Oncogene (2007) 26, 11–20. doi:10.1038/sj.onc.1209756; published online 19 June 2006

Fusion tyrosine kinases: a result and cause of genomic instability

E T P Penserga1 and T Skorski1

1Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA, USA

Correspondence: Professor T Skorski, Department of Microbiology and Immunology, School of Medicine, Temple University, MRB 548A, 3400 N. Broad Street, Philadelphia, PA 19140, USA. E-mail:



Reciprocal chromosomal translocations may arise as a result of unfaithful repair of spontaneous DNA double-strand breaks, most probably induced by oxidative stress, radiation, genotoxic chemicals and/or replication stress. Genes encoding tyrosine kinases are targeted by these mechanisms resulting in the generation of chimera genes encoding fusion tyrosine kinases (FTKs). FTKs display transforming activity owing to their constitutive kinase activity causing deregulated proliferation, apoptosis, differentiation and adhesion. Moreover, FTKs are able to facilitate DNA repair, prolong activation of G2/M and S cell cycle checkpoints, and elevate expression of antiapoptotic protein Bcl-XL, making malignant cells less responsive to antitumor treatment. FTKs may also stimulate the generation of reactive oxygen species and enhance spontaneous DNA damage in tumor cells. Unfortunately, FTKs compromise the fidelity of DNA repair mechanisms, which contribute to the accumulation of additional genetic abnormalities leading to the resistance to inhibitors such as imatinib mesylate and malignant progression of the disease.


fusion tyrosine kinase, genomic instability, ROS, DNA damage, DNA repair, imatinib mesylate



The sequencing endeavor of the Human Genome Project (HGP) has discovered that at least 520 genes encode kinases (Blume-Jensen and Hunter, 2001). This enzyme class can be further subdivided based on their catalytic specificity: tyrosine, threonine, serine or a combination. There are 90 tyrosine kinase (TK) genes known to date: 58 encode transmembrane TKs distributed into 20 subfamilies, and 32 encode cytoplasmic, non-receptor TKs in 10 families (Robinson et al., 2000).

TKs represent a large cohort of signaling molecules that are targeted chronically by genetic errors leading to their uncontrolled activity. There are at least three general mechanisms by which TKs can become constitutively activated and lead to the development of neoplastic disease: first, by chromosomal translocation; second, by overexpression; and third, by activating mutations (Kolibaba and Druker, 1997). These changes can lead to perturbed signal transduction; thus, deregulated differentiation, proliferation and cellular development transpire.


Fusion tyrosine kinases

Chromosomal reciprocal translocations are responsible for the emergence of oncogenes encoding fusion tyrosine kinases (FTKs) such as: BCR/ABL, BCR/FGFR1, TEL/ABL, TEL/JAK2, TEL/PDGFbetaR, TEL/TRKC(L), NPM/ALK, ZNF198/FGFR1, PCM1/JAK2 and others (Kolibaba and Druker, 1997; Blume-Jensen and Hunter, 2001; De Keersmaecker and Cools, 2006). These unique chromosomal rearrangements have been coupled with specific cancers and have become a vital tool for clinical diagnoses (Cross and Reiter, 2002). Hungerford and Nowell discovered the first of these genetic hallmarks in 1960 at the University of Pennsylvania (Nowell and Hungerford, 1960). Their identification of a peculiar chromosomal anomaly, christened the 'minute' chromosome, led to the discovery of the BCR/ABL kinase that became the founder of a family of related FTKs (Figure 1).

Figure 1.
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A diagram showing BCR/ABL-related family of the FTKs.

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BCR/ABL is a result of a t(9;22) reciprocal translocation of a segment of the c-ABL gene from chromosome 9 to a portion of the BCR gene locus on chromosome 22. It is present in chronic myelogenous leukemia (CML) and a cohort of acute lymphoblastic leukemia (ALL) patients (Shtivelman et al., 1986; Clark et al., 1988; Epner and Koeffler, 1990). BCR/FGFR1 is produced by the fusion between BCR exon 4 and FGFR1 exon 9 and was reported in a spectrum of myeloproliferative disorders that include CML-like disease (Demiroglu et al., 2001; Fioretos et al., 2001). TEL/ABL originates from a t(9;12) translocation reported in ALL, acute myelogenous leukemia (AML) and atypical CML. It consists of the amino terminal fragment of the TEL (ETV6), a member of the ETS family of transcription factors, domain fused in-frame with exon 2 of ABL (Golub et al., 1996). TEL/JAK2 is characterized as a product of a t(9;12) translocation, which includes the TEL oligomerization domain and JAK2 catalytic domain; it is found in ALL (Lacronique et al., 1997; Peeters et al., 1997). TEL/PDGFbetaR (platelet-derived growth factor receptor beta) is associated with a t(5;12) translocation, which juxtaposes the amino terminal region of TEL to the transmembrane and TK domains of' the PDGFbetaR; it is found in chronic myelomonocytic leukemia (CMML) (Carroll et al., 1996). The consequence of t(12;15) is the expression of TEL/TRKC associated with AML, infantile fibrosarcoma and congenital mesoblastic nephroma (Liu et al., 2000). NPM/ALK, formed by the t(2;5) translocation, is implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL) (Morris et al., 1995). ZNF198/FGFR1, a product of the t(8;13) translocation, is associated with the disease known as the 8p11 myeloproliferative syndrome (EMS) (Reiter et al., 1998; Xiao et al., 1998). ZNF198/FGFR1 is formed by the fusion of the N-terminal of ZNF198 to the entire catalytic domain of FGFR1. PCM1/JAK2 results from t(8;9) translocation observed in atypical chronic myeloid leukemia/chronic eosinophilic leukemia, secondary AML and pre-B-cell ALL (Bousquet et al., 2005; Reiter et al., 2005).


FTKs formation

Chromosomal translocations basically arise as a result of the fusion (mis-repair) of two or more broken ends of chromosomes that occur in spatial proximity of one another (Rabbitts, 1994; Hussain et al., 2003; Vilenchik and Knudson, 2003; Aplan, 2006). Elegant studies by Jasin and co-workers demonstrated that two double-strand breaks (DSBs), each on different chromosomes, are sufficient to promote frequent reciprocal chromosomal translocations (Richardson and Jasin, 2000b). However, what induces the chromosome strands to finally break and why DNA repair mechanisms do not act properly and produce chromosomal translocations is open to conjecture.

Generation of DSBs

Free radicals such as reactive oxygen species (ROS), ionizing radiation, genotoxic chemicals, and DNA replication stress are likely factors to consider as a source of DSBs (Figure 2).

Figure 2.
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Hypothetical mechanisms for the formation of reciprocal chromosomal translocations encoding FTKs. Signals from activated growth factor receptors and other extra- and intra-cellular sources stimulate the production of ROS, which cause oxidative DNA damage. BER, NER and MMR are involved in the repair of oxidative DNA lesions and prevention of DSBs formation. DSBs can result from uncompleted repair of two oxidative lesions located on different strands at a distance of 7 or less base pairs, or if the replication fork encounters an oxidative lesion. In addition, DSBs can be generated by radiation, replication stress and special chromatin structures. DSBs, if repaired unfaithfully, may cause chromosomal translocations encoding for FTKs.

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The cells in our body must unremittingly counteract the constant assault by ROS (e.g. superoxide anions (O2-), hydroxyl radicals (filled circleOH), singlet oxygen (1O2) and hydrogen peroxide (H2O2)). It is estimated that about 104 oxidative DNA lesions occur per human cell per day (Beckman and Ames, 1997).

The role of ROS in the generation of DSBs is supported by several observations: (1) cellular oxygen tension causes chromosome breaks (Karanjawala et al., 2002), (2) overexpression of c-Myc elevated ROS-mediated DSBs (Vafa et al., 2002), (3) treatment with H2O2 induced DSBs (Yu and Anderson, 1997), (4) ROS-dependent DNA single-strand interruptions in replicating chromosomes generate DSBs (Slupphaug et al., 2003) and (5) chromosomally unstable cells display persistent oxidative stress (Limoli et al., 2003). Moreover, translocation breakpoints are GC-rich (Abeysinghe et al., 2003) and oxidative damage is predominantly detected in GC-rich sequences (Akman et al., 2000). Thus, it is tempting to speculate that clustered oxidative damage may generate multiple DNA lesions in a short DNA fragment, which pose a serious obstacle for replication forks and may result in a DSB.

ROS can be elevated by various physiological stimuli such as hematopoietic growth factors (Sattler et al., 1999). In addition, elevated release of ROS by leukocytes is observed during infections and inflammations, which are implicated in the induction of a quarter of all cancer cases worldwide (Hussain et al., 2003). Moreover, the activation of cellular stress signals from unfavorable conditions such as aberrant oxygen tension may lead to the release of ROS from the mitochondria (Semenza, 2000).

Two primary mechanisms are responsible for the repair of oxidative lesions: base excision repair (BER) and eventually nucleotide excision repair (NER) (Croteau and Bohr, 1997). BER, in short, excises the damaged moiety with a normal nucleotide restoring it to its original state (Powell et al., 2005). NER, on the other hand, recognizes general distortions in DNA structure rather than the specific chemistry of individual bases (Reed, 2005). Both BER and NER repair mechanisms utilize the undamaged strand as the repair template. Misincorporated bases, for example, 8-oxoG-A, resulting from the lack of BER, eventually may be recognized by mismatch repair (MMR) and subsequently removed (Skinner and Turker, 2005). Unrepaired oxidative damage may result in the formation of DSBs (Slupphaug et al., 2003). In conclusion, since oxygen metabolism causes chromosome breaks, chromosomal insults by ROS may be responsible for the initiating events leading to FTK formation.

In addition to oxidative stress, common chromatin structures at the breakpoint regions may lead to DSBs and chromosomal translocations (Strick et al., 2006). Chromatin structural elements including topoisomerase II (topo II), DNAse I cleavage sites and scaffold-associated regions (SARs) closely associate with BCR and ABL breakpoints. Topo II and scaffold protein II are essential for chromosome condensation. For example, topo II is a key protein with enzymatic and structural functions, responding to torsional stress of DNA. Therefore, the aberrant activity of these elements may result in DSBs.

Moreover, there is strong evidence of radiation-induced risks for CML. Experimental data as well as cancer incidence records of atomic bomb survivors indicated that BCR/ABL translocation might occur after irradiation (Preston et al., 1994; Deininger et al., 1998).

Aberrant repair of DSBs leading to chromosomal translocations

It has been estimated that approx50 DSBs occur during a typical mammalian cell division cycle (Vilenchik and Knudson, 2003). The specific recombination mechanisms responsible for generation of chromosomal translocations producing FTKs are currently unknown. Localization of DSBs may be important for the formation of chromosomal translocations. It has been estimated that approximately 6–13% of genomic DNA consists of repetitive Alu sequences (Mighell et al., 1997; Roy-Engel et al., 2002). DNA sequences of surrounding breakpoint regions involved in the formation of FTKs often revealed homology to Alu (Chen et al., 1989; Chou and Morrison, 1993; Rudiger et al., 1995; Ford et al., 1998; Jeffs et al., 1998; Blanco et al., 2001). However Alu sequences are not always close to the sites of recombination, therefore their direct role in chromosomal translocations is not clear. Alu elements may work as structural modifiers of chromatin organization, because translin-binding sites were identified within the Alu consensus (Jeffs et al., 1998; Martinelli et al., 2000). Translin protein binds chromosomal breakpoint sequences and may promote illegitimate conjunctions to favor chromosomal translocations.

Mammalian cells have multiple pathways to repair DSBs that represent a 'clear and present danger' to survival and genomic integrity: homologous recombination repair (HRR), non-homologous end-joining (NHEJ) and single-strand annealing (SSA) (Bassing and Alt, 2004). Experimental data implicate NHEJ, involving small deletions and microhomology, in the formation of chromosomal translocations (Varga and Aplan, 2005; Weinstock et al., 2006). In accordance, microhomology at the BCR/ABL junction region has been detected (Papadopoulos et al., 1990). HRR does not appear to be involved in the overwhelming majority of cancer-associated translocations, as breakpoint junctions lack extensive homology (Elliott and Jasin, 2002), and translocations involving this pathway are not recovered in model systems (Richardson and Jasin, 2000a, 2000b; Elliott et al., 2005). However, another homology-driven pathway, SSA, efficiently generates translocations in experimental models (Richardson and Jasin, 2000b; Elliott et al., 2005).

Additional factors

The intriguing observations that peripheral blood leukocytes from normal healthy individuals may carry BCR/ABL transcripts suggests that BCR/ABL and perhaps other FTKs are generated relatively frequently, but inconsequently in hematopoietic cells, that is, without necessarily leading to a selective growth advantage (Biernaux et al., 1995; Bose et al., 1998). These reports raised speculations about the role of other factors in FTK-induced transformation. First, the fusion genes must allow for the production of functional FTKs; several of those detected in normal leukocytes have an aberrant structure owing to wrong junctions between BCR and ABL exons or to the insertion of intervening sequences (Bose et al., 1998). Second, FTKs may not reflect incipient leukemias, because they were generated in relatively mature progenitors from which the derived clones are eventually lost through normal cell differentiation and death; only those formed in leukemia stem cells may produce malignancies (Holyoake et al., 1999). Third, FTK-positive cells may need to acquire additional genetic and/or epigenetic changes before becoming tumorigenic (Shteper and Ben-Yehuda, 2001). Fourth, a defect in immune surveillance may be needed since the immune system of normal persons is eventually able to recognize and to eliminate the BCR/ABL-expressing cells, preventing their uncontrolled expansion (Barrett and Jiang, 1992).

Also, the possibility of familial inheritance cannot be disregarded. Multiple studies have reported cross-generation and sibling-related cases (Lessen et al., 2005). For example, two identical twins and a brother were diagnosed at age 64, 64 and 68, respectively, with Philadelphia chromosome (Ph)+ CML (Tokuhata et al., 1968). A mother (Ph+), her daughter (Ph-), and the grandfather (unknown), were diagnosed with CML at age 54, 14 and 69, respectively (Lillicrap and Sterndale, 1984). Heritable alterations in genes regulating expressions of natural antioxidants may provide the necessary microenvironment for the accumulation of ROS-mediated DNA aberrations.


Consequences of FTKs expression

FTKs exhibit two complementary roles in cancer. The first role is stimulation of signaling pathways, which contribute to malignant transformation, including proliferation in the absence of growth factors, protection from apoptosis in the absence of external survival factors and invasion (Kolibaba and Druker, 1997; Liu et al., 2000; Cross and Reiter, 2002; Arlinghaus and Sun, 2004). The second role of FTKs in hematological malignancies is the modulation of responses to DNA damage, rendering cells resistant to genotoxic therapies and causing genetic instability (Alimena et al., 1987; Kelman et al., 1989; Laneuville et al., 1992; Bedi et al., 1995; Nishii et al., 1996; Amarante-Mendes et al., 1998; Dubrez et al., 1998; Villamor et al., 1999; Honda et al., 2000; Salloukh and Laneuville, 2000; Sercan et al., 2000; Aoki et al., 2001; Greenland et al., 2001; Slupianek et al., 2001).

Signaling leading to transformation

FTKs stimulate numerous major signaling molecules, including Ras, PI-3k and STAT5, which are essential for oncogenesis (Skorski et al., 1994, 1995, 1997; Goga et al., 1995; Sawyers et al., 1995; de Groot et al., 1999; Sillaber et al., 2000; Nieborowska-Skorska et al., 2001). FTKs display common and unique characteristics of activation of these pathways; for example, PI-3k is stimulated by all FTKs listed above, whereas STAT5 and PLCitalic gamma seem to be activated by the BCR/ABL-related FTKs, with exception to TEL/TRKC (Liu et al., 2000; Nieborowska-Skorska et al., 2001; Slupianek et al., 2002; Baumann et al., 2003). In addition, leukemogenic properties of TEL/ABL seem to be distinct from those of BCR/ABL (Million et al., 2002). Furthermore, although FTKs are generally localized in the cytoplasm, NPM/ALK also is found in the nucleus (Bischof et al., 1997). Therefore, NPM/ALK may display some unique functions because it can interact more directly with the DNA repair machinery. These common and unique properties of FTK-transformed cells in the activation of signaling pathways may have substantial influence on their response to DNA damage.

Drug resistance

BCR/ABL and related FTKs such as TEL/ABL TEL/PDGFbetaR, TEL/JAK2 and NPM/ALK demonstrate an enhanced ability to survive genotoxic stress probably owing to enhanced DNA repair, prolonged S and G2/M checkpoints for extended repair and inhibition of proapoptotic pathways (Bedi et al., 1995; Amarante-Mendes et al., 1998; Skorski, 2002; Slupianek et al., 2002, 2006; Canitrot et al., 2003; Lauren et al., 2003; Nieborowska-Skorska et al., 2006) (Figure 3). These three factors may work in concert to provide the necessary protection from DNA damage-induced apoptosis.

Figure 3.
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Major pathways leading to drug resistance in BCR/ABL-transformed cells.

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Drug resistance depends also on the high expression levels of BCR/ABL suggesting amplification/hyperactivation of signaling pathways and/or DNA repair mechanisms relevant for response to genotoxic stress (Cambier et al., 1998; Issaad et al., 2000; Keeshan et al., 2001). Since drug resistance depended on the BCR/ABL kinase activity, it was most likely not owing to clonal evolution arising from the accumulation of additional genomic aberrations. The expression/activity of BCR/ABL kinase may increase at the accelerated phase and blast crisis, or accompany resistance to imatinib mesylate (IM) (Gaiger et al., 1995; Gorre et al., 2001; Yamamoto et al., 2004); therefore, it seems reasonable to speculate that at the later stages of the disease high levels of BCR/ABL kinase trigger more pronounced resistance. Thus, if selection is involved in the development of resistance to DNA damage-induced apoptosis in CML cells, than it should be associated with the emergence of clones displaying elevated BCR/ABL kinase expression/activity. However, as CML progresses, cells can also accumulate additional genetic abnormalities, which further increase the resistance of these cells to genotoxic treatment (Makin and Hickman, 2000) – but this effect may no longer depend on BCR/ABL catalytic activity.

DNA repair

DNA lesions emerge in various forms. Damaged bases, mismatches and adducts are repaired by BER, NER and MMR. Earlier studies suggested negative influence of BCR/ABL kinase on the NER machinery, that is, XPB and p44, in non-hematopoietic cells (Takeda et al., 1999; Maru et al., 2001). However, BCR/ABL-positive myeloid leukemia cells exhibited elevated NER activity in response to ultraviolet (UV) radiation (Canitrot et al., 2003; Lauren et al., 2003).

DSBs can be induced by genotoxic drugs and irradiation, and are lethal if unrepaired. Three distinct mechanisms repair DSBs: HRR, NHEJ and SSA (Pastink et al., 2001). HRR and NHEJ can play a pivotal role in genotoxic drug resistance. The former mechanism involves RAD51-driven invasion and pairing of a single-stranded DNA to the homologous template. Elevated levels of RAD51 have been observed in various tumors and positively associated with genotoxic therapy resistance (Vispe et al., 1998; Collis et al., 2001; Raderschall et al., 2002; Slupianek et al., 2002, 2006). Leukemias and lymphomas expressing BCR/ABL-related FTKs, such as TEL/ABL, TEL/PDGFbetaR, TEL/JAK2, NPM/ALK and ZNF198/FGFR1, display elevated levels of RAD51 and enhanced HRR activity (Slupianek et al., 2001, 2002, 2006; Heath and Cross, 2004). Although Deutsch et al. (2001) indicated that DNA-PKcs, an important kinase in NHEJ, may be downregulated in CML cells, subsequent reports employing various in vitro and in vivo methods detected enhanced activity of NHEJ in BCR/ABL-transformed leukemia cells and CML patient cells (Gaymes et al., 2002; Brady et al., 2003; Nowicki et al., 2004; Slupianek et al., 2006).

Inhibition of apoptosis

In addition to modulation of DNA repair mechanisms, BCR/ABL related-kinases activate also another line of defense against genotoxicity. FTKs may stimulate antiapoptotic proteins such as BCL2 and BCL-XL and inhibit proapoptotic proteins BAD and BAX, thus preventing the release of cytochrome c from the mitochondria and activation of caspase-3 (Skorski, 2002; Slupianek et al., 2002).

Checkpoint activation

The time allotted for repair is as crucial as the repair mechanisms themselves. Cell cycle checkpoints are responsible for the mediation of phase transitions, activation of repair mechanisms and the movement of DNA repair proteins to lesion sites. Studies from our lab, as well as others, have implicated that cells transformed by BCR/ABL-related FTKs exhibit extended activation of the S and G2/M cell cycle phase checkpoints when exposed to chemotherapeutic drugs and italic gamma-radiation (Bedi et al., 1995; Slupianek et al., 2002; Nieborowska-Skorska et al., 2006). We have recently reported that BCR/ABL leukemia cells might display enhanced stimulation of the ATR-Chk1 axis, which plays an important role in the activation of intra-S-phase checkpoint and drug resistance (Nieborowska-Skorska et al., 2006). This observation is in accordance with another report indicating elevated activation of Chk1 kinase in BCR/ABL cells after italic gamma-irradiation (Goldberg et al., 2004). However, using tetracyclin-induced BCR/ABL expression, Dierov et al. (2004) reported inhibition of ATR kinase, abrogation of Chk1 phosphorylation and disruption of intra-S-phase checkpoint resulting from translocation of BCR/ABL kinase to the nucleus in response to genotoxic treatment. We did not observe nuclear re-location of BCR/ABL kinase in response to DNA damage caused by various drugs and irradiation (Nieborowska-Skorska et al., 2006). The reason for this discrepancy is not known, but the effect described by Dierov and co-workers may depend on the BCR/ABL-inducible expression system. In addition, ATR/ATM-mediated phosphorylation of p53-Ser15 associated with abundant accumulation of p53 in response to DNA damage (Stoklosa et al., 2004). This effect contributed to G2/M delay and drug resistance. Moreover, the phosphorylation of cdc2 may be attributable to the delay (Bedi et al., 1995).

Facilitation of genomic instability

It is well known that cancers exhibit chromosomal abnormalities: translocations, deletions, insertions, amplifications, etc. Such chromosomal anomalies have been observed at various stages of tumor progression, particularly in the latter phases such as CML blast crisis (CML-BC) (Suzukawa et al., 1997; Johansson et al., 2002). Jackson and Loeb (2001) have suggested that there may be an accumulation of these anomalies even before cancer is clinically diagnosed, resulting from unfaithful repair of elevated level of DNA DSBs caused by DNA replication stress (Bartkova et al., 2005; Gorgoulis et al., 2005).

Genomic instability in FTK induced leukemias and lymphomas is manifested by the accumulation of chromosomal aberrations and mutations leading to malignant progression of the disease and acquired resistance to small molecule inhibitors such as IM (Ott et al., 1998; Wlodarska et al., 1998; Villamor et al., 1999; Salloukh and Laneuville, 2000; Shet et al., 2002; Brain et al., 2003; Nardi et al., 2004; Nowicki et al., 2004).

Genetic aberrations leading to malignant progression of the disease

CML cells accumulate genetic abnormalities during the course of the disease (Rowley and Testa, 1982; Alimena et al., 1987; Johansson et al., 2002; Shet et al., 2002; Calabretta and Perrotti, 2004). The aberrations associated with the progression of BCR/ABL-positive CML chronic phase to the aggressive blast crisis (CML-BC) include additional chromosomes (Ph1, +8, +19), isochromosome 17q (associated with the loss of p53), reciprocal translocations (3;21 and 7;11 – associated with the expression of AML-1/Evi-1 and NUP98/HOXA9 fusion proteins, respectively), other translocations and inversions associated with AML/myelodysplasia (inv(3), t(15;17)), loss-of-heterozygosity at 14q32, homozygous mutations/deletions of pRb and p16/ARF, and mutations in p53 and RAS (reviewed by Calabretta and Perrotti, 2004). In addition, it has been reported that NPM/ALK-positive ALCL cells may acquire additional chromosomal abnormalities, which are associated with a more malignant recurrent disease (Ott et al., 1998; Wlodarska et al., 1998; Villamor et al., 1999).

Mutations usually result from enhanced DNA damage and/or deregulated mechanisms of DNA repair. Reports from our laboratory, as well as others, have shown that BCR/ABL leukemia cells display higher levels of spontaneous DNA damage such as oxidized bases and DSBs caused by the elevation of ROS (Brady et al., 2003; Nowicki et al., 2004). In addition, they acquire more DNA lesions after genotoxic treatment (Hoser et al., 2003; Lauren et al., 2003; Nieborowska-Skorska et al., 2006; Slupianek et al., 2006). As indicated earlier, BCR/ABL may modulate DNA repair by HRR, NHEJ and NER, which, in combination with cell cycle arrest and protection from cytochrome c-dependent apoptosis, eventually promotes survival. Unfortunately, the repair mechanisms are not faithful. For example, BCR/ABL stimulated NHEJ and HRR, but large deletions and numerous point mutations, respectively, were found in the repair products. The reasons for repair infidelity in BCR/ABL-positive cells are currently not known.

RAD51 plays a fundamental function in HRR, which is generally an accurate process that repairs DSBs without intermediary deletions, insertions and chromosomal arrangements (Thompson and Schild, 2001, 2002). However, increased RAD51 expression not only enhances HRR efficiency to cause drug resistance (Vispe et al., 1998; Collis et al., 2001; Raderschall et al., 2002; Slupianek et al., 2002, 2006) but also promotes crossing over, involving gene conversion associated with an exchange of flanking markers leading to chromosomal translocations (Richardson et al., 2004). Increased RAD51 also promoted aneuploidy and multiple chromosomal rearrangements. In addition, error-prone DNA polymerases, such as polymerase beta, which expression is elevated in BCR/ABL cells (Canitrot et al., 1999), may eventually replace other polymerases usually involved in DNA replication during HRR (Servant et al., 2002). Interestingly, base misincorporations made during DSB repair in Saccharomyces cerevisiae were not substrates for the MMR machinery (McGill et al., 1998). Therefore, mismatched bases incorporated to the HRR sites might not be removed efficiently, causing mutations in the recombination products. In conclusion, these data provide a link between elevated RAD51 protein levels, genome instability and tumor progression.

The molecular explanation for extensive degradation of DSBs preceding NHEJ in BCR/ABL cells is not known. It could be speculated that downregulation of DNA-PKcs in CML cells may imbalance the repair promoting extensive modification of DSB ends before re-joining (Deutsch et al., 2001). Aberrantly regulated exonucleases like ExoI, Mre11 and Artemis could be suggested as potential mediators of this effect, too (Lieber et al., 2003).

Moreover, NER in p210 BCR/ABL-positive cells was associated with mutations in the hprt gene (Canitrot et al., 2003). Altogether, these observations implicate faulty DNA repair mechanisms in malignant progression of CML.

Mutations in FTKs leading to resistance to the kinase inhibitors

IM (Gleevec, STI571), a selective inhibitor of the ABL kinase activity, revolutionized the treatment of CML (Druker et al., 1996; Sawyers, 2002; Tsao et al., 2002). Moreover, patients with myeloproliferative disorders carrying FIP1L1/PDGFRalpha and activated forms of PDGFRbeta were also successfully treated with IM (Apperley et al., 2002; Cools et al., 2003). In addition, IM was proven to be effective against cells transfected with TEL/ABL (Carroll et al., 1997). However, clinical and experimental observations reveal that resistance to the drug has become a rising problem (Weisberg and Griffin, 2001; Gorre and Sawyers, 2002). Resistance may be achieved by enhanced expression of the kinase (Mahon et al., 2000; Gorre and Sawyers, 2002; Hochhaus et al., 2002), blocking of the drug (Gambacorti-Passerini et al., 2000), reduction of cellular concentration of the drug (Mahon et al., 2003) and also by mutations in the BCR/ABL gene (Mahon et al., 2000; Branford et al., 2002; Gorre and Sawyers, 2002; Hofmann et al., 2002; Azam et al., 2003). The latter phenomenon appears to play a major role in IM resistance of Ph+ leukemias (Hochhaus et al., 2002); however, the mechanisms causing mutations are not known. It seems likely that mutations encoding resistance to IM may develop in genes encoding other FTKs as well. This speculation is supported by the report that T674I mutation in FIP1L1/PDGFRalpha in hypereosinophilic syndrome confers resistance to IM (Cools et al., 2003). The site of this point mutation corresponds to that of the T315I mutation in BCR/ABL, which confers resistance to IM in patients with CML (Gorre and Sawyers, 2002).

Novel inhibitors are being generated to overcome IM resistance (Reddy, 2003; O'Hare et al., 2004; Shah et al., 2004), but mutations causing resistance against new drugs are likely to emerge (Burgess et al., 2005; von Bubnoff et al., 2005).

Our recent studies implicated ROS-induced oxidative DNA damage as a source of mutations in the BCR/ABL kinase domain encoding IM resistance (Koptyra et al., 2006). Interestingly, a GC-rich region is present in the BCR/ABL kinase and is a 'hot-spot' for ROS-induced DSB. Moreover, we showed that point mutations might be introduced during HRR and NER in BCR/ABL-positive cells (Canitrot et al., 2003; Nowicki et al., 2004; Slupianek et al., 2006). Therefore, clustered oxidative damage in GC-rich region may cause a DSB in the BCR/ABL kinase, whereas DNA polymerase-mediated mispairing opposite to an oxidized base during HRR-dependent DNA replication may be responsible for the mutagenic effect. We hypothesize that ROS work in concert with unfaithful DNA repair mechanisms to introduce mutations into the sequence encoding FTKs in leukemia cells (Figure 4). Although ROS appears to play a major role in BCR/ABL mutagenesis, other factors may be important, too. For example, DNA polymerase beta is overexpressed in BCR/ABL cells, which may diminish the fidelity of BER and HRR (Canitrot et al., 1999; Matsuda et al., 2003).

Figure 4.
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FTK right arrow ROS right arrow mutagenesis pathway causes IM resistance. BCR/ABL elevates ROS, which enhance the pool of oxidized nucleotides. DNA polymerases may incorporate oxidized nucleotides into DNA causing oxidative DNA damage (Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author) eventually resulting in DSBs (Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author). FTKs-induced aberrations of the repair mechanisms causing unfaithful and/or inefficient repair of these lesions may generate mutations, including those encoding for IM resistance. Inhibition of FTK kinase as well as scavenging of ROS should abrogate mutagenesis.

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In conclusion, we postulate that reciprocal chromosomal translocations carrying FTK genes result from unfaithful repair of DNA DSBs. FTKs, the products of hybrid genes, are able to initiate malignant transformation and further accelerate genomic instability leading to malignant progression of the disease and induce resistance to genotoxic treatment. However, since the effects of BCR/ABL kinase are much better characterized than those induced by other FTKs, we cannot exclude the FTKs-specific phenomena in drug resistance and genomic instability.



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TS was supported by the grants from NIH/NCI, American Cancer Society, and Department of Defense. ETPP was sponsored by the Physician Scientist Training Program 5R25DK059644-05 from NIH/NIDDK.