Antisense Inhibition of P210 bcr-abl in Chronic Myeloid Leukemia
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1 Antisense Inhibition of P210 bcr-abl in Chronic Myeloid Leukemia J. L. Vaerman, R Lewalle, R Martiat Department of Hematology and Laboratory of Clinical Molecular Biology, Cliniques Universitaires Saint-Luc, Brussels, Belgium Key Words. Leukemia Chronic Myeloid Antisense bcr-abl Retroviral *Transduction Oligodeoxynucleotides Abstract. The evidence that the bcr-ubl gene product (P210) of the Philadelphia chromosome plays a crucial role in the pathogenesis of chronic myeloid leukemia (CML), and the absence of the bcr-abl fused transcript in non-malignant cells makes this messenger RNA an ideal candidate for antisense strategies in CML. To inhibit the expression of the bcr-abl gene, and to try to eradicate Philadelphiapositive cells, Merent methods can be used: 1) the introduction into the cells of antisense oligonucleotides, 2) the use of specfie ribozymes, or 3) the transduction, using retroviral vectors, of stably integrated sequences coding for antisense RNA. Each of these approaches has potential advantages and drawbacks that are discussed below. Although many data emerge that support the use of anti-bcr-lrbl antisense molecules in CML, numerous questions remain to be completely answered before the most efficient strategy can be designed, either for in vitro or in vivo purposes. Introduction Antisense approaches in leukemia aim at selectively suppressing the expression of a gene involved in leukemogenesis, while sparing the normal cellular gene products, thus leaving the normal hematopietic cells intact. The hallmark of chronic myeloid leukemia (CML), the Philadelphia chromosome, results in the formation of a hybrid gene, transcribed into an 8.5 kb mrna which, in turn, is translated into a 210 kd protein (P210) with deregulated tyrosine kinase activity [l-51. The consistency of this Correspondence: Dr. F'hilippe Martiat, Department of Hematology, Cliniques Universitaires Saint-Luc, 10, avenue Hippocrate, 1200, Brussels, Belgium. Received April 29, 1993; accepted for publication April 29,1993. OAlphaMed Press m.OOlO finding-there seems to be no typical CML without activation of the abl gene through the bcr genomic rearrangement [6]-and the fact that introducing this gene into murine hematopoietic cells can cause a CML-like disease [7-91 are strong evidence that P210 plays a crucial role in the pathogenesis of the disorder. These facts, together with the absence of the bcr-abl fused transcript in non-malignant cells, make this messenger RNA an ideal candidate for antisense strategies in CML. Achieving a complete blockade of P210 could lead to important therapeutic breakthroughs. Insofar as CML cells depend on P210 for their survival or the maintenance of their leukemic phenotype, blockading p210 could result in a selective therapeutic effect on the malignant cells. Nevertheless, other strategies that can produce a differential, although less specific, effect on the leukemic cells are also of major interest. Targeting genes, the role of which is more crucial in leukemic than in normal cells, is an important alternative approach. One of these candidate genes is c-myb, the importance of which in human normal and malignant hematopoiesis has been extensively investigated [ 10, 111. From a more fundamental point of view, antisense inhibition of p210 could help to solve some of the more fundamental problems related to the leukemogenic role of this protein. As a matter of fact, it should be pointed out that, despite recent progress, several questions regarding its exact role in the transformation of hematopoietic cells and its relative importance in the chronic and acute phases of the disease remain unanswered [12]. The answers to these questions may also have an important impact on the conception of antisense treatments in the future. To inhibit the expression of the bcr-ubl gene, different methods can be used: the introduction into the cells of antisense oligonucleotides STEM CEUS 1993;11(~~~~13):89-95
2 90 Antisense Inhibition of P2 10 bcr-abf in Chronic Myeloid Leukemia [ , the use of specific ribozymes [ 171 or the transduction, using retroviral vectors, of stably integrated sequences coding for antisense RNA [ 181. The use of ribozymes is not discussed in this paper because more experimental data still have to be produced before integrating this approach in the currently used strategies. In parallel with bcr-abl targeted antisense molecules, some authors have concentrated their efforts on investigating the possible use of antisense agents directed against the c-myb transcripts [ 10, 11, 191. When designing antisense approaches against the bcr-abl transcript, the choice of the target sequences is still a matter of debate. The ideal antisense strategy should affect only the expression of the bcr-abl gene, leaving intact the bcr and c-abl gene products, which are expressed in normal cells, and the roles of which are not yet fully understood. Therefore, the optimal targets are the junctional sequences that contain both bcr and c-abl nucleotides; but the actual secondary structures of the target mrna, and in the case of antisense RNA, of the antisense sequences themselves, are not well characterized. The exact role of these structures in sense-antisense interactions and the precise mechanisms leading to inhibition of a gene expression (RNAse H, diminution of translation, etc.) remain largely unpredictable. This implies that only experimental data can answer the question of the most efficient and specific antisense tool in a particular target cell. Another point is that the results of a given strategy must be evaluated in terms of the function of the chosen experimental system, going from very basic considerations to the type of cells in which the effects are assessed. Antisense experiments can indeed be performed on cell lines or fresh CML cells. The former are derived from blast crises, and subsequent genetic changes may have occurred during culture. Both of these facts may possibly have changed the impact of the abnormal protein on the maintenance of the leukemic phenotype. The latter may be investigated in chronic phase or in blast crisis, and antisense treatments of the cells could have a different effect according to the phase of the disease in which one tries to affect P210 expression. Antisense oligonucleotides In the last few years, different authors have described potentially fruitful approaches toward selective growth inhibition of Philadelphia-positive leukemic cells by antisense molecules [ 10, 11,13-15,19,16]. These experiments have been performed using various experimental conditions: cell lines in culture, fresh CML cells in culture, and animal models. The target RNA is either the bcr-abl [ or the c-myb transcripts [lo, 11, 191. When oligonucleotides are used, the type (phosphodiester or phosphorothioate) differs from one paper to another, and the methodology used (dosage, incubation conditions, assessment of the effect) is variable, making it sometimes difficult to compare different authors' results and to evaluate the best strategy for purging leukemic cells in vitro or in vivo. The efficacy of an antisense oligonucleotide depends on several factors related to the oligomer itself (size, specificity [20] and stability in culture medium or inside the cellular compartment [21]); to the mrna (targeted sequences, transcription level); to the protein product (half-life); and to the target cell (uptake). To design the best possible strategy and to obtain widely applicable results, all these parameters have to be mastered. The next paragraphs review what is known at the present time and what the questions are that would deserve further investigations. The Effects of Antisense Oligonucleotides on Cell Lines In our first experiments [ 131, phosphorothioate oligonucleotides in the K562 cell line, which expresses the bcr-abl message at a high level [22], were used. HL60, a promyelocytic Ph-negative cell line was used as a control. Since plain incubation did not yield any reproducible effect, the cells were electroporated with the oligonucleotides to obtain a higher intracellular concentration. The antisense oligomer directed against the AUG region of the bcr-abl mrna specifically killed the K562 cells leaving HL60 cells unaffected. Sequential 210 assays demonstrated a dramatic (more than 80%), but transient (24 h) decrease of P210 expression at 72 h. The control oligonucleotide had no effect on either cell line. Recently, it was reported that phosphorothioate antisense oligomers were effective in suppressing the growth of a lymphoid cell line (BV173) in a leukemic severe combined immunodeficiency (SCID) mouse model [15]. Yet, not so much is known about the efficacy of bcr-abl antisense oligomers in cell lines. From ongoing experiments in our laboratory using anti-bcr-abl
3 VaermannRwallelMartiat 91 phosphodiester oligomers, only lymphoid Phpositive cell lines seem to be affected, while myeloid cell lines appear refractory, even with doses up to 100 pm, for yet unknown reasons. In contrast, anti-c-myb oligomers appear to be efficient mainly in myeloid cell lines. These cell lines might behave differently for several reasons that are important to explore for exploiting the potential of antisense oligonucleotides in CML. The problem of toxicity, specific (inhibitory effect of the anti-bcr-abl oligonucleotide on other mrna species such as bcr or abl) or aspecific (toxicity of the oligomers or of their degradation products on other metabolic pathways of the cells) is also incompletely investigated and may be essential, especially in view of future in vivo use of these compounds. Preliminary data in our laboratory suggest that the more quickly the degradation of the oligomers into smaller fragments occurs, the higher the aspecific toxicity. This happens much more rapidly in media containing fetal calf serum, which are widely used in bone marrow cultures, but also occurs, although more slowly, with human serum [21]. Our preliminary experiments show that control oligomers can degrade at different rates, sometimes more slowly, therefore inducing a lower aspecific toxicity. This implies that one should be very cautious when interpreting the results of an experiment as a specific effect, especially when no simultaneous data are available on P2 10 expression or mrna inhibition. The Effects of Antisense Oligonucleotides on CML Cells in Culture In the last two years, unmodified oligonucleotides targeted to the bcr-abl junctional sequences [14, 161 or against the c-myb transcript [ 1 11 were shown to have a specific effect on the growth of CML leukemic progenitors as demonstrated by colony assays. The authors investigated the effects of the antisense oligonucleotides in a specific context-cells from CML in blast crisis [14], chronic phase [16], or both [ 1 11-and did not examine the amount of transcripts or the level of expression of P210 during or just after incubation. Again, a preferential non-specific toxicity of the antisense oligomers (especially for phosphorothioates at relatively high doses) or of their degradation products (for phosphodiesters mainly) cannot always be excluded, and only investigating the target RNA or protein can provide a reliable proof of the specificity of the observed effects. The results observed on CML bone marrow cells in culture are not in complete concordance [ 14, 161, and it remains difficult so far to tell which cells (chronic phase or blast crisis) are the best targets for anti-bcr-abl oligonucleotides. The anti-c-myb approach offers the advantage of being equally efficient on both types of CML cells [ 111 and certainly deserves consideration if one wishes to achieve a purging effect on CML bone marrow cells. Another point worth mentioning is that the assays used to assess the efficiency of the antisense strategies (number of colony-forming units in methyl-cellulose) investigate mainly cells that are already committed, and that the efficacy on the CML stem cells is difficult to evaluate. Since the uptake of oligomers could be related to the growth status of the targeted cells, at least in some cell types, it may be important to answer that question, and other experimental systems may be needed to better investigate this effect. As far as purging CML bone marrow is concerned, a last but important question arises from an observation made using cell lines: what causes the persistence of cells surviving the incubation with antisense oligomers? In no case was it possible so far to achieve complete eradication of a sensitive cell population. Previous research regarding the use of antisense oligomers in CML cells in culture also shows the persistence of a diminished but nevertheless significant population of leukemic progenitors [14, 161. Among the speculative mechanisms that could be considered are the possibility of some of these cells being primarily resistant (having acquired some secondary changes rendering them more resistant to 9 10 inhibition) or acquiring some form of resistance during incubation (upregulation of the target message or different splicing of the bcr-abl message). Whether this cell resistance will prove relevant to the autografting context is a matter of clinical trials, but it has to be kept in mind. Animal Models So far, two leukemic SCID mouse models have been used to test the in vivo efficacy of antisense oligonucleotides. The fist model consisted of a mouse rendered leukemic using K562, in which the authors could successfully demonstrate an antileukemic effect of anti-c-myb phosphorothioate oligonucleotide [ 191. No toxicity
4 92 Antisense Inhibition of P210 bcr-abl in Chronic Myeloid Leukemia of the control oligomer was observed. A second type of experiments using BV173 cells in the same SCID mouse model demonstrated the in vivo efficacy of an anti-bcr-abl phosphorothioate oligomer [ 151. Again, these models demonstrate the efficacy of this strategy on cell lines transplanted in animals, and again anti-c-myb oligomers seem active against a myeloid cell line, whereas anti-bcr-abl oligomers show efficacy against the same lymphoid cell line. As far as is known, there are no available data about the efficacy of anti-bcr-abl antisense molecules on other cell lines in the same mouse model. Whether these compounds are also active against fresh CML cells will be the subject of future experiments. The absence of toxicity of the anti-c-myb oligonucleotide on mouse cells is difficult to extrapolate to a human situation since the normal murine hematopoietic cells are not a target of the oligomer, which could be different in a human context. Another question will be the aspecific toxicity of the phosphorothioate compounds in humans, after these compounds have degraded into smaller molecules (shorter oligomers or single nucleotides). Nevertheless, these fascinating experiments open the door to future in vivo approaches in CML patients using antisense oligonucleotides. Conclusions Currently, the oligonucleotide approach looks very promising for the treatment of CML. But from the literature and from our own experiments, several questions emerge that are important to be answered, both from a basic point of view (a better understanding of the actual processes taking place) and from a therapeutic one (design of future treatments). First, it should be noted that there are not many data available regarding the effect of these antisense oligonucleotides on the target RNA or protein. So far, most of the conclusions are drawn from viability or growth studies. Most authors assume that a negative effect on the viability or on the growth of a Philadelphia-positive cell is equivalent to a specific effect on the protein, and vice versa (a lack of effect meaning absence of inhibition). This assumption may not be correct in all cases (for example, one might speculate that different cell types rely differently on the presence of P210 for their survival). Other incompletely answered points may prove very important too, such as the importance of the cell growth status on oligonucleotide uptake and the way the cell lineage affects the efficacy of an oligonucleotide. As far as cell lineage is concerned, one may speculate about several mechanisms generating different responses to the anti-bcr-abl oligonucleotides: 1) the uptake could be lower, although this looks unlikely given the c-myb data published by Anfossi et al. [ 101; 2) the intracellular oligonucleotide/target RNA ratio could be lower in these cells because of a higher concentration of bcr-abl transcripts or a quicker intracellular degradation of the oligomer; and 3) the myeloid cell lines may rely less on P210 for survival than their lymphoid counterpart. Of course, these explanations are speculative and should be experimentally substantiated. Finally, satisfactory answers need to be found to the following questions: 1) to what extent is resistance to degradation relevant, and what will be the toxicity of modified compounds on the normal cellular metabolism? 2) can an oligonucleotide be aspecifically toxic (itself or its degradation products)? 3) what is the specificity of the antibcr-abl (in terms of mrna)? and 4) is there any form of resistance to antisense treatment? The answers to these questions may be very important for the choice of an optimized antisense strategy in CML. Retroviral Transduction of Antisense Sequences Given the only transient inhibition of P210 expression that had been obtained using oligonucleotides in K562 cells [ 131, the efficacy of antisense sequences that could be transduced in the same CML cell line using a retroviral vector was tested. Vectors generating RNA molecules containing sequences complementary to the 5 portion and the junctional sequences of the hybrid bcr-abl gene were constructed. First, a 5 restriction fragment was isolated from a plasmid containing the entire bcr-abl cdna and cloned both in a sense and antisense orientation in a retroviral expression vector [18]. In a transient expression model investigated in cells rendered independent from interleukin 3 (IL-3) by transduction of the P210 encoding cdna [23], the antisense transcripts were able to specifically kill them in the absence of IL-3 while not affecting their growth in IL-3 supplemented culture medium. The effect on
5 Vaerman/L,ewalle/Martiat 93 cell viability and P210 cellular content was maximal between 48 and 72 h after transfection. An amphotropic packaging cell line was then transfected with the sense or antisense constructs to produce viral particles capable of infecting human cells. The constructs were introduced into K562 cells by retroviral infection followed by neomycin resistance selection. In K562 cells the antisense sequences led to a dramatic reduction of P210 expression and increased the doubling time of the cells surviving the procedure time by more than twofold. This effect was not reversed by the addition of exogenous IL-3 to the culture medium. Control HeLa or HL60 cells infected with the same constructs did not show any change in proliferation rate, despite abrogation of the normal bcr gene products. This showed that almost complete inhibition of P210 expression was achievable using retrovirally transduced antisense sequences targeted against the 5' portion of the hybrid bcr-abl mrna in cells overexpressing the bcr-abl mrna. Two points should be mentioned here. First, our experiment did not conclusively demonstrate whether this inhibition is equally effective in all the infected cells, and only slows them down without a killing effect; or whether the majority of the cells were killed, a few of them surviving the procedure, perhaps those in which a weak P210 synthesis had been preserved. The second point is that the surviving cells in which inhibition has occurred, as documented by RT-PCR and kinase assay, seem to lose that effect after several weeks of culture, either by selection of the cells with the lower expression of the antisense construct (by a positional effect) or by further rearrangement of the antisense sequences due to the instability of the retroviral constructs [24]. Yet, the results seem at least equivalent to the results usually obtained with oligonucleotides (partial eradication of a CML population). The junctional antisense constructs are currently being tested. Preliminary results suggest that they are equally effective, and more specific as far as the normal bcr and abl genes are concerned, but further experiments are under way to verify these points. After the retroviral approach has been tested on CML cell lines, experiments on fresh CML cells in culture will be needed to evaluate whether infection of these cells with antisense constructs, followed by antibiotic selection, will lead to eradication of Ph-positive cells, or simply to the persistence of these cells, despite abolition of P210 expression, with possible modifications of their leukemic phenotype. Another technical problem that has to be solved is obtaining a high infectivity rate. Of concern also is the well-known switch-off effect that can occur in a retroviral construct or the instability of the retroviral sequences. Nevertheless, these results suggest an alternative approach to antisense therapy in CML: Philadelphia-negative hematopoiesis might be restored by autografting patients with bone marrow cells that had been incubated with the antisense retroviral supernatant, followed by selection to ensure that all re-infused stem cells have integrated the antisense sequences. Conclusions The two approaches (oligonucleotides and retroviral transduction) discussed above can lead to specific inhibition of the P210 protein generated by the bcr-abl fusion gene. As far as retroviral constructs are concerned, junctional antisense inserts apparently achieve a specific effect on the bcr-abl transcript, leaving unaffected the expression of the normal bcr and abl genes. Although antisense oligomers seem to have achieved definitive breakthroughs, these results support an alternative, though more speculative, approach to purging CML bone marrows. On the other hand, antisense anti-bcr-abl oligonucleotides may prove the most efficient approach in CML, for in vivo or in vitro purposes, provided that satisfactory answers can be found for the Merent questions discussed above. The most crucial point is to definitively confm their specific efficacy (i.e., via the inhibition of the bcr-abl message) on CML fresh cells. Concentrations of anti-bcr-abl oligonucleotides, depending on the type of oligomers used, will not affect the remaining normal cells, or, for in vivo use, the rest of the human organism. The effect, if any, on the human organism must be demonstrated either at short term (absence of aspecific toxicity of the oligomer itself), or at long term (absence of toxicity of the degradation products for the normal cell metabolism). In the case of bone marrow purging, the problem of some of the Philadelphia-positive cells, although important, may be less crucial. As a matter of fact, if one attempts to purge bone marrow in a culture system, which under certain
6 94 Antisense Inhibition of P210 bcr-abl in Chronic Myeloid Leukemia conditions of culture favors the growth of normal progenitors, then the finishing touch given by the adjunction of antisense oligonucleotides may be sufficient, even if the oligomers cannot by themselves eradicate the whole population of leukemic progenitors. As has been discussed throughout this paper, the problems to be solved remain numerous, and many basic questions have to be answered before this strategy can be used in human patients. Yet, the fascinating possibility of treating human leukemia in vivo, using for the first time a specific agent that would totally spare normal cells, remains a potent stimulus to continue exploring this approach. References 1 Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science 1960; 132: Rowley JD. A new consistent abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence. Nature 1973;243: de Klein A, Geurts van Kessel A, Grosveld G, Bartram CR, Hagemeijer A, Bootsma D, Spurr N, Heisterkamp N, Groffen J, Stephenson JR. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia. Nature 1982;300: Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcripts of abl and bcr genes in chronic myeloid leukemia. Nature 1985;315: Konopka JB, Watanabe SM, Witte ON. An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell 1984;37: Martiat P, Michaux JL, Rodhain J. Philadelphianegative chronic myeloid leukemia: comparison with Ph-positive CML and chronic myelomonocytic leukemia. Blood 1991;78: Daley GQ, Van Emn RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210 bcr/abl gene of the Philadelphia chromosome. Science 1990;247: Elefanty AG, Cory S. bcrhbl, the hallmark of chronic myeloid leukemia in man, induces multiple hematologic neoplasms in mice. EMBO J 1990;9: Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukemia in bcr/ubf transgenic mice. Nature 1990;344: Anfossi G, Gewirtz AM, Calabretta B. An oligomer complementary to c-rnyb encoded mrna inhibits proliferation of human myeloid cell lines. Proc Natl Acad Sci USA 1989;86: Ratajczak MZ, Hijiya N, Catani L, Deriel K, Luger SM, McGlave P, Gewirtz AM. Acute and chronic phase chronic myelogenous leukemia colony forming units are highly sensitive to the growth inhibitory effects of c-myb antisense oligodeoxynucleotides. Blood 1992;79: Goldman JM, Grosveld G, Baltimore D, Gale RP. Chronic myelogenous leukemia: the unfolding saga. Leukemia 1990;3: Taj AS, Martiat P, Dhut S, Chaplin TL, Dowding C, Th ng KH, Goldstein I, Daley GQ, Young BD, Goldman JM. Inhibition of P210 bcr-abl expression in K562 cells by electroporation with antisense oligonucleotides. Leukemia and Lymphoma 1990;3 : Szczylik C, Sk6rski T, Nicolaides NC, Manzella L, Malaguarnera L, Venturelli D, Gewirtz A, Calabretta B. Selective inhibition of leukemia cell proliferation by bcr-abl antisense oligonucleotides. Science 1991;253: Calabretta B. In vitro and in vivo suppression of Philadelphia-positive leukemia cells growth by bcr-abl antisense oligodeoxynucleotides. 2nd Int Conference on Chronic Myeloid Leukemia, Bologna Abstract Mahon FX, Belloc F, Reiffers J. Antisense oligomers in chronic myeloid leukaemia. Lancet 1993;341:566 (letter). 17 Snyder DS, Wang JL, Wu Y, Rossi JJ, Forman SJ. Ribozyme-mediated inhibition of bcr-abl gene expression in a Philadelphia-positive cell line. Blood 1991;78(Suppl 1):330a. 18 Martiat P, Lewalle P, Taj AS, Philippe M, Larondelle Y, Vaerman JL, Wildmann C, Goldman JM, Michaux IL. Retrovirally transdud antisense sequences stably suppress P210 bcr-abl expression and inhibit the proliferation of bcr-abl containing cell lines. Blood 1993;81: Ratajczak MZ, Kant JA, Luger SM, Huiya N, Zhang J, Zon G, Gewirtz AM. In vivo treatment of human leukemia in a SCID mouse model with c-myb antisense oligonucleotides. Proc Natl Acad Sci USA 1993;89: Woolf TM, Melton DA, Jennings CGB. Specificity of antisense oligonucleotides in vivo. Proc Natl Acad Sci USA 1992;89: Akhtar S, Kole R, Juliano RL. Stability of antisense DNA oligonucleotide analogs in cellular extracts and sera. Life Sciences 1991;49:
7 VaermanLewallelMartiat Grosveld G, Verwoerd T, van Agthoven T, de by the chronic myeloid leukemia-specific P210 Klein A, Ramachadran KL, Heisterkamp N, Stam bcr-ubl protein. Proc Natl Acad Sci USA K, Groffen J. The chronic myelocytic - - cell line 1988;85: K562 contains a breakpoint in bcr and produces 24 Merrouche Y, Favrot MC. Retroviral gene therapy a chimeric bcr/ubl transcript. Mol Cell Biol and its application in onco-hematology. Hum 1986;6: Gene Ther 1992:3: Daley GQ, Baltimore D. Transformation of an interleukin-3 dependent hematopoietic cell line
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