of Pennsylvania, and David
Hungerford, at the Fox Chase Cancer Center, had taken a close
look at patients with
chronic myeloid leukesciencemag.org
mia (CML) and found
Podcast interview
that regardless of sex,
with author Janet
they had a very small
Rowley (http://scim.ag/
chromosome. It was a
ed_6139).
turning point in cancer biology—the beginning of a story that
would draw new attention to chromosome
abnormalities as a cause of cancer, a phenomenon that still influences our understanding of the disease.
To appreciate the importance of the discovery of Nowell and Hungerford, it is necessary
to understand the state of biomedical science
in the 1950s. The prevailing view from studies of experimentally induced cancer was that
chromosome abnormalities were the result
of genomic instability in cancer cells, not the
cause. It was assumed that loss of DNA from
the Philadelphia (Ph) chromosome (originally thought to be a deletion in chromosome
21) included genes that regulate cell growth,
thereby leading to unrestrained proliferation
of leukocytes. The situation was complicated
because some patients with CML lacked the
Ph chromosome and surprisingly, they had a
shorter survival than did those with a Ph chromosome (2). Nonetheless, the presence of the
Ph chromosome became an important diagnostic tool in hematology, and it appeared to
be the exception to the established view that
chromosome changes were variable and irrelevant in cancer.
The situation changed dramatically in the
1970s when several new staining techniques
revealed chromosomes with unique banding
patterns (transverse stripes) that allowed them
to be distinguished individually and precisely
(3, 4). Having learned a banding technique at
Oxford University, I returned to the University of Chicago to apply the method to chromosome samples from leukemia patients.
Downloaded from www.sciencemag.org on July 16, 2013
Janet D. Rowley
PERSPECTIVES
tions is the same in both. Moreover, the genes
involved have the same function in both cases
(17). Thus, translocations are remarkably
similar in function, though not necessarily in
their frequency in individual cancers.
It is likely that next-generation sequencing
will reveal a much higher incidence of gene
fusions in solid tumors. But this method is a
two-edged sword. It has identified numerous
chromosomal translocations and deletions,
but which of these lead to altered gene function and which are inconsequential? It will
be difficult to distinguish them in the future
without characterizing RNA from the tumors.
A goal of personalized medicine is to identify virtually all of the targetable genetic and
epigenetic abnormalities in a patient’s tumor
through next-generation sequencing and other
technologies. To evolve targeted treatments
for cancer, we also need a more sophisticated
understanding of tumor-specific antigens and
chromatin modifications, for example. There
likely will be many surprises along the way,
and paradigms will be discarded. Neverthe-
less, the goal will always be the same—to
treat disease and benefit the patient.
Reference and Notes
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17.
P. C. Nowell, D. A. Hungerford, Science 132, 1497 (1960).
J. Whang-Peng et al., Blood 32, 755 (1968).
T. Caspersson et al., Exp. Cell Res. 60, 315 (1970).
A. T. Sumner et al., Nat. New Biol. 232, 31 (1971).
J. D. Rowley, Ann. Genet. 16, 109 (1973).
J. D. Rowley, Nature 243, 290 (1973).
N. Heisterkamp et al., Nature 299, 747 (1982).
A. de Klein et al., Nature 300, 765 (1982).
N. Heisterkamp et al., Nature 306, 239 (1983).
J. Groffen et al., Cell 36, 93 (1984).
E. Shtivelman et al., Nature 315, 550 (1985).
R. Dalla-Favera et al., Proc. Natl. Acad. Sci. U.S.A. 79,
6497 (1982).
R. Taub et al., Proc. Natl. Acad. Sci. U.S.A. 79, 7837
(1982).
B. J. Druker et al., N. Engl. J. Med. 344, 1031 (2001).
B. Vogelstein et al., Science 339, 1546 (2013).
A. T. Shaw et al., Lancet Oncol. 12, 1004 (2011).
F. Mitelman et al., Nat. Rev. Cancer 7, 233 (2007).
Acknowledgements: I gratefully acknowledge the thoughtful criticisms of B. Drucker, K. Janssen, M. Le Beau, F. Mitelman, Y. Nakamura, and D. Rowley.
10.1126/science.1241318
PHYSICS
Critical Mass in Graphene
Contact with a layer of boron nitride provides
a route to control the electronic properties of
graphene.
Michael S. Fuhrer
O
ne of the most striking properties
of graphene, a single-atom-thick
layer of carbon, is that the electrons
behave as if they have no mass. They move
at a constant velocity, regardless of their
energy, much like photons, the more familiar
massless particles of light. Special relativity
tells us that a minimum energy E = 2m0c2 is
required to create a particle and antiparticle
of rest mass m0 (c is the speed of light; the
2 occurs because two particles are created).
Because photons have no rest mass, a pair of
photons can be created with energies all the
way down to zero energy. In a solid, the band
gap energy Eg = 2m0v2 is the energy required
to create an electron and hole (particle and
antiparticle), where m0 is the effective mass
and v is the Fermi velocity (typically less than
the speed of light by a factor of several hundred). Thus, mass and band gap are intimately
related; no mass equates to no band gap, and
until now that was the end of the story in graphene. On page 1427 of this issue, Hunt et al.
(1) show that electrons in graphene can gain a
mass under the right circumstances.
School of Physics, Monash University, Monash, 3800 Victoria, Australia. E-mail: [email protected]
The massless property of graphene’s
electrons is due to the symmetry of the lattice: The simplest repeat unit, the unit cell,
has two identical carbon atoms (see the
figure, panel A). There are thus two zeroenergy states: one in which the electron
resides on atom A, the other in which the
electron resides on atom B. Both the elec-
tron and hole states exist at exactly zero
energy, hence zero band gap and zero mass
(see the figure, panel B). But what happens
if the two atoms in the unit cell are not identical? An extreme case is hexagonal boron
nitride (hBN)—it too has a hexagonal lattice
structure analogous to that of graphene, but
with one boron atom and one nitrogen atom
Mass and band gap. (A) Graphene has two atoms in its unit cell, labeled A and B. (B) If A and B are identical
(have the same energy), then graphene electrons have zero mass and a gapless dispersion relation [energy E
versus momentum (px, py)]. All electronic states exist equally on both atoms (denoted by magenta in dispersion
relation). (C) When the energy of atom A is raised relative to atom B, electron states primarily on atom A (red in
dispersion relation) have higher energy than electron states primarily on atom B (blue in dispersion relation)
and a band gap Eg is opened. If we examine electron states that reside primarily on atom A (red in dispersion
relation), we find a positive curvature of the energy versus momentum relation (red dashed curve) and thus
positive mass for these states. (D) When the energy of atom A is lowered relative to atom B, states on atom A
have an energy versus momentum relation with negative curvature (red dashed curve) and thus negative mass.
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effective despite mutations in the activation
domain of the ABL protein.
Whereas translocations were first identified in leukemias, lymphomas, and sarcomas, they are now cropping up in many common epithelial tumors, prostate cancer, and
lung cancer, among others. Next-generation
sequencing of leukemias and solid tumors has
revealed a host of translocations (often small
deletions or inversions) (15), some of which
involve genes that are targets of drugs already
approved for therapy of other conditions. It
took only a few years from the discovery of
the EML4-ALK translocation in lung cancer to
the development of the tyrosine kinase inhibitor crizotinib (16), indicating that the discovery of new translocations may be more rapidly
translatable to drug discovery. Although data
on the occurrence and types of new translocations, based on karyotype analysis, are more
frequently reported for hematologic cancers
(75%) than for solid cancers (mainly epithelial) (25%), the proportion of malignancies
that have recurring chromosomal transloca-