Insights from Bel-2 and Mye: Malignancy Involves Abrogation of Apoptosis As Well As Sustained Proliferation 1 Suzanne Cory, 2'3 David L

[CANCER RESEARCH(SUPPL.) 59, 1685s-1692s, April 1, 1999] Insights from Bel-2 and Mye: Malignancy Involves Abrogation of Apoptosis as well as Sustained Proliferation 1 Suzanne Cory, 2'3 David L. Vaux, Andreas Strasser, Alan W. Harris, and Jerry M. Adams The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria 3050, Australia

It is indeed an enormous honor and pleasure to introduce Drs. Suzanne Cory and Stanley Korsmeyer, this year's winners of the Mott Prize. I think no one would question the view that their seminal experiments radically changed the way we think about the process of cancer. If we look back about 10 or 15 years, programmed celt death was a very interesting phenomenon, but we had no idea what this meant in terms of cancer, although suggestions were made. It was certainly interesting in terms of development, but we had no idea about the mechanisms involved. Of course, all this has changed enormously over the last decade, and in terms of cancer particularly, through the seminal contributions of Suzanne Cory and Stan Korsmeyer and their colleagues. Now we know that not only do cancer cells have to escape proliferation controls, they also have to abolish cell death pathways. Not only is this incredibly important for our understanding of the mechanisms underlying cancer, but the way we think about therapy has been radically altered. And as was said already, it is very exciting and a great coincidence, perhaps, that the Sloan Prize this year is awarded to Bob Horvitz who has used very elegant genetics to dissect cell death pathways in C. elegans. And, of course, what is particularly exciting is the convergence of the studies on bcl-2 in humans and mice with those in C. elegans to show these pathways are conserved. What an exciting combination of studies. So, now, to introduce Dr. Suzanne Cory. Suzanne has made many seminal contributions over the years, and I would say one thing that has typified her approach has been to use pioneering transgenic experiments to dissect gene interaction in cancer--together with her collaborator over many years, Dr. Jerry Adams, who is here in the audience. Suzanne got her degree at the University of Melbourne in Australia and then made a very visionary and wise choice in coming to Britain to do her Ph.D. I wasn't going to crack any jokes, just a slight one.., to do her Ph.D., as she says, in the Department of One Called Francis Crick. She survived that experience and came out with a very important paper on sequencing transfer RNA which was a breakthrough at the time. After a productive post-doctoral period in Switzerland, Suzanne then set up a joint laboratory with Jerry Adams in the Walter and Eliza Hall Institute in Melbourne. First, they concentrated on normal B cell development and identified immunoglobulin gene clusters, showed that deletions were important in rearranging those clusters in B cells to bring about the formation of the immunoglobulin genes, and then they moved to pathology and made a very important observation, that in mouse plasmacytomas and Burkitt's lymphoma, the myc gene is deregulated by translocations. However, they went one step further than that. They actually recreated the myc rearrangements in transgenic animals which then developed lymphomas, proving causality which is a very important thing we all have to do. The next move that they made was to use transgenic approaches to look at the interaction of different oncogenes and how they cooperate in oncogenesis in mice. Then, in terms of this particular prize, the seminal finding, after the isolation of the bcl-2 oncogene by Stan Korsmeyer and other groups, was the study published in Nature in 1988. Together with David Vaux and Jerry Adams, Suzanne Cory showed that the introduction of bcl2 into B-cells in culture increased their survival. This was, of course, a very, very important observation. Suzanne then went on to pursue aspects of the biology of bcl-2, showing for example that bcl-2 can cooperate with myc in oncogenesis in transgenic animals, and has continued to study the function of bcl-2 and interacting partners. Suzanne is now the director of the Walter and Eliza Hall, a very famous, wonderful institute in Melbourne, and she has had many honors over the years, including election to the Royal Society in London in 1992, and foreign membership of the National Academy of Sciences in 1997. She has also won the Burnet's Medal and shared the 1998 Australia Prize of the Australian Academy of Sciences. Nicholas D. Hastie Medical Research Council Human Genetics Unit Western General Hospital Edinburgh, United Kingdom

Abstract Transgenic mouse models have illuminated how each contributes to lymphomagenesis. Constitutive myc expression provokes sustained cell pro- The chromosome translocations typifying Burkitt's lymphoma and liferation and retards differentiation. However, the resulting expansion in follicular lymphoma deregulate very different oncogenes, myc and bcl-2. cell number is self-limiting, because the cells remain dependent on cytokines and undergo apoptosis when these become limiting. In contrast, Received 11/11/98; accepted 1/27/98. bcl-2 is the prototype of a new class of oncogene that enhances cell survival 1 Presented at the "General Motors Cancer Research Foundation Twentieth Annual Sci- but does not promote proliferation. Coexpression of these genes leads to entific Conference: Developmental Biology and Cancer," June 9-10, 1998, Bethesda, MD. Most of the research reviewed here was suppolted by the National Health and Medical the rapid transformation of lymphocytes, probably because each can Research Council of Australia (NHMRC Reg. Key 977171), the National Cancer Institute in counter an antioncogenic aspect of the other. Several close homologues of the United States (CA43540), and the Howard Hughes Medical Institute (75193-531101). Bcl-2 also enhance cell survival and are thus potential oncogenes; each is 2 To whom requests for reprints should be addressed. 3 Co-recipient of the Mott Prize along with Stanley Korsmeyer, whose article can be essential for maintenance of particular major organs. More distant Bcl-2 found on pages 1693s-1700s of this supplement. relatives instead promote apoptosis and can be regarded as tumor sup- 1685s

Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1999 American Association for Cancer Research. INSIGHTS FROM BCL-2 AND MYC pressors. For many but not all apoptic signals, the balance between these Close analysis of the E/x-myc mouse model was enlightening. competing activities determines cell survival. Learning how to adjust the Although newborn mice were healthy and devoid of transplantable apoptotic threshold in cancer cells should promote development of more tumor cells, they showed clear evidence of a preneoplastic condition: effective therapeutic strategies. a marked increase in pre-B cells, most of which were in cycle, accompanied by a reduction in mature B cells (22). Thus, enforced Introduction myc expression had promoted proliferation and retarded differentia- Many leukemias and lymphomas are hallmarked by specific karyo- tion. The lymphomas that subsequently arose stochastically were typic abnormalities, the first recognized being the Philadelphia chro- monoclonal and highly transplantable. Furthermore, the kinetics of mosome of chronic myeloid leukemia (1), produced by a reciprocal their onset suggested that the myc-driven pre-B cells became malig- translocation between chromosomes 9 and 22 (2). Such abnormalities nant at a frequency of about 1 per 10 ~~ cell divisions (18). The strong have been the rosetta stone tbr identifying causative oncogenic mu- implication was that tumor onset required one or two somatic muta- tations. tions as well as constitutive myc expression. Genetic background also By modeling in transgenic mice the translocations specific to Bur- played a significant role; tumor onset on a BALB/c background was kitt's lymphoma and follicular lymphoma, we showed that these considerably faster than on a C57BL/6 background (Fig. 1). Such B-lymphoid malignancies stem from fundamentally different types of background effects in transgenic models should prove valuable in the oncogenic mutation. The Burkitt's mutation, deregulation of c-myc, coming search for genes modifying susceptibility to human cancer. results in loss of control of cell division, whereas that in follicular The myc mice provided a fertile testing ground for identifying lymphoma, deregulation of bcl-2, results in decreased susceptibility to synergistic oncogenic mutations. Some 10% of the lymphomas har- cell death. Importantly, these mutations can act in concert, driving the bored mutated ras (N- and K-ras) genes (23). The inferred myc-ras inexorable and rapid development of lymphoma. The lessons learned synergy, noted earlier in other cell types (24, 25), was proven by are relevant to diverse neoplasms. showing that mice bearing both an E/x-N-ras and an E/x-myc transgene succumbed to lymphomas much faster than those bearing either myc: An Oncogene That Provokes Loss of Growth Control alone (20). In an alternative approach for identifying synergistic mutations, neonatal E/x-myc mice were infected with Moloney murine Burkitt's lymphoma is an aggressive malignancy common in chil- leukemia virus, which can activate and thereby tag a cellular proto- dren in equatorial Africa and Papua New Guinea. The majority of oncogene. The proviral insertion sites associated with accelerated these tumors exhibit a translocation involving chromosomes 8 and 14; lymphomagenesis included pim-1, which encodes a ser/thr kinase, and its murine counterpart is the t(12; 15) tbund in most of the plasmacy- a novel gene dubbed bmi-1 (26, 27), which encodes a transcriptional tomas arising in BALB/c mice injected with mineral oil (3). As repressor of certain homeotic genes. How these proteins collaborate reviewed previously (4), several laboratories, including ours, inde- with Myc is still unclear, but it is intriguing to speculate that Bmi-1, pendently established in the early 1980s that both these translocations for example, might repress certain homeobox genes necessary for result from a reciprocal recombination event involving c-myc and the differentiation. immunoglobulin heavy chain (Igh) locus (5-11). As Ohno et al. (12) Finally, it is noteworthy that lymphocytes from E/x-myc mice first hypothesized, these interchromosomal recombination events ap- remained dependent on cytokines and in fact died faster than those pear to be an accidental by-product of the intrachromosomal rear- rangement of Igh genes obligatory in normal B-lymphoid ontogeny. The critical outcome of the reciprocal translocation (13) is consti- 100 tutive expression of c-myc, enforced by its subjugation to an Igh enhancer (14). The c-myc gene product is a basic/helix-loop-helix transcription factor that regulates several genes that maintain cells in cycle. The oncogenic potential of myc had already been flagged by retrovirus studies. Indeed, its name derives from avian m_yelocytoma- tosis virus, the genome of which bears a mutated form of the gene, and m retroviral activation of the cellular gene is frequent in chicken B lymphomas (15) and in murine T lymphomas (16).

Despite the tight association of the myc translocation with Burkitt' s ,m lymphoma and murine plasmacytoma, the case for an etiological role E remained circumstantial. To obtain direct proof, we generated mice ..Q---~ 10 bearing a transgene comprised of myc linked to the intronic Igh > enhancer (E/x), to mimic the translocation and enforce constitutive Myc production throughout the B-lymphoid compartment. The E/x- myc transgene proved a potent, heritable lymphomagenic agent; within the first year of life, all of the mice acquired disseminated lymphoma accompanied by leukemia (17, 18). Similar findings were made by Leder's laboratory (19). The oncogenic potential of myc was not confined to a single differentiation stage, because both pre-B and B lymphomas developed, and some E/x-myc mice treated with mineral oil succumbed to plasmacytoma (20). These experiments established beyond doubt that the deregulation of myc contributes to the devel- 1 I I I I opment of most Burkitt's lymphomas and plasmacytomas. A minor 0 10 20 30 40 subclass of such tumors bearing variant translocations involving im- Age (wk) munoglobulin light chain loci probably also activate myc albeit from Fig. 1. Rate of Etx-myc transgene-induced lymphomagenesis varies with genetic a greater distance (4, 21). background. 1686s

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Fig. 2. Bcl-2 enhances cell survival. A, interleukin 3 (IL-3)-dependent FDC-P1 myeloid cells and a derivative line expressing bcI-2 retrovirus were cultured for 3 days with and without 1L-3. In the presence of IL-3, both lines proliferated and remained viable (e.g., left panel). In the absence of IL-3, the parental cells died rapidly (center panel). Those expressing the bcl-2 retrovirus survived well in the absence of IL-3 (right panel) but withdrew from cycle, as evidenced by their smaller size. B, viability of independent clones of parental FDC-PI myeloid cells and LyH7 pro-B cells (open symbols) and bcl-2 virus-infected derivatives (closed symbols) after 3 days in the absence of IL-3. from normal mice when deprived of cytokines (28). The clear impli- branes (35) [more specifically, the endoplasmic reticulum and the outer cation was that cells forced to cycle by myc die rapidly when cyto- membranes of mitochondria and the nucleus (36)], but apart from a kines become limiting, thus accounting for the plateau in lymphocyte hydrophobic COOH terminus, thought to be a membrane anchor, its numbers observed in vivo and in vitro. Askew et al. (29) and Evan et amino acid sequence revealed no recognizable motifs. al. (30) subsequently established that myc promotes programmed cell The function of Bcl-2 remained a mystery, until Vaux et al. (37) death (apoptosis) under adverse growth conditions. introduced the gene into interleukin 3-dependent cell lines. Most unexpectedly, withdrawal of the cytokine revealed that the depend- bcl-2: An Oncogene That Regulates Cell Death ency had now been altered (Fig. 2). Although the cells still could not Following the paradigm established by Burkitt's lymphoma, the karyo- multiply in the absence of interleukin 3, they survived for many days typic abnormalities in many leukemias and lymphomas have been cloned and proliferated again when resupplied with cytokine. This now- as aberrant rearrangements of immunoglobulin or T cell receptor genes classic experiment demonstrated that cell survival is regulated sepa- (31). Among these was the 14;18 translocation found in the relatively rately from proliferation and that the function of Bcl-2 is to inhibit indolent but common follicular lymphoma. Studies by Tsujimoto et al. apoptosis. Thus, Bcl-2 became the prototype of a new class of onco- (32), by Bakhshi et al. (33), and by Cleary et al. (34) revealed that the gene, one that exerts its action by enhancing cell survival rather than gene brought into the Igh locus was a novel one, and it was dubbed bcl-2 stimulating cell division. (B-cell lymphoma gene 2). As in the myc translocation, the bcl-2 coding Studies of bcl-2 transgenic mice developed by us and by Korsmey- region remained intact, and the critical outcome was constitutive produc- er's group (38-41) confirmed and extended these observations. The tion at high levels of Bcl-2 in the affected B cell and its clonal progeny. B-lymphoid compartment was expanded 4- to 5-fold, but in contrast The Bcl-2 protein was found to be associated with cytoplasmic mem- to the myc mice, the cells were not in cycle. B and T lymphocytes

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bc/-2 100 .o bcl-2+m/ o" Fig. 3. Synergy between Bcl-2 and Myc. A, I I Bcl-2 expression facilitates survival. B-lymphoid 8O l cells from the bone marrow of young healthy bcl-2, I myc, and bcl-2/myc mice and nontransgenic litter- myc / mates were cultured in conventional culture me- dium (i.e., lacking exogenous cytokines such as = 10 60 IL-7), and viability was measured by trypan blue I exclusion; bars, SD. B, Bcl-2 enhances lym- > I phomagenesis induced by Myc. Cumulative mortal- I 40 o- ,,.o ity from lymphoma in mice carrying both El~-bcl-2 I and El~-myc transgenes versus that in mice carrying O I each alone. ii 20i 2- bcl-2 1 I I 0 2 4 6 8 20 40 60 80 100 Days in culture Age (days) 1687s

53 +1- myc + lymphomas con I[--q Fig. 4. A, p53 deficiencyaccelerates lymphoma onset in Eix-myc mice. Hererozygous p53 +/- mice were crossed with EIx-myc mice, and lymphoma onset was determined in progeny bearing both mu- - tations versus each alone. B, PCR analysisreveals mut that lymphomagenesis in p53+/- animals is ac- 40[-" ~ "" / -wt companied by loss of the wild-typep53 allele. / I

4 8 12 16 20 Age (weeks)

expressing the bcl-2 transgene proved remarkably robust in the face of Dangerous Liaisons diverse cytotoxic insults. The normally fragile CD4+CD8 + thymocytes, for example, were recalcitrant to treatment with ionizing radi- Many of the tumors arising in bcl-2 mice exhibited a rearranged ation, glucocorticoids, phorbol ester, or calcium ionophore. myc gene, implicating collaboration between myc and bcl-2 (42, 43). As predicted, the bcl-2 transgene proved oncogenic, albeit less so That synergy had first been inferred from the demonstration that than myc. The incidence of B-lymphoid tumors was higher in the bcl-2 infection of bone marrow cells from pretumorous myc mice with a mice than their nontransgenic littermates, although the penetrance was bcl-2 retrovirus yielded immortal tumorigenic pre-B cell lines (37). low (10-15% over 12 months), and the latency was long (42, 43). Striking evidence emerged from crosses of myc and bcl-2 mice (46). Thus, the transgenic models paralleled the human diseases; Myc Young bitransgenic offspring had copious pre-B cells, with blood produced an aggressive malignancy, whereas Bcl-2 produced an in- leukocyte levels 50-100-fold higher than normal and even 25-fold dolent one. higher than littermates bearing only the myc transgene. Importantly, Another oncogenic mutation that can enhance survival of certain however, these cycling bcl-2-myc pre-B cells were not fully malig- cell types is loss or inactivation of the tumor suppressor p53. Such nant; despite their greatly enhanced survival in the absence of cyto- cells normally undergo apoptosis when p53 levels increase in re- kines (Fig. 3A), they were not transplantable. Thus, even this potent sponse to DNA damage (44). The protection against DNA damage oncogene combination does not fully transform lymphoid cells. Nev- proffered by Bcl-2, however, is broader than that conferred by loss of ertheless, every bcl-2-myc mouse went on to develop a transplantable p53; Bcl-2 inhibits apoptosis of both resting and cycling T cells, lymphoma before 7 weeks of age (Fig. 3B). Unexpectedly, each tumor whereas the absence of p53 protects only the quiescent cells (45). had the phenotype of a primitive progenitor cell and retained both High levels of Bcl-2 in tumor cells may therefore be a graver imped- B-lymphoid and macrophage differentiation potential (46, 47). Pre- iment to genotoxic cancer therapy than loss of p53. sumably, additional mutation(s) were involved, but it remains unclear

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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1999 American Association for Cancer Research. INSIGHTS FROM BCL-2 AND MYC why a rare stem cell is so susceptible to transformation by the tissues because it is the sole guardian expressed there. However, it myc/bcl-2 combination. also remains possible that individual inhibitors block certain cell death Curiously, despite this clear potential for synergy, no bcl-2 trans- pathways more effectively than others. locations were detected in lymphomas arising spontaneously in mvc mice (23). However, inactivation of p53 was detected in some 10- The Bel-2 Family Controls Many but not All Roads to Death 20% of early passage lines derived from the E~-myc tumors 4 and in How does the Bcl-2 family control apoptosis? The engine driving a significant proportion of Burkitt's lymphomas (48, 49). In accord cellular suicide is a family of proteases homologous to Ced-3, the with that finding, introduction of the Etx-myc transgene into a het- product of one of three genes (ced-3, ced-4, and egl-1) shown by erozygous p53 +/- background by breeding led to very early lymphoma Horvitz and co-workers (68, 69) to be essential for developmental cell (Fig. 4A). Remarkably, almost every tumor had lost the wild-type p53 deaths in Caenorhabditis elegans (Fig. 5). These proteases, now allele (e.g., Fig. 4B), as also observed by Hsu et al. (50). Clearly, loss called caspases, cleave their targets after aspartate residues. To protect of p53, like gain of Bcl-2, synergizes very effectively with constitu- the cell, they are synthesized as almost inactive zymogens. Activation tive Myc expression to transform lymphocytes. requires cleavage at sites that are themselves caspase consensus sites; These studies indicate that the combination of an oncogenic muta- therefore, apoptosis entails a caspase cascade (70). tion that suppresses the intrinsic cell death program with one that In C. elegans, the ced-9 gene inhibits programmed cell death by overrides the physiological brakes on cell division is a potent recipe antagonizing the action of ced-4 and ced-3 (71). Importantly, Vaux et for cancer. Most likely, mutations that enhance cell survival counter al. (72) and Hengartner and Horvitz (73) found that human bcl-2 can the "safety net" of apoptosis, which normally swings into action when inhibit cell death in the nematode, a striking demonstration of the cells are induced to divide under adverse or restrictive conditions (29, evolutionary conservation of the machinery of apoptosis (74). How 30). Bcl-2 and Ced-9 function remains uncertain. In keeping with the The Expanding Bcl-2 Family localization of Bcl-2, some evidence links its function to the perme- ability or integrity of organelles, particularly the mitochondrion (75). A great deal is now known about Bcl-2, although its biochemical An alternative view, aligned more obviously with the C. elegans mode of action remains controversial (51-54). Bcl-2 is in fact but one genetics, favors a more direct role for the prosurvival molecules. of a complex family of proteins regulating apoptosis (Fig. 5). The 15 Some recent evidence has suggested that the prosurvival proteins may or so members fall into three subfamilies. Some, like Bcl-2, enhance function by binding to and inhibiting Ced-4-1ike adaptor molecules cell survival, and each of these is a potential oncogene. Other rather needed to facilitate aggregation and autocatalysis of caspases (re- similar proteins, such as the prototype Bax, discovered by Oltvai et al. viewed in Refs. 54 and 76). The conserved NH2-terminal BH4 region (55), counter this survival function and even promote apoptosis when of Bcl-2 homologs, required for their prosurvival activity, may be expressed at high concentrations. A third, more recently recognized critical for any such interaction (77). In mammalian cells, proapop- group comprises proteins largely unrelated to each other or to Bcl-2, totic cousins such as Bax and Bim may act by binding to Bcl-2 except for a short (9-16 amino acids) central domain known as BH3. homologues, thereby allowing Apaf-1 homologues to induce death via These "BH3-only" proteins are potent inducers of apoptosis. Indeed, caspase-9 (Fig. 5). Other putative adaptors may similarly activate Bim, a novel BH3-only protein we identified recently, is so potent that other caspases. Likewise, in nematodes, the BH3 domain protein stable lines cannot be isolated from cells transduced with bim cDNA Egl-1 interacts with Ced-9, probably releasing the adaptor Ced-4 to unless they also overexpress bcl-2 (56). The pro- and antiapoptotic activate Ced-3 (69). The very divergent sequences of the BH3-domain cousins can heterodimerize and seemingly titrate one another's func- subfamily may hint that each responds to a distinct death/survival tion, suggesting that their relative concentration acts as a rheostat for signal, one to a damaged cytoskeleton, for example, and another to the suicide program (55). Heterodimerization involves insertion of the damaged DNA. Some may also preferentially target subsets of the BH3 domain of the prodeath proteins into a pocket created by three death repressors. conserved domains of the prosurvival proteins, as shown by Fesick Bcl-2 is not a panacea for mammalian cell death. In several cell and co-workers (57, 58). The ability of BH3-dolnain and Bax family lines and activated normal T cells (78) and in cells targeted by members to counter Bcl-2 action suggests that the proapoptotic pro- cytotoxic T cells (40, 62, 79), it is ineffectual against the signal teins may act as tumor suppressors, and indeed, many human gastro- induced by "death receptors" such as CD95 (Fas/APO-1) and other intestinal cancers and some leukemias have been shown recently to members of the tumor necrosis factor receptor family. Ligand-induced contain nmtations of bax (59). aggregation of these receptors leads, via the adaptor protein FADD/ Mortl, to activation of caspase-8 (80; Fig. 5). This pathway appears A Bel-2 Homolog Essential for Spermatogenesis to be independent of Apaf-1 and caspase-9 (81, 82). Additional mammalian death pathways undoubtedly remain to be discovered, The two closest homologs of Bcl-2 are Bcl-x L (60) and Bcl-w, because neither gain of Bcl-2 nor inactivation of FADD/Mortl pre- discovered in our laboratory (61). All three protect cells from the same vents, for example, the culling of autoreactive thymocytes (40, 79, 83). array of cytotoxic agents and do so equally well, when expressed at a comparable concentration (62). Nevertheless, gene disruption has A Restraint on Entry into Cell Cycle revealed tissue-specific requirements. Whereas Bcl-2 is essential for the maintenance of the mature lymphoid system (63) and Bcl-x L for Bcl-2 and its homologs not only control cell survival but can also the development of erythroid and neuronal cells (64, 65), Bcl-w is modulate the cell cycle. An early hint of this connection was the quies- necessary for spermatogenesis (66, 67). In bcl-w-null mice, testicular cence of Bcl-2-expressing cells that survived cytokine withdrawal (37), development and prepubertal spermatogenesis are largely unaffected, and their reentry into cycle on restimulation was subsequently found to be but adult seminiferous tubules are disorganized, Sertoli cells and germ retarded (84, 85). Furthermore, thymocyte turnover is slowed in bcl-2 cells of all types are reduced in number, and there are no mature transgenic mice, as is the mitogenic response of their lymphocytes (86- sperm. Most likely a particular prosurvival gene is required in certain 89). Bcl-2 also hastens withdrawal from cycle (90). Importantly, the inhibitory effect of Bcl-2 on cell cycle entry is genetically separable from 4 Our unpublished results. its survival function; the former but not the latter is ablated by mutation 1689s

oncogenc is altered by chromosome translocation to an immunoglobulin locus in murine plasmacytomas and is rearranged similarly in human Burkitt lymphomas. Proc. Natl. Acad. Sci. USA, 80: 1982-1986, 1983. 7. Harris, L. J., Lang, R. B., and Marcu, K. B. Non-immunoglobulin-associated DNA rearrangements in mouse plasmacytomas. Proc. Natl. Acad. Sci. USA, 79: 4175- 4179, 1982. 8. Calame, K., Kim, S., Lalley, P., Hill, R., Davis, M., and Hood, L. Molecular cloning of translocations involving chromosome 15 and the immunoglobulin C a gene from Cell survival Proliferation chromosome 12 in two murine plasmacytomas. Proc. Natl. Acad. Sci. USA, 79: 6994-6998, 1982. 9. Taub, R., Kirsch, I., Morton, C, Lenoir, G., Swan, D., Tronick, S., Aaronson, S., and Leder, P. Translocation of the c-rnyc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc. Natl. Acad. Sci. USA, 79: 7837-7841, 1982. 10. Shen-Ong, G. L., Keath, E. J., Piccoli, S. P., and Cole, M. D. Novel myc oncogene RNA from abortive immunoglobulin-gene recombination in mouse plasmacytomas. Cell, 31: 443-452, 1982. 11. Dalla-Favera, R., Martinotti, S., Gallo, R. C., Erikson, J., and Croce, C. M. Trans- Fig. 6. Complementarity of Bcl-2 and Myc function (see text). location and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science (Washington DC), 219: 963-967, 1983. 12. Ohno, S., Babonits, M., Wiener, F., Spira, J., Klein, G., and Potter, M. Nonrandom chromosome changes involving the Ig gene-carrying chromosomes 12 and 6 in of a tyrosine residue near the NHa-terminal BH4 domain (91) or by a pristane-induced mouse plasmacytomas. Cell, 18: 1001-1007, 1979. deletion in the adjacent nonconserved loop (92). Inhibition of cell cycle 13. Gerondakis, S., Cory, S., and Adams, J. M. Translocation of the myc cellular entry might involve a protein that can bind to this region, such as the oncogene to the immunoglobulin heavy chain locus in murine plasmacytomas is an imprecise reciprocal exchange. Cell, 36: 973-982, 1984. phosphatase calcineurin (93). Whatever the mechanism, the cell cycle 14. Bernard, O., Cory, S., Gerondakis, S., Webb, E., and Adams, J. M. Sequence of the inhibitory effect may have evolved to reduce the oncogenic impact of murine and human cellular myc oncogenes and two modes of myc transcription Bcl-2. It seems pertinent that progressed follicular lymphomas often resulting from chromosome translocation in B lymphoid tumours. EMBO J., 2: 2375-2383, 1983. display missense mutations in the relevant NH2-terminal region (94). 15. Hayward, W. S., Neel, B. G., and Astrin, S. M. Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature (Lond.), 290: 475- Concluding Remarks 480, 1981. 16. Corcoran, L. M., Adams, J. M., Dunn, A. R., and Cory, S. Murine T lymphomas in The long-observed multistage development of malignancy is now which the cellular myc oncogene has been activated by retroviral insertion. Cell, 37: 113-122, 1984. seen to be due to the sequential acquisition of the diverse genetic 17. Adams, J. M., Harris, A. W., Pinkert, C. A., Corcoran, L. M., Alexander, W. S., Cory, alterations needed to subvert controls on critical cellular processes. S., Palmiter, R. D., and Brinster, R. L. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature (Lond.), 318: Deciphering the molecular basis of karyotypic abnormalities has 533-538, 1985. revealed key mutations underlying many neoplasms, and transgenic 18. Harris, A. W., Pinkert, C. A., Crawford, M., Langdon, W. Y., Brinster, R. L., and models (95-97) have provided valuable insight into how specific Adams, J. M. 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Suzanne Cory, David L. Vaux, Andreas Strasser, et al.

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