DNA Repair Deficiency Associated with Hematological Neoplasms

polymorphisms of DNA repair genes that predispose to certain hematological malignancies. We also discuss how defects in DNA repair affect sensitivity to chemotherapy. Over the past decades, great advances have been made in understanding the cellular DNA repair pathways. At the same time, a wealth of descriptive knowledge of human diseases has been accumulated. Now, the basic research of the mechanisms of DNA repair is merging with clinical research, placing the action of the DNA repair pathways in the context of the whole organism. Such integrative approach enables understanding of the disease mechanisms and is invaluable in improving diagnostics and prevention, as well as designing better therapies. This book highlights the central role of DNA repair in human health and well-being. The reviews presented here, contain detailed descriptions of DNA repair pathways, as well as analysis of a large body of evidence addressing links between DNA damage repair and human health. They will be of interest to a broad audience, from molecular biologists working on DNA repair in any model system, to medical researchers.


Homologous Recombination (HR)
Homologous Recombination (HR) is a highly complex pathway that uses an intact homologous template to repair a double strand break (DSB) accurately. It is the predominant pathway in lower eukaryotes, whereas it accounts only for the repair of 10% of DSBs in mammalian cells (reviewed in (Hakem 2008)). HR operates at S and G2 phase of the cell cycle, where a sister chromatid exists, and acts on rapidly dividing cells (Helleday et al. 2007). Furthermore, it fulfills specialized roles; it participates in meiosis and the repair of DNA interstrand crosslinks, which are highly cytotoxic DNA lesions (reviewed in (Scharer 2003)). The whole HR process is summarized in Figure 1.

Non Homologous End Joining (NHEJ)
Non Homologous End Joining (NHEJ) is the predominant pathway for repair of DSBs in higher eukaryotes (Kanaar et al. 2008). It is a conceptually simple pathway that involves the religation of broken ends and as the DNA ends may be damaged, this mode of repair is not necessarily accurate (Lieberman 2008). NHEJ is more important in quiescent or terminally differentiated cells and in G1 phase of the cell cycle. It also plays a crucial role in the generation of diversity in the immune system in V (D) (J) recombination and in telomere maintenance (reviewed in (Hakem 2008)). The NHEJ mechanism is illustrated in Figure 1. Model for DSB initial response and repair. Initial recognition of DSB is performed by various sensor proteins (ATM, MRN complex, BRCA1, RAD51, DNA-PKcs). A DSB is repaired either by NHEJ or HR. In NHEJ, the heterodimer Ku70/80 binds to DSB and recruits DNA-PKcs, which promotes ends juxtaposition. Gaps are filled by polymerases or and nicks are sealed by ligase complex (Ligase IV, XRCC4). In HR, after resection of DSB, Rad51 forms a nucleoprotein filament. Then, a strand-exchange reaction generates a joint molecule between the damaged and the undamaged DNA. Then, repair synthesis is performed by DNA polymerases / .

Design and nomenclature of Single Nucleotide Polymorphisms (SNPs)
Single Nucleotide Polymorphism (SNP) is a DNA sequence variation occurring when a single nucleotide -A, T, C, or G -in the genome differs between members of a biological species or paired chromosomes in an individual (Stenson et al. 2009). It indicates a non disease-causing change or a change found at a frequency of 1% or higher in the population. SNPs may fall within coding sequences of genes, non-coding regions of genes, or in the intergenic regions between genes. SNPs within a coding sequence do not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy (redundancy) of the genetic code (den Dunnen and Antonarakis 2003). The nomenclature for SNPs can be confusing: several variations can exist for an individual SNP and consensus has not yet been achieved. One approach is to write SNPs with a prefix showing the wild-type and altered nucleotide or amino acid. Variants can be described either at the DNA, RNA or protein level (Ogino et al. 2007). Descriptions at DNA level refer to a single nucleotide substitution designated by a ">"character that indicates the change from the wild type to the altered nucleotide. Description is made in relation to a coding or genomic reference sequence. Regarding nucleotide numbering, when a coding reference is used, nucleotide 1 is the A of the ATG-translation initiation codon and the nucleotide 5' of the ATG-translation initiation codon is -1; the previous -2 etc. When a genomic reference is used, nucleotide numbering is purely arbitrary and starts with 1 at the first nucleotide of the database reference file Antonarakis 2000, 2003). For example, SNP RAD51 135 G>C, denotes that at nucleotide 135 a G is changed to a C. On the other hand, SNP RAD50 -38C>T denotes a C to T substitution 38 nucleotides 5' of the ATG translation initiation codon. Descriptions at RNA and protein level are often deduced and not based on experimental evidence. Sequence changes at RNA level are basically described like those at the DNA level, with a few modifications. Description starts with the nucleotide number, followed by the nucleotide (in lower case), for example 78 u>a. In this chapter, none of the SNPs is described at RNA level. Descriptions at protein level start with the amino acid, followed by its number and the altered amino acid (den Dunnen and Antonarakis 2000, Ogino et al. 2007). For example, SNP XRCC1 Arg194Trp indicates a change of amino acid Arginine 194 to Tryptophan. Finally, frequently SNPs are reported in relation to their reference SNP ID number, which is assigned to them from the Single Nucleotide Polymorphism Database (dbSNP). dbSNP is a free public archive for genetic variation within and across different species developed and hosted by the National Center for Biotechnology Information (NCBI) in collaboration with the National Human Genome Research Institute (NHGRI) (Wheeler et al. 2007). When submitted, SNPs receive a reference SNP ID number ("rs#"; "refSNP cluster"). For example, XRCC4 rs13178127 refers to the SNP of the gene XRCC4 that has received the reference ID number rs13178127.

DNA repair deficiency related to hematological malignancies
Below, we summarize the existing data concerning abnormalities of DNA repair pathways in the most common hematological malignancies.

Acute Myeloid Leukemia (AML)
Acute Myeloid Leukemia (AML) is a group of marrow-based neoplasms that have clinical similarities but distinct morphologic, immunophenotypic and cytogenetic features (Monzo www.intechopen.com et al. 2006). Clinical features are similar at any age and are the result of suppression of normal marrow elements by malignant blasts. Although many environmental and genetic factors have been suggested to play a role in AML pathogenesis, the mechanism still remains uncertain. Through the last years many studies have focused on indentifying genetic differences that could contribute to a patient's predisposition to develop AML. These differ e n c e s c o u l d b e i n p a r t a t t r i b u t e d t o polymorphisms that lead to increased or decreased activity of the encoded genes; and DNA repair genes are attractive candidates for studies, since their ineffectiveness causes chromosomal instability. This is further supported by the higher incidence of AML in patients with syndromes characterized by defective DNA repair (Schwartz and Cohen 1988). So far, several polymorphisms have been associated with an increased risk of developing AML, such as polymorphisms of Homologous Recombination genes XRCC3 Thr241Met and RAD51 135G>C (Voso et al. 2007). In another study, these two polymorphisms have been reported to have a synergistic effect on AML development (Seedhouse et al. 2004). In addition, XRCC3 Thr241Met has been found to specifically increase the risk of inv(16)/t(16;16) AML and to be an independent poor prognostic factor for this AML subtype, since it reduces disease free survival in patients that achieved complete remission (CR) . This is an interesting finding, since it could help us substratify patients with inv (16)/t (16; 16) AML, which has favorable prognosis. On the other hand, RAD51 135 G>C has also been associated with a decreased risk of AML (Rollinson et al. 2007). In this study, the authors claim that this polymorphism results in overexpression of RAD51 that might modulate HR in favor of the cells, protecting them from aberrant DNA repair events. Among other polymorphisms, XPD 2251A>C has been associated with increased risk of developing AML, mainly attributed to the C allele (Shi et al. 2011). It is also known that patients with AML have different response rates to the same treatment agents. Although administration of Ara-C, in conjunction with an anthracycline, is the cornerstone of therapy, the question of the best therapy for AML in first remission remains unanswered, and perhaps it could be stratified according to certain features. In this regard, several studies have focused on finding polymorphisms that have impact on the effects of chemotherapy and as a result, clinical outcome. It is known that good response to chemotherapy is usually associated with low DNA repair capacity, whereas chemoresistance is usually associated with a high DNA repair activity. Although there has been much effort on identifying DNA repair polymorphisms that could predict chemotherapy effectiveness in order to allow appropriate selection of drugs in specific patients, the existing results are of no clinical use and are sometimes contradictory. For example, polymorphism XPD Lys751Gln has been correlated with reduced risk of resistant disease (RD) due to an increased chemotherapy response rate (Kuptsova et al. 2007). However, in another study, the same polymorphism has also been associated with poor response to chemotherapy and decreased survival in patients with intermediate risk AML and normal cytogenetics (Strom et al. 2010). Of course, this controversy might be explained by different patient groups involved in these studies and it could be claimed that XPD Lys751Gln is a predictor of poor response to front line chemotherapy only in patients with normal karyotype. Among other polymorphisms, XPD Asp312Asn is reported to have a positive impact on drug effectiveness (Kuptsova et al. 2007) and XPC Ala499Val has been associated with decreased overall survival in AML patients with normal karyotype (Strom et al. 2010). Furthermore, in a study that included 110 AML patients, patients with XPA genotype -4A>G have been shown to have a higher frequency of chemoresistant disease when compared to wild type carriers (30% vs. 6, 5 % genotype AA) (Monzo et al. 2006). Finally ATM variant 4138C>T has been associated with poor response to chemotherapy in Chinese population (Shi et al. 2011); however this finding is difficult to be confirmed in European studies, due to its low penetrance (Choudhury et al. 2008, Johnson et al. 2007. Apart from the above polymorphisms, several studies implicate BRCA1 (involved in initial recognition of a double strand break) and BRCA2 gene (involved in Homologous Recombination) deficiencies in AML pathogenesis. Scardocci et al. observed that 32% of primary AML samples present with hypermethylated BRCA1 (Scardocci et al. 2006). Although this finding has not been confirmed in other studies (Bianco et al. 2000, Esteller et al. 2001), a meta-analysis performed in 2007 which reviewed risks for hematological malignancies associated with mutations in BRCA1/2 pathway, showed that defects in this pathway increase the risk for a subset of AML that are related to gene rearrangements (Friedenson 2007). Consequently, it could be hypothesized that BRCA1/2 pathway's proper function is essential to prevent a group of leukemias. Consistent with these data is the observation that Fanconi anemia patients with biallelic mutations in BRCA2 present with a high risk of AML (Wagner et al. 2004). Recent evidence suggests a role of error-prone Non Homologous End Joining (NHEJ) in AML development. In preclinical studies, sequencing of breakpoint junctions in AML cells has revealed microhomologous sequences and small deletions, indicative of NHEJ repair (Gillert et al. 1999, Olive 1998, Wiemels et al. 2000, Wiemels et al. 2002, Yoshida et al. 1995. This increased NHEJ activity must, however, be confirmed in other studies. Regarding Mismatch Repair (MMR) Mechanism, published data in AML are somewhat conflicting. Although there are studies demonstrating increased rates of microsatellite instability in certain types of leukemia (mostly therapy-related AML and myelodysplastic syndromes (Ben-Yehuda et al. 1996, Kaneko et al. 1995), most reports have described little or no evidence of deficient MMR in AML (Boyer et al. 1998, Sill et al. 1996, Tasak et al. 1996. However, while none of these studies focused on MMR deficiency in different stages of AML, in 2008 Mao et al. showed that more than 30% of AML patients presented with mutations in MMR genes and that MMR deficiency was higher in patients with relapsed/ refractory AML (Mao et al. 2008). Authors suggest the possibility of leukemia relapse generating from leukemic cells defective in MMR that have survived chemotherapy and present the minimal residual disease (Mao et al. 2008). In conclusion, many polymorphisms of DNA repair genes have been associated with individual susceptibility to AML, as well as pathogenesis and sensitivity to chemotherapy. The precise functional mechanism of their effect remains to be determined; however results strongly support the importance of considering them as prognostic factors or indicators of treatment strategy. Hopefully, further studies will elucidate their role with the view to use them in clinical setting.

Acute Lymphoblastic Leukemia (ALL)
Acute Lymphoblastic Leukemia (ALL) is a malignant disease characterized by accumulation of immature lymphoblasts. It is the most common leukemia in children, accounting for 70-80% of all childhood leukemias. In the contrast, ALL accounts for 15-20% of leukemias in adults (Faderl et al. 1998). There is strong evidence that acquired genetic changes are central to the development of ALL. Polymorphisms of DNA repair genes have been investigated as potential pathogenetic and prognostic factors. The majority of studies are focused on childhood ALL, due to its www.intechopen.com high frequency in children. Several polymorphisms have been implicated, but results are somewhat conflicting, probably because of the different ethnic groups involved in each study. Thus, polymorphism XRCC1 Arg399Gln has been associated with increased risk of childhood ALL, in Indians (Joseph et al. 2005), Chinese (Zhu et al. 2005) and Thais (Pakakasama et al. 2007), but no correlation was found in Mexican (Meza-Espinoza et al. 2009), Brazilian (da Silva Silveira et al. 2009) and Turkish children (Batar et al. 2009). Perhaps this polymorphism has a stronger effect or a higher penetrance in Asian populations. In other studies, it has been proposed that it has a synergistic effect with CYP2E1*5B polymorphism of detoxification enzyme CYP2E1 (Tumer et al. 2010), as well as polymorphism OGG1 Ser326Cys (Stanczyk et al. 2011) in ALL development. Similarly, polymorphism XRCC1 Arg194Trp, has been found to have a protective effect in Thais (Pakakasama et al. 2007), while opposite results have been found in another study (Joseph et al. 2005). Moreover, several XRRC1 haplotypes have been related to ALL; haplotype B, as well as C, have been associated with an increased ALL risk (Meza-Espinoza et al. 2009, Pakakasama et al. 2007). On the other hand, polymorphisms of Nucleotide Excision Repair genes have also been investigated in ALL in a few studies. XPD Asp312Asn and Lys751Gln polymorphisms, which have been previously associated with AML, have not been found to be correlated with ALL risk (Batar et al. 2009, da Silva Silveira et al. 2009). On the contrary, CC genotype of ERCC18092C>A polymorphism has been suggested to increase susceptibility to ALL in Chinese children (Wang et al. 2006). In the same study, ERCC1 19007G>A was not found to be associated with ALL (Wang et al. 2006). Regarding Mismatch Repair (MMR) mechanism, most of the existing studies have failed to show an association between MMR deficiency and ALL development (Molenaar et al. 1998, Takeuchi et al. 1997, although preclinical studies have demonstrated MSI in ALL cell lines (Gu et al. 2002, Hangaishi et al. 1997). In addition, no relationship was found between polymorphisms in MMR genes MLH1 and MSH3 and childhood ALL (Mathonnet et al. 2003), although a combined effect was demonstrated with CYP2A1*2A and CYP2E1*5 polymorphisms of detoxification enzymes, suggesting a possible interaction between DNA repair enzymes and detoxification enzymes in childhood ALL. In addition, in another study that evaluated the risk of childhood ALL and the presence of variants in DNA repair enzymes in children exposed to diagnostic X-rays, hMLH1 was found to protect against Xray exposure (Infante-Rivard et al. 2000). Finally, it is worth mentioning that a positive correlation has been found between polymorphism 8360G>C in NBS1 gene (component of MRN complex) and ALL. It is interesting that this study included ALL patients from different ages, but results are potentially questionable, since the study was limited to a small size group of Chinese population (Jiang et al. 2011). In summary, although many polymorphisms have been associated with ALL, investigation remains still at an early stage. Further studies are needed in order to be able to draw definite conclusions for the potential use of polymorphisms for the stratification of patients in different prognostic and treatment groups.

Myelodysplastic Syndromes (MDS)
Myelodysplastic syndromes (MDS) represent a spectrum of stem cell malignancies that manifest dysplastic and ineffective hematopoiesis, which is associated with a variable risk of transformation to AML. They usually arise de novo with the risk of developing MDS increasing proportionally to age (Doll andList 1989, Noel andSolberg 1992).

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It is known that genetic lesions in hematopoietic progenitor cells play a major role to their malignant transformation and there is accumulating evidence that genetic factors modify a person's cumulative risk to MDS (Janssen et al. 1989). It has also been suggested that disease progression of MDS to AML is attributed to accumulation of mutations that cause defects in DNA repair (Rowley 1999); as a consequence, most of the existing studies are interested in identifying whether DNA repair polymorphisms implicated in AML are also involved in MDS. However, only one study found a positive correlation between polymorphism RAD51 135G>C and MDS risk; and it is difficult to interpret this result, since the study is limited to a Chinese population (Li et al. 2010). All other studies did not show any association between DNA repair polymorphisms and MDS (Baumann Kreuziger and Steensma 2008, Fabiani et al. 2009). This contradiction might be interpreted by the fact that these polymorphisms have been associated with de novo AML, whose pathogenesis is a different molecular procedure compared to MDS. Finally, in an effort to examine a possible role of Non Homologous End Joining (NHEJ) repair mechanism in MDS, we have previously tested the expression of NHEJ protein components in 48 cases of adult de novo MDS (Economopoulou et al. 2009). We reported a significantly lower Ligase IV expression level in MDS patients compared to controls and an association of Ku70 expression with more aggressive disease, suggesting a potential role of these two molecules in MDS pathogenesis and clinical presentation. However, a larger number of cases need to be examined in order to confirm these findings.

Chronic Myeloid Leukemia (CML)
Chronic Myeloid Leukemia (CML) is a clonal stem cell disorder characterized by increased proliferation of myeloid elements at all stages of differentiation (Champlin and Golde 1985). It is caused by the Bcr-Abl oncoprotein, the product of the t (9;22) chromosomal translocation that generates the Philadelphia chromosome. CML is a multistep disease, which involves a chronic phase (CP) that finally progresses to a blast crisis (BC). Although imatinib, a selective inhibitor of the ABL kinase, has revolutionized the treatment of CML (Druker et al. 1996), it has not completely eradicated it, and has a poorer response rate in patients with CML and blast crisis (BC) (Oehler et al. 2007). Progression to BC has been associated with the appearance and accumulation of new cytogenetic abnormalities; therefore, there are many studies focusing on transformation to BC pathogenesis. It has been recently found that BCR-ABL transformed cells have an increased level of Reactive Oxygen Species (ROS) that induces numerous double strand breaks (DSBs) (Nowicki et al. 2004). It was also shown that BCR-ABL upregulates error-prone DSB repair pathways (Non Homologous End Joining-NHEJ) rather than the high-fidelity mechanism of Homologous Recombination, promoting mutagenic DSB repair (Nowicki et al. 2004, Salles et al. 2011 . Therefore, it could be suggested that mutagenic DSB repair might provoke chromosomal abnormalities found in the progression to BC (Nowicki et al. 2004). Furthermore, it was recently demonstrated that BCR-ABL increases expression and activation of WRN (involved in NHEJ), which promotes unfaithful repair and protects leukemia cells from apoptosis, resulting in genomic instability (Slupianek et al. 2011). Moreover, several DNA Repair proteins have been found to be associated with CML and have been suggested to play a potential role in CML-BC pathogenesis. DNA-PKcs has been found to be decreased in BCR-ABL transfected cells, as well as CD34+ cells from CML patients (Deutsch et al. 2001). This reduced expression of DNA-PKcs was correlated with DNA repair deficiency, that might contribute to genetic instability found in BC (Deutsch et www.intechopen.com al. 2001). It could be therefore suggested that low expression of DNA-PKcs is involved in progression to CML-BC. Among other proteins, XPB has been isolated from BCR domain and it has been shown that continuous interaction with BCR-ABL provokes XPB deficiency and chromosomal instability (Takeda et al. 1999). Finally, hMSH3 Mismatch Repair protein has been found to be reduced in CML patients (Inokuchi et al. 1995). However, we can't ignore that the percentage of CML patients with reduced hMSH3 expression in that study was very high (90%), but the number of CML samples examined was small (10). Given the fact that the finding has not been confirmed in other studies, its reliability is questionable. Abnormalities of DNA repair components and their impact on myeloid malignancies are summarized in Table 1.

Non Hodgkin's Lymphoma (NHL)
Non Hodgkin's Lymphoma (NHL) includes multiple neoplastic disorders of the lymphoid system with overlapping features. They most commonly derive from mature B-cells of germinal center origin. Clinical presentation is highly variable and depends on a number of factors; however NHL share a number of common clinical and pathologic features. DNA repair has a pivotal role in NHL development. Defects in DNA repair can lead to the development of chromosomal aberrations, a hallmark of lymphoma (Palitti 2004). This is further supported by the fact that several hereditary syndromes, including Ataxia telangiectasia and Nijmegen breakage syndrome are characterized by defective DNA repair and high occurrence of lymphoma. Among studies focused on DNA repair polymorphisms and their impact on NHL, three parallel studies conducted in the US and Australia have reported different or contradictory results. In the first one, DNA ligase IV (Lig4) 9 I variant allele has been found with lower frequency in NHL patients, including follicular lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) patients, compared to controls (Hill et al. 2006). This finding is in accordance with another case control study, where LIG4 9 I/I homozygotes had a 3 fold reduced NHL risk (Roddam et al. 2002). Among other polymorphisms examined, RAG1 K820R variant allele (involved in V (D) J recombination), BRCA2 Arg372His genotype and XRCC1 Arg194Trp were associated with an increased risk of NHL (Hill et al. 2006). However, the latter has not been confirmed in other studies that evaluated the impact of XRRC1 polymorphisms in NHL (Liu J. et al. 2009, Smedby et al. 2006. Finally, WRN V114I variant was found to be associated with a decreased risk of NHL (Hill et al. 2006). In contrast, in the second study conducted in Connecticut, these results were not confirmed. However, a negative association was demonstrated between NHL and another WRN polymorphism, Cys1367Arg, suggesting a protective role of WRN in NHL (Shen et al. 2006). On the other hand, polymorphism XPG Asp1104His has been for the first time correlated with elevated NHL risk, including DLBCL and T-cell lymphomas (Shen et al. 2006). Finally, the third study which included patients from Australia, found no association between the above polymorphisms and NHL (Shen et al. 2007). However, it has been found that MGMT SNPs Ala143Val and Lys178Arg are associated with elevated NHL risk, including FL, DLBCL and MALT lymphoma (Shen et al. 2007). Interestingly, a pooled investigation of genetic variation in 27 DNA repair genes based on the three above studies, revealed different results (Shen et al. 2010). Among the examined SNPS, BLM rs441399 was significantly associated with follicular lymphoma and XRCC4 rs13178127 was correlated with NHL overall (Shen et al. 2010). Of note, products of BLM and XRCC4 genes are both involved in DSB repair and they both interact with Ligase IV.

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Moreover, in the same study, ERCC3 rs4150506 was associated with reduced risk for marginal zone lymphoma (MZL) (Shen et al. 2010). Similarly, Worrillow et al. (Worrillow et al. 2009) analyzed polymorphisms in XPD gene, in a UK population study that involved 747 NHL cases. This is the largest study assessing the impact of XPD polymorphisms on NHL. There were no statistically significant case control differences in the distribution of XPD polymorphisms. However, a decreased risk of diffuse large B-cell lymphoma was observed in variants for XPD Lys751Gln. This finding has been previously reported (Shen et al. 2006). Furthermore, XPD 156 A>C was found to be associated with an increased risk of follicular lymphoma (Worrillow et al. 2009). Similarly, Rollinson et al. (Rollinson et al. 2006) studied the haplotypic variation of tricomplex MRE11-RAD50-NBS1 and its relationship with NHL risk. The main findings of the study were a protective effect for MRE11 rs601341 variant in follicular lymphoma and for the MRE11 GCTCA haplotype in diffuse large B-cell lymphoma (DLBCL), suggesting a possible role of protein MRE11 in DLBCL pathogenesis. No altered NHL risk associated with haplotypes of NBS1 and RAD50 was observed in this study. Another similar study was performed by Schuetz et al (Schuetz et al. 2009). The authors suggest an association of a RAD50 SNP -38C>T with Mantle Cell Lymphoma (MCL), but the low incidence of both the SNP and MCL make these data questionable. No association was observed between NBS1 haplotypes and NHL (Schuetz et al. 2009). In contrast to the previous study, this one failed to show any correlation of MRE11 rs601341 variant with NHL, but the authors propose that this disparity is due to the fact that the part of intron where rs601341 was located was not sequenced. Additionally, ATM protein, also involved in double strand break response, has been associated with NHL. Schaffner et al. (Schaffner et al. 2000) reported inactivation of both alleles of ATM gene in a high proportion of patients with Mantle Cell Lymphoma (MCL), suggesting that ATM functions as a tumor suppressor gene in MCL. This finding has been confirmed in subsequent studies that provide evidence for somatic mutations in ATM in MCL (Fang et al. 2003, Taylor et al. 1996. On the other hand, ATM has been associated with NHL of B-origin (B-NHL) clinical outcome, since deletion of one ATM allele has been found to strongly influence B-NHL survival (Vorechovsky et al. 1997). However, another study reported contradictory results claiming that common variants in ATM do not influence NHL susceptibility (Sipahimalani et al. 2007). The authors suggest that individuals with common ATM variants are phenotypically normal and that only rare variants could possibly influence NHL susceptibility. The role of rare ATM variants in NHL remains to be elucidated. Among other DNA repair proteins, it is worth mentioning the role of Nucleotide Excision Repair component hHR23B as an apoptosis-associated protein in Burkitt Lymphoma (Vogel et al. 2005). Finally, the role of Mismatch Repair (MMR) pathway in NHL has also been investigated, although limited published data exist. Kotoula et al. (Kotoula et al. 2002) described a low expression of proteins hMLH1 and hPMS1 in B-cell lymphomas and in Mantle Cell Lymphoma (MCL) of blastoid type compared to normal controls, although in B-Chronic Lymphocytic Leukemia and Mantle cell Lymphoma of centrocyte-like type the expression of MMR genes remained intact. The small sample size and the heterogeneity of the specimens, along with the lack of additional published data that could support the findings, make these data questionable. Furthermore, Morimoto et al. (Morimoto et al. 2005) observed a reduced expression of MMR genes in patients with adult T-cell Leukemia (ATL), supporting a role of www.intechopen.com MMR gene inactivation in disease progression and development of ATL. Although the number of patients included in the study is small, the results are promising and give insight for further investigation.

Hodgkin's Lymphoma (HL)
Hodgkin's lymphoma (HL) is a hematolymphoid neoplasm, primarily of B-cell lineage, with unique molecular, histologic, immunophenotypic and clinical features. The diagnosis of classical HL requires the recognition of Reed-Steinberg cells in an appropriate cellular milieu (Liu A. et al. 2008). To date, the effect of DNA repair polymorphisms on HL has not been yet thoroughly investigated. However, few studies have tried to assess their role on HL development. In a large study that involved 200 newly diagnosed adult HL patients, a positive association was demonstrated between XRCC1 Arg399Gln and risk of HL (El-Zein et al. 2009). Interestingly, the authors observed that combined analysis of XRCC1/XRCC3 and XRCC1/XPC polymorphisms revealed significant association with increase in HL risk. For example, XRCC3 Thr241Met was associated with an OR of 2.38 when combined with homozygous XRCC1 Arg/Arg genotype. XRCC1 Gln/Gln along with XRCC3 variant led to a 3 fold increased HL risk. Similarly, XRCC1 Arg399Gln together with XPC Lys/Lys was found to significantly increase HL risk. Similar findings were reported in a recent study that evaluated potential gene-gene interaction between DNA repair genes and their contribution to individual susceptibility to HL (Monroy et al. 2011). Polymorphism XRCC1 Arg399Gln was again associated with increased HL risk, as well as polymorphisms XPC Ala499Val, XRCC3 Thr241Met and XRCC1 Arg194Trp. Most importantly, it was observed that HL risk increases as the number of adverse alleles in Base Excision Repair (BER) and repair of double strand breaks (DSBR) increases. Taken together these two studies suggest a potential cooperation between BER and DSBR mechanisms in HL development; however the exact procedure remains to be elucidated. Furthermore, there is strong evidence that ATM gene is involved in the pathogenesis of HL. The existing data refers to identification of four SNPs of ATM gene with a defective protein activity (Takagi et al. 2004). Consequently, it could be proposed that in the presence of genotoxic stress, these defects might be amplified and lead to accumulation of mutations that may contribute to a malignant phenotype. Similarly, Liberzon at al. showed that variants of ATM were associated with aggressive disease in children (Liberzon et al. 2004). The main limitation of both these studies is the small sample size that consisted only of children. Further investigation is necessary in order to draw safe conclusions. Finally, it is worth mentioning that a relationship was recently found between telomere shortening and development of second cancers in HL patients (M'Kacher et al. 2007). Telomere dysfunction is linked to DNA repair and probably to decreased Ku70 expression, although further studies are required to elucidate the mechanism of telomere shortening in HL patients.

Chronic Lymphocytic Leukemia (CLL)
Chronic Lymphocytic Leukemia (CLL) is the most common form of adult leukemia in the Western hemisphere (Ganster et al. 2009). It is a neoplastic disorder of mature B lymphocytes that is determined by genetic, molecular and environmental factors. The clinical course of CLL is highly variable. There are two groups of patients with diverse www.intechopen.com clinical outcomes that are separated by the mutational status of immunoglobulin variable region (IgV) gene (Hamblin et al. 1999). Although mutation status of IgV gene, as well as acquired chromosomal abnormalities [del(13q), del(11q), del(17p), trisomy 12] have been identified as prognostic factors in CLL, discovery of further prognostic factors would help to predict disease progression among different patient groups. Recently, polymorphism XPD Lys751Gln not only has been found to be associated with CLL development but it also occurred significantly more frequently in high risk patients. In the same study, polymorphisms XRCC1 Arg399Gln and XPF Arg415Gln were similarly positively correlated with cytogenetically high risk CLL patients. In contrast, polymorphism RAD51 135 G>C was associated with low risk CLL. The most important aspect of this study is that it examines the effect of SNPs on cytogenetic aberrations in CLL and suggests that polymorphisms XPD Lys751Gln and XRCC1 Arg399Gln might predict the unfavorable clinical outcome of CLL. Notably, polymorphism XPD Lys751Gln has been previously been described as a negative prognostic factor in acute myeloid leukemia. However, contradictory results were produced in another study, where XPD Lys751Gln was associated with a decreased risk of developing CLL; there was no distribution among different cytogenetic risk subgroups though (Enjuanes et al. 2008). Similarly, XRCC1 Arg399Gln has not been correlated with CLL in previous studies, although there was again no distinction between different subgroups (Enjuanes et al. 2008, Sellick et al. 2008 . These data suggest that individual genetic polymorphisms may predict the clinical outcome of CLL; however, future studies should focus on confirming the results in a larger group of patients, with the view for clinical application. It is known that one of the therapies used in CLL is treatment with alkylating agents, which is associated with low rates of complete remission. The ability of CLL cells to efficiently repair alkylator-induced DNA damage might explain lack of response to treatment. Therefore, DNA repair may be linked to chemoresistance in CLL (Sampath and Plunkett 2007). There is strong evidence that both HR and NHEJ play an important role in CLL resistance to chemotherapy. For instance, there is evidence that CLL cells exposed to chlorambucil demonstrate an increase in RAD51 foci (Christodoulopoulos et al. 1999). In addition, resistance to alkylating agents has been associated with enhanced HR repair in CLL cells (Aloyz et al. 2004, Bello et al. 2002, Xu et al. 2005). Similarly, a high level of XRCC3 was associated with lack of response of CLL cells to nitrogen mustards (Bello et al. 2002). Furthermore, it has been reported that low levels of Non Homologous End Joining protein component DNA-PKcs is strongly associated with drug sensitivity in CLL cells, whereas increases in DNA-PK activity resulted in increased resistance to neocarzinostatin and chlorambucil (Amrein et al. 2007, Austen et al. 2005. Inhibition of DNA-PKcs (Amrein et al. 2007), as well as dual inhibition of both RAD51 and DNA-PK (Amrein et al. 2011) has been found to induce drug sensitivity in CLL cells. Recently, the effect of DNA-PK inhibitors in CLL cells was investigated in combination with mitoxantrone. Interestingly, DNA-PK inhibitors provoked mitoxantrone cytotoxicity in CLL cells, especially cells with unfavorable cytogenetic anomalies [del(17p) and del(13q)] (Elliott et al. 2011). These findings could be of vital importance regarding CLL treatment, since DNA repair inhibitors could be used as potential therapeutic targets in combination with alkylating agents for a better clinical outcome, especially in high risk CLL. Finally, association of DNA repair enzymes' abnormalities with CLL prognosis has been the subject of investigation of several studies. ATM has been implicated in CLL, since it has been shown that approximately 14% of patients with untreated CLL harbor deletions of the long arm of chromosome 11 at the 11q22-23 (ATM) locus, which is associated with poor survival. An explanation could be that since ATM is an upstream regulator of p53, defects in ATM lead to attenuation of p53-dependent apoptosis, which results in a chemo-refractory phenotype. Furthermore, a correlation was described between protein DNA-PKcs component of Non Homologous End Joining and poor prognosis in CLL in terms of enzyme over-expression in del (17p) and del (11q) unfavorable CLL cases (Willmore et al. 2008). In the same study, high DNA-PKcs levels predicted for reduced treatment-free survival. These findings suggest that DNA-PKcs might contribute to disease progression in CLL, possibly by enhancing error-prone Non Homologous End Joining activity.

Multiple Myeloma (MM)
The diagnosis of multiple myeloma (MM) requires 10% or more plasma cells on bone marrow examination, M protein in the serum and/or urine (except in patients with true non-secretory myeloma) and evidence of end-organ damage (hypercalcaemia, renal insufficiency and anemia or bone lesions) secondary to the underlying plasma cell disorder. Almost all patients are thought to evolve from an asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS) (Kyle and Rajkumar 2004). Genetic instability is a prominent feature of MM, since malignant plasma cells display aneuploidy and complex cytogenetics associated with poor prognosis (Calasanz et al. 1997, Rajkumar et al. 1999, Smadja et al. 2001. Two pathways are considered important for disease progression; hyperploid MM involves trisomies of several chromosomes, whereas non-hyperploid MM is characterized by translocations in immunoglobulin heavy chain locus at 14q32 (Bergsagel and Kuehl 2005, Fonseca et al. 2004, Ho et al. 2001). The latter events represent aberrant class switch recombination (CSR), a process that normally alters immunoglobulin isotype with the maturation of immune response (Fenton et al. 2002, Liebisch andDohner 2006). Given the fact that CSR requires formation of double stand breaks, the role of Homologous Recombination (HR) and Non Homologous End Joining (NHEJ) in MM pathogenesis has been investigated in many studies. Among DNA repair polymorphisms, XRCC4 rs963248 and rs1051685 Ku80 have been found in a higher frequency in MM patients compared to controls (Hayden et al. 2007). At a protein level, XRCC4 was also recently found to be overexpressed in MM (Roddam et al. 2010) Furthermore, recently, protein Ku80 has been associated again with MM, since it was demonstrated that Ku80/Ku70 are translocated to human MM cells surface and that this localization has functional implications which could contribute to MM pathogenesis (Tai et al. 2002). Homologous Recombination (HR) has also been investigated in MM. Rad50 has been recently found to be overexpressed in MM patients (Roddam et al. 2010). In another study by Shammas et al. model MM cell lines were used in order to evaluate the molecular mechanisms of genetic instability and progression in malignancies (Shammas et al. 2009). An elevated HR activity is reported in MM cells, which leads to mutations. The authors show that inhibition of HR activity by siRNAs leads to reduction of genetic changes. Therefore, we could presume that HR can be targeted not only for prevention of disease progression, but also for therapy improvement. In another study focused on assessing the role of NHEJ in MM phenotype, authors observed that DSBs, when induced in MM cell lines, exhibited corrupt NHEJ (Yang et al. 2009). Interestingly, with the use of DNA-PK inhibitor was used, NHEJ process was suppressed and DNA ends were processed by intact HR. This finding suggests that deregulated DSB repair in MM might contribute to complex chromosomal aberrations that, as mentioned above, is typical feature of the disease. Apart from DSB repair, Mismatch Repair deficiency in MM has been investigated in several studies. Microsatellite instability has been reported in MM patients (Timuragaoglu et al. 2009, Velangi et al. 2004 and has been associated with more aggressive forms of the disease (e.g. plasma cell leukemia-PCL) (Velangi et al. 2004). On the other hand, Martin et al. (Martin et al. 2006) examined the methylation status and expression of enzymes MGMT and hMLH1 in 44 cases of plasma cells disorders [(Multiple Myeloma, Monoclonal Gammopathy of Undetermined Significance (MGUS), Plasma Cell Leukemia (PCL)]. Protein hMLH1 was found to be underexpressed in 50% of cases of MM, but not in patients with MGUS, whereas hMLH1 gene promoter was hypermethylated in 10% patients with MM but not in cases with MGUS. This finding suggests that inactivation of hMLH1 could be implicated in the evolution of MGUS to MM. On the contrary, 33% of MGUS and 44% MM patients had lost the MGMT expression, suggesting that MGMT deficiency is an initial alteration in plasma cell disorders. Additionally, Nucleotide Excision Repair (NER) enzymes and have been associated with MM. Peng et al. reported epigenetic silencing of NER protein XPD in MM cells that was found to promote clonal expansion of MM cells (Peng et al. 2005). As a consequence, it might contribute to MM pathogenesis. NER has also been studied in the context of autologous bone marrow transplantation (ASCT) in MM. It has been observed that the combination of variant alleles of NER proteins XPD K75Q and XRCC3 T241M correlates with prolonged time to treatment failure in MM patients treated with ASCT (Vangsted et al. 2007). This finding is very important, since polymorphisms in XPD and XRCC3 could potentially predict the outcome in MM patients undergoing ASCT. Finally, there is recent evidence that DNA repair polymorphisms are related to treatment response rate (RR) in MM. In a study conducted in Spain, it was found that polymorphisms ERCC1 rs735482 and Ku80 rs1051685 were associated with higher RR and longer overall survival in patients with relapsed/refractory myeloma treated with thalidomide (Cibeira et al. 2011). Similarly, RR was better in MM patients with SNPs in ERCC5 rs17655 (Cibeira et al. 2011). Although sample size is relatively small and belongs to a specific group of patients, this study provides very useful information, which, if confirmed in other studies, could be used in clinical practice to predict favorable outcome in relapsed myeloma. Abnormalities of enzymes involved in DNA repair mechanisms and their influence on hematological malignancies are summarized in Table 1.

Conclusions
Genomic instability is the hallmark of all hematological malignancies. Since DNA repair mechanisms are responsible for correcting DNA damage and preserving genomic integrity, it is obvious that abnormalities of these mechanisms are strongly related to hematological cancers. Mutations and polymorphisms of DNA repair genes are associated with alteration of an individual's susceptibility to malignancy. In addition, they are related to prognosis, drug resistance and clinical outcome and represent potential targets for therapy. We have presented the existing published data that show association of DNA repair mechanisms with the most common myeloid and lymphoid malignancies. in CLL with favorable prognosis -. Rad51 foci in CLL exposed to chlorambucil resistance to chlorambucil ?
-HR activity in CLL cells exposed to alkylating agents resistance to alkylating agents NHEJ:-DNA-PKcs expression chemosensitivity -DNA-PK activity resistance to chlorambucil -D N A -P K c s e x p r e s s i o n i n C L L p a t i e n t s w i t h p o o r p r o g n o s i s disease progression?  www.intechopen.com