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PERSPECTIVES

GENETICS

Forty years ago, a chromosomal translocation was discovered to cause and revealed A Story of Swapped Ends as a genetic disease. Janet D. Rowley

t was dubbed the “Philadelphia chro- There the matter stood for a decade. In mosome,” named after the city where the meantime, Herbert Abelson had iso- Ithe abnormal was first lated a virus that induced B cell leukemia. described in 1960 ( 1). , of The “Abelson” virus could transform nor- the University of Pennsylvania, and David mal murine lymphocytes and fi broblasts, and Hungerford, at the Fox Chase Cancer Cen- the causative viral factor was a protein with ter, had taken a close tyrosine kinase activity (v-Abl). The human look at patients with counterpart of the Abelson viral gene, ABL, Online chronic myeloid leuke- was mapped to chromosome 9 (7 ). More- sciencemag.org mia (CML) and found over, the only additional DNA found in the Podcast interview that regardless of sex, Ph chromosome was from chromosome 9

with author Janet Downloaded from Rowley (http://scim.ag/ they had a very small (8 ).The laborious task of cloning the chromo- ed_6139). chromosome. It was a somal breakpoint in CML revealed that the turning point in can- ABL gene on chromosome 9 was translocated cer biology—the beginning of a story that into part of a gene called the breakpoint clus- would draw new attention to chromosome ter region (BCR) in chromosome 22, creating abnormalities as a cause of cancer, a phe- a BCR-ABL gene fusion (9 –11 ). nomenon that still influences our under- The only previously cloned translocation http://science.sciencemag.org/ standing of the disease. breakpoints, namely the t(8;14) in Burkitt To appreciate the importance of the discov- lymphoma (B cells), had involved an onco- ery of Nowell and Hungerford, it is necessary gene called MYC (the human counterpart of to understand the state of biomedical science Distinguishing . New staining tech- the viral oncogene v-myc), and the immuno- in the 1950s. The prevailing view from stud- niques developed in the 1970s allowed the visual- globulin gene on chromosome 14 (12 , 13). ies of experimentally induced cancer was that ization of characteristic banding patterns on chromo- The discovery that oncogenes were involved chromosome abnormalities were the result somes. Janet Rowley (shown) used images of banded in translocation breakpoints proved to be a of genomic instability in cancer cells, not the chromosomes (white on black background) to show remarkable validation of virology and of that the in CML was a cause. It was assumed that loss of DNA from , fields that were struggling

translocation between chromosomes 9 and 22. on December 18, 2017 the Philadelphia (Ph) chromosome (origi- to show their relevance to human cancer. nally thought to be a deletion in chromosome Among these patients were two with acute That CML involved the human oncogene 21) included genes that regulate cell growth, myeloid leukemia (AML), where banding ABL was welcome corroboration. Addi- thereby leading to unrestrained proliferation revealed that a piece of chromosome 8 had tional translocations were found to involve of leukocytes. The situation was complicated broken off and joined chromosome 21. This oncogenes as well, a few of which encoded because some patients with CML lacked the was the fi rst recurring chromosomal trans- tyrosine kinases like ABL; others involved Ph chromosome and surprisingly, they had a location [t(8;21)] to be identifi ed (5 ). Were genes that activate transcription factors that shorter survival than did those with a Ph chro- chromosomal changes consistent in other function in cell growth, differentiation, and mosome (2 ). Nonetheless, the presence of the ? It was already known that CML even cell death. It was fortuitous that at the Ph chromosome became an important diag- patients in terminal blast crisis showed a gain same time, drug companies were developing nostic tool in hematology, and it appeared to in middle-size chromosomes; these, I discov- tyrosine kinase inhibitors. From this focus be the exception to the established view that ered, all turned out to be chromosome 8. What emerged imatinib (marketed as Gleevec), chromosome changes were variable and irrel- was even more startling was that chromosome the compound eventually approved in 2001 evant in cancer. 9 had an extra piece of material whose stain- to treat CML (and later, for other ). The situation changed dramatically in the ing resembled that of the missing piece of Like all tyrosine kinase inhibitors, imatinib 1970s when several new staining techniques the Ph chromosome (by then, known to be prevents the protein (BCR-ABL, in the case revealed chromosomes with unique banding chromosome 22). This suggested that the of CML) from phosphorylating proteins patterns (transverse stripes) that allowed them Ph chromosome could be the result of a that promote cancer development ( 14). This to be distinguished individually and precisely translocation involving the swapped ends of pharmaceutical breakthrough came almost (3 , 4). Having learned a banding technique at chromosome 9 and chromosome 22. Leu- 50 years after the discovery of the Ph chro- Oxford University, I returned to the Univer- kemia cells from the same patients in the mosome. Imatinib changed CML from a dis- sity of to apply the method to chro- chronic phase of CML showed the same ease with a 3- to 5-year average life span to mosome samples from leukemia patients. (9;22) translocation, whereas nonleukemia one where patients have an almost normal cells from their peripheral blood had a nor- life expectancy, especially with the advent mal karyotype. It seemed quite likely that the of new second- and third-generation tyrosine Department of Medicine, , 5841 S. Maryland Avenue, Chicago, IL 60637, USA. E-mail: Ph chromosome was an acquired transloca- kinase inhibitors. These later drugs, espe-

[email protected] tion, a fi nding I reported 40 years ago (6 ). cially ponatinib, have been designed to be UNIVERSITYCHICAGO OF MEDICAL CENTER CREDIT:

1412 21 JUNE 2013 VOL 340 SCIENCE www.sciencemag.org Published by AAAS PERSPECTIVES effective despite mutations in the activation tions is the same in both. Moreover, the genes less, the goal will always be the same—to domain of the ABL protein. involved have the same function in both cases treat disease and benefi t the patient. Whereas translocations were first iden- (17 ). Thus, translocations are remarkably tifi ed in leukemias, lymphomas, and sarco- similar in function, though not necessarily in Reference and Notes mas, they are now cropping up in many com- their frequency in individual cancers. 1. P. C. Nowell, D. A. Hungerford, Science 132, 1497 (1960). mon epithelial tumors, prostate cancer, and It is likely that next-generation sequencing 2. J. Whang-Peng et al., Blood 32, 755 (1968). 3. T. Caspersson et al., Exp. Cell Res. 60, 315 (1970). lung cancer, among others. Next-generation will reveal a much higher incidence of gene 4. A. T. Sumner et al., Nat. New Biol. 232, 31 (1971). sequencing of leukemias and solid tumors has fusions in solid tumors. But this method is a 5. J. D. Rowley, Ann. Genet. 16, 109 (1973). revealed a host of translocations (often small two-edged sword. It has identifi ed numerous 6. J. D. Rowley, Nature 243, 290 (1973). 7. N. Heisterkamp et al., Nature 299, 747 (1982). deletions or inversions) ( 15), some of which chromosomal translocations and deletions, 8. A. de Klein et al., Nature 300, 765 (1982). involve genes that are targets of drugs already but which of these lead to altered gene func- 9. N. Heisterkamp et al., Nature 306, 239 (1983). approved for therapy of other conditions. It tion and which are inconsequential? It will 10. J. Groffen et al., Cell 36, 93 (1984). took only a few years from the discovery of be diffi cult to distinguish them in the future 11. E. Shtivelman et al., Nature 315, 550 (1985). 12. R. Dalla-Favera et al., Proc. Natl. Acad. Sci. U.S.A. 79, the EML4-ALK translocation in lung cancer to without characterizing RNA from the tumors. 6497 (1982). the development of the tyrosine kinase inhibi- A goal of personalized medicine is to iden- 13. R. Taub et al., Proc. Natl. Acad. Sci. U.S.A. 79, 7837 tor crizotinib (16), indicating that the discov- tify virtually all of the targetable genetic and (1982). ery of new translocations may be more rapidly epigenetic abnormalities in a patient’s tumor 14. B. J. Druker et al., N. Engl. J. Med. 344, 1031 (2001). 15. B. Vogelstein et al., Science 339, 1546 (2013). translatable to drug discovery. Although data through next-generation sequencing and other 16. A. T. Shaw et al., Lancet Oncol. 12, 1004 (2011). Downloaded from on the occurrence and types of new transloca- technologies. To evolve targeted treatments 17. F. Mitelman et al., Nat. Rev. Cancer 7, 233 (2007). tions, based on karyotype analysis, are more for cancer, we also need a more sophisticated frequently reported for hematologic cancers understanding of tumor-specifi c antigens and Acknowledgements: I gratefully acknowledge the thought- ful criticisms of B. Drucker, K. Janssen, M. Le Beau, F. Mitel- (75%) than for solid cancers (mainly epithe- chromatin modifi cations, for example. There man, Y. Nakamura, and D. Rowley. lial) (25%), the proportion of malignancies likely will be many surprises along the way, that have recurring chromosomal transloca- and paradigms will be discarded. Neverthe- 10.1126/science.1241318 http://science.sciencemag.org/

PHYSICS

Contact with a layer of boron nitride provides Critical Mass in Graphene a route to control the electronic properties of graphene. Michael S. Fuhrer

ne of the most striking properties The massless property of graphene’s tron and hole states exist at exactly zero

of graphene, a single-atom-thick electrons is due to the symmetry of the lat- energy, hence zero band gap and zero mass on December 18, 2017 Olayer of carbon, is that the electrons tice: The simplest repeat unit, the unit cell, (see the fi gure, panel B). But what happens behave as if they have no mass. They move has two identical carbon atoms (see the if the two atoms in the unit cell are not iden- at a constant velocity, regardless of their fi gure, panel A). There are thus two zero- tical? An extreme case is hexagonal boron energy, much like photons, the more familiar energy states: one in which the electron nitride (hBN)—it too has a hexagonal lattice massless particles of light. Special relativity resides on atom A, the other in which the structure analogous to that of graphene, but 2 tells us that a minimum energy E = 2m0c is electron resides on atom B. Both the elec- with one boron atom and one nitrogen atom 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 2 gap energy Eg = 2m0v 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 hun- dred). Thus, mass and band gap are intimately related; no mass equates to no band gap, and Mass and band gap. (A) Graphene has two atoms in its unit cell, labeled A and B. (B) If A and B are identical until now that was the end of the story in gra- (have the same energy), then graphene electrons have zero mass and a gapless dispersion relation [energy E versus momentum (p , p )]. All electronic states exist equally on both atoms (denoted by magenta in dispersion phene. On page 1427 of this issue, Hunt et al. x y relation). (C) When the energy of atom A is raised relative to atom B, electron states primarily on atom A (red in (1 ) show that electrons in graphene can gain a dispersion relation) have higher energy than electron states primarily on atom B (blue in dispersion relation) mass under the right circumstances. and a band gap Eg is opened. If we examine electron states that reside primarily on atom A (red in dispersion relation), we fi nd a positive curvature of the energy versus momentum relation (red dashed curve) and thus School of Physics, Monash University, Monash, 3800 Victo- positive mass for these states. (D) When the energy of atom A is lowered relative to atom B, states on atom A ria, Australia. E-mail: [email protected] have an energy versus momentum relation with negative curvature (red dashed curve) and thus negative mass.

www.sciencemag.org SCIENCE VOL 340 21 JUNE 2013 1413 Published by AAAS A Story of Swapped Ends Janet D. Rowley

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