Over the last decade, a growing number of tumor suppressor genes have been discovered to play a role in tumorigenesis. Mutations of p53 have been found in hematological malignant diseases, but the frequency of these alterations is much lower than in solid tumors. These mutations occur especially as hematopoietic abnormalities become more malignant such as going from the chronic phase to the blast crisis of chronic myeloid leukemia. A broad spectrum of tumor suppressor gene alterations do occur in hematological malignancies, especially structural alterations of p15INK4A, p15INK4B and p14ARF in acute lymphoblastic leukemia as well as methylation of these genes in several myeloproliferative disorders. Tumor suppressor genes are altered via different mechanisms, including deletions and point mutations, which may result in an inactive or dominant negative protein. Methylation of the promoter of the tumor suppressor gene can blunt its expression. Chimeric proteins formed by chromosomal translocations (i.e. AML1-ETO, PML-RARα, PLZF-RARα) can produce a dominant negative transcription factor that can decrease expression of tumor suppressor genes. This review provides an overview of the current knowledge about the involvement of tumor suppressor genes in hematopoietic malignancies including those involved in cell cycle control, apoptosis and transcriptional control.
Since the first proposal of a potential tumor suppressor gene being involved in the formation of retinoblastomas in 1983 (Benedict et al., 1983), a growing number of genes with proven or suspected tumor suppressor activity have been discovered. In addition, a complex picture of the function of different tumor suppressor genes has evolved. Knudson's ‘two-hit’ hypothesis (Knudson, 1971) holds true for most tumor suppressor genes, meaning that both alleles of a gene have to be inactivated to promote transformation. However, recent data suggest that the function of some tumor suppressor genes can be disrupted solely by haploinsufficiency; that is, alteration of one allele of a gene with the other allele remaining normal. Also, over the past years a growing understanding of the role of tumor suppressor genes in the normal differentiation of tissues has evolved. The aim of this review is to summarize the current knowledge about the importance of tumor suppressor genes in hematopoietic differentiation and in the formation or progression of hematopoietic malignancies.
Regulation of the G1/S checkpoint of the cell cycle
Malignant diseases are characterized by either rapid or unbridled cell division. Cell division is governed by the concerted action of cyclins and cyclin-dependent kinases (CDKs). The tight control of proteins involved in the regulation of the cell cycle is critical for an orderly cell division; and not surprisingly, almost any cancer type has an alteration of genes involved in the cell cycle (Sherr, 2000). The cell cycle can be separated in four distinct phases: initial growth (G1), DNA replication (S), a gap (G2) and mitosis (M) (Hirama and Koeffler, 1995). A critical point in the cell cycle control is the G1 to S transition. After passing this checkpoint, the cell is irreversibly committed to the next cell division (Hirama and Koeffler, 1995). The G1/S checkpoint is schematically drawn in Figure 1.
Key regulators of the G1 to S checkpoint are the Cyclin D: CDK4/CDK6 and the Cyclin E: CDK2 complexes (Dictor et al., 1999). These complexes phosphorylate the retinoblastoma protein (Rb) and related family proteins, p107 and p130 (Dyson, 1998; Nevins, 1998). Hypophosphorylated proteins of the Rb family complex with the transcription factors of the E2F family (Chellappan et al., 1991; Dyson, 1998; Nevins, 1998). Five of the six members of the E2F family, E2F1-5, interact with Rb or other family members (Nevins, 1998). These Rb family: E2F complexes inhibit the transcription of several genes involved in the S phase by the following mechanisms: First, they act as active repressors on the promoters of the target genes (Sellers et al., 1995; Weintraub et al., 1995). Second, they recruit histone deacetylases to the target genes which condensate the nucleosomes blocking access of transcription factors to the promoters (Brehm et al., 1998; Luo et al., 1998; Magnaghi-Jaulin et al., 1998). Third, by recruiting E2Fs, they prevent them from acting as transactivators on target genes (Arroyo and Raychaudhuri, 1992). Upon phosphorylation of Rb, the E2Fs are released and transactivate target genes involved in DNA-synthesis by binding to the E2F-response elements in the promoters of the target genes. Transcription of these genes leads to cell cycle progression into the S phase (Leone et al., 1998).
The kinase activity of the Cyclin D: CDK4/6 and Cyclin E: CDK2 complexes are negatively regulated through two cyclin-dependent kinase inhibitor (CDKIs) families, the INK4 (inhibitor of CDK4) proteins: p16/INK4A/multiple tumor suppressor 1 (MTS1)/CDK4 inhibitor 2A (CDKN2A); p15/INK4B/MTS2/CDKN2B; p18/INK4C/CDKN2C; p19/INK4D/CDKN2D, and the KIP (kinase inhibitor protein) molecules: p21/CDK-interacting protein 1 (CIP1)/CDKN1A/wild type p53-activated fragment 1 (WAF1); p27/CDK inhibitor 1 (KIP1)1; p57/KIP2. The p21CIP, the best characterized KIP-family member, is activated upon DNA-damage by the p53-pathway, preventing cell cycle progression. Unphosphorylated p53 activates MDM-2, which in return destabilizes p53 as a negative feedback mechanism. DNA injury, i.e. by UV-irradiation, leads to phosphorylation of p53 by either Chk1 or Chk2 mediated through ATM; phosphorylated p53 is resistant to degradation by MDM-2, thus providing a stabilizing effect (Tominaga et al., 1999). In addition, MDM-2 is also a target of ATM; it is inactivated by phosphorylation (Khosravi et al., 1999). MDM-2 is also inactivated by p14/alternate reading frame (ARF), a gene product sharing the same locus with p16INK4A (see below). p53 in turn induces transcription of p21CIP (el-Deiry et al., 1993). p21CIP then binds and inhibits Cyclin D: CDK4/6 and Cyclin E: CDK2 complexes (Morgan, 1997).
The INK4 family of CDKIs are induced during cellular senescence (Serrano, 1997) and upon growth-inhibitory signals, i.e. TGFβ (Ekholm and Reed, 2000). They bind to CDK4 and CDK6, preventing the kinases from forming complexes with Cyclin D (Ekholm and Reed, 2000). Inactivation of many of these G1 checkpoint genes occur during the development of cancer.
Rb, the retinoblastoma susceptibility gene, was cloned and identified as the first tumor suppressor gene in 1986 (Friend et al., 1986). The epidemiology of inherited retinoblastomas, caused by a germline mutation of one Rb allele and an acquired somatic mutation of the remaining allele of the Rb gene, led to the proposal of the ‘two hit’ model of carcinogenesis (Knudson, 1971) and the proposal of the existence of tumor suppressor genes (Benedict et al., 1983; Murphree and Benedict, 1984). As shown in Figure 1, the Rb : E2F complexes are key regulators for the G1 to S transition.
In 1992, three independent groups described the phenotype of the Rb knockout mouse (Clarke et al., 1992; Jacks et al., 1992; Lee et al., 1992). All three groups reported deficiencies in definitive erythropoiesis in homozygous Rb−/− embryos, finally leading to death of the embryos due to severe anemia at day 15 post conception. Surprisingly, heterozygous Rb+/− mice are not prone to retinoblastomas, but have a high incidence of pituitary adenocarcinomas. Rb expression increases during erythroid differentiation of hematopoietic progenitor cells, and antisense treatment results in a dose-dependent decline of erythroid colony numbers (Condorelli et al., 1995). Rb interacts with the transcription factor PU.1 (Hagemeier et al., 1993). PU.1 blocks erythroid differentiation in the proerythroblast stage when ectopically overexpressed in bone marrow cells (Schuetze et al., 1993) and represses GATA-1 activity (Zhang et al., 2000). GATA-1 activity is required for erythroid differentiation (Rekhtman et al., 1999). Hypothetically, Rb inhibits PU.1 activity when upregulated during erythroid differentiation, so GATA-1 is activated and transactivates genes important for erythroid differentiation (Figure 2).
Also, the hypophosphorylated form of Rb promotes monocytic differentiation in favor of neutrophilic differentiation of CD34+ cells (Bergh et al., 1999). The treatment of these cells with antisense-oligonucleotides for Rb switched the lineage commitment towards neutrophilic differentiation. This suggests that Rb plays a role in the differentiation of hematopoietic cells independent of cell cycle control.
A composite of four studies showed that a reduced or negligible expression of Rb was found in 27% of the samples of acute myelogenous leukemia (AML), and the decreased expression was associated with a poor prognosis in three out of the four studies (summarized in Sauerbrey et al., 1998). The mechanism of this downregulation remains unsolved, as no deletions (Jamal et al., 1996) or mutations (Barbosa et al., 1998) of the Rb gene or methylations of CpG islands in the Rb promoter (Kornblau and Qiu, 1999) could be found as a possible mechanism for its downregulation in AML. A functional inactivation of Rb can occur by maximal phosphorylation of the protein. This has been reported to occur in 15% of AML samples (Kornblau et al., 1998); and these individuals have a significantly lower survival. No Rb mutations have been found in 90 myelodysplastic syndrome (MDS) samples (Preudhomme et al., 1994b).
Rb is inactivated by mutation, deletion or loss of expression in 18% of individuals with accelerated phase or blast crisis of chronic myelogenous leukemia (CML), especially associated with a megakaryoblastic or lymphoblastic phenotype (Towatari et al., 1991; Ahuja et al., 1991b; Beck et al., 2000). In BCR/ABL negative chronic myeloproliferative diseases, no alterations of the Rb gene could be detected (Gaidano et al., 1994a,b).
Acute lymphoblastic leukemia (ALL) have decreased expression of Rb in 47% of cases (summarized in Sauerbrey et al., 1998). A negative correlation has been reported between levels of Rb mRNA and relapse-free survival in a multivariate analysis involving 56 cases of childhood ALL; however, this correlation could not be confirmed in studies that measured levels of Rb protein in 112 cases of ALL (reviewed in Sauerbrey et al., 1998). Deletions of Rb are rare in ALL, occurring in only 2% of ALL (Hangaishi et al., 1996). Thus, the pathway leading to decreased levels of Rb protein in ALL also remains unknown.
Adult T-cell leukemia/lymphoma (ATL) is a malignant T-cell proliferation associated with infection with the human T-cell leukemia virus (HTLV). We found homozygous deletions of Rb in only 5% of ATL cases (Hatta et al., 1997), and no point mutations were detected in those samples.
The Rb status in multiple myeloma is unclear. One study detected deletions of Rb in 50% of the samples (Dao et al., 1994), two other studies (Corradini et al., 1994; Zandecki et al., 1995) found only one rearrangement and no mutations in the ‘mutational hot spots’ of Rb (exons 20 to 24). However, reduced Rb protein expression could be detected in 18% of cases in these studies.
In various other lymphoid malignancies, reduced Rb expression was found in 25% of samples (Hangaishi et al., 1996; Sauerbrey et al., 1998). Genetic loss of the chromosome 13q14 region, the region where the Rb gene is located, is a common finding in Non-Hodgkin lymphomas (NHL) and B-cell chronic lymphocytic leukemia (B-CLL), but this deletion does not seem to involve the Rb gene (Brown et al., 1993; Hawthorn et al., 1993). In Hodgkin's lymphoma, 16% showed loss of the Rb protein (Sanchez-Beato et al., 1996) and individuals with high Rb protein expression (>20% positive staining) had a better survival of 100 vs 70% after 100 months (Morente et al., 1997).
The p130 gene, a Rb family member, has a mutation in its nuclear localization site in four of four lymphoblastic cell lines (three T-ALL and one Burkitt-lymphoma cell line) (Cinti et al., 2000a), and in about 50% of primary Burkitt lymphoma samples (Cinti et al., 2000b), resulting in aberrant cytoplasmatic localization of this tumor suppressor protein. Decreased p130 protein expression was found in 25% of non-Hodgkin lymphomas (NHL) which correlated with a better survival (Leoncini et al., 1999). For the remaining Rb family protein, p107, genomic alterations were detected in one T-ALL and one diffuse large cell lymphoma (DLCL) cell line as well as in one primary ALL sample (Takimoto et al., 1998). The likelihood that these alterations of p130 and p107 are causally linked to lymphomagenesis is supported by the following: Both p130 and p107, like Rb, negatively regulate cell cycle progression (Claudio et al., 1994; Zhu et al., 1995). For p130, high expression levels in various solid tumor samples correlated with more differentiated tumors and better prognosis of the patients (Baldi et al., 1996, 1997; Susini et al., 1998, 2001; Tanaka et al., 1999, 2001; Massaro-Giordano et al., 1999; Zamparelli et al., 2001). Even though mice with targeted disruption of either p130 (LeCouter et al., 1998) or p107 (Lee et al., 1996) are not predisposed to cancer, chimeric mice deficient for Rb and p107 (Rb−/−/p107−/−) display a high frequency of retinoblastomas (Robanus-Maandag et al., 1998), as compared to chimeric Rb−/− mice (Maandag et al., 1994; Williams et al., 1994). However, no data showing a functional role of mutations of p130 or p107 in lymphomagenesis exist to date and the role of mutations of p130 and p107 in lymphomas requires further elucidation.
INK4 family of proteins
The INK4 family of proteins all function as inhibitors of CDK4 and CDK6 (Figure 1). Two genes, p16INK4A and p14ARF, are localized at the same INK4A gene locus (Quelle et al., 1995). Each gene uses a different promoter and is transcribed in a different reading frame, thus resulting in totally different amino acid sequences despite utilizing the same exons 2 and 3 (Sidransky, 1996). Both proteins act as inhibitors of the G1 to S transition, even though they function in two different pathways: p16INK4A acts as an inhibitor of Cyclin D: CDK4/6 complexes; and p14ARF stabilizes p53 by inhibition of MDM-2 (Figure 1). The p16INK4A protein is highly expressed in hematopoietic CD34+ progenitor cells and is downregulated in later stages of development, suggesting its role in differentiation (Furukawa et al., 2000). The gene for p15INK4B is localized in close proximity to the INK4A locus on chromosome 9p21 (Kamb et al., 1994). All three genes are frequently altered in various hematological malignancies. An excellent review (Drexler, 1998) summarized the alterations of the INK4 family members in leukemias/lymphomas of 4700 primary samples and 320 cell lines. Most alterations occur by inactivation of p16INK4A and p15INK4B due to hypermethylation of CpG islands in their promoters or by deletions in the 9p21 region, frequently involving all three genes. A high frequency of hypermethylation of the p15INK4B promoter occurs in AML (79%) including acute promyelocytic leukemia (APL) (73%) (Chim et al., 2001a) and MDS (42%). T-ALL and Pre-B-ALL cells often have hypermethylation of the p15INK4B promoter (44%) and deletions of the p16INK4A (33%) and the p15INK4B (32%) genes. p16INK4A promoter methylations often is present in Burkitt's lymphomas (52%) (Herman et al., 1997; Klangby et al., 1998), Hodgkin's lymphomas (61%) (Garcia et al., 1999) and multiple myeloma (46%) (Tasaka et al., 1998; Lo et al., 1999; Ng et al., 1999; Gonzalez et al., 2000; Uchida et al., 2001).
Controversy arises concerning the prognostic relevance of p16INK4A/p14ARF/p15INK4B inactivation. Several attempts have been carried out to link the occurrence of p16INK4A/p14ARF/p15INK4B alterations with prognosis or disease progression (reviewed in Drexler, 1998; Tsihlias et al., 1999). Whereas many studies show p16INK4A deletions as an independent risk factor for a poor outcome in childhood ALL (Okuda et al., 1995; Zhou et al., 1997; Yamada et al., 1997; Kees et al., 1997; Tsihlias et al., 1999; Moreno et al., 2000; Ramakers-van Woerden et al., 2001; Carter et al., 2001) or as a marker for disease progression (Diccianni et al., 1994; Ohnishi et al., 1996; Kees et al., Maloney et al., 1999; Carter et al., 2001), one large study (Rubnitz et al., 1997) found no correlation between p16INK4A deletion and either the survival or relapse rate in 155 ALL patients. Only a few studies to date have attempted to correlate p15INK4B promoter methylation with clinical outcome. In ALL, no correlation between p15INK4B promoter methylation with outcome (Chim et al., 2001b) or disease progression (Batova et al., 1997) was found. An inverse correlation between p15INK4B methylation and overall survival was reported in adult AML (Wong et al., 2000). Two studies found a worse prognosis in MDS patients whose hematopoietic cells had a methylated p15INK4B promoter compared to samples with an unmethylated p15INK4B promoter, but this correlation was due to a strong correlation of p15INK4B methylation with disease progression and disappeared in multivariate analyses (Quesnel et al., 1998; Tien et al., 2001). Given the discrepancies of these studies, no definitive conclusions regarding the prognostic significance of inactivation of either the p16INK4A and/or the p15INK4B gene can be drawn. Even though the data suggest that inactivation of the p16INK4A or p15INK4B gene might lead to an unfavorable prognosis, prospective studies on large groups of similarly treated individuals are necessary to answer this yet unresolved question.
In vivo and in vitro models provide insight into the role of p16INK4A and/or the p14ARF. The p19ARF is the murine equivalent of the human p14ARF. Mice with targeted disruption of both the p16INK4A/p19ARF loci (p16INK4A−/−/p19ARF−/−) developed lymphomas and lymphoid leukemias with a low penetrance, as well as other tumors (Serrano et al., 1996). Homozygous disruption of only the p19ARF alleles with retained p16INK4A alleles (p16INK4A+/+/p19ARF−/−) also resulted in tumor formation including lymphomas; and tumors that developed in the heterozygous p19ARF+/− mice showed a loss of the wild type allele p19ARF, suggesting a selective growth advantage for hematological malignancies which lose p19ARF (Kamijo et al., 1997, 1999). Mice with a disruption of both alleles of p16INK4A and an intact p19ARF (p16INK4A−/−/p19ARF+/+) have a moderately increased cancer susceptibility (Krimpenfort et al., 2001; Sharpless et al., 2001). However, mice heterozygous for loss of p19ARF and homozygous null for p16INK4A (p16INK4A−/−/p19ARF+/−) do show an increased rate of malignancies compared to mice heterozygous for both genes (p16INK4A+/−/p19ARF+/−), and three out of five tumors arising from these mice did not show loss of the wild type p19ARF allele (Krimpenfort et al., 2001). This might lead to the following conclusions: (1) Homozygous loss of p14/p19ARF, but not homozygous loss of p16INK4A, predisposes to tumor formation; (2) p16INK4A has a tumor suppressive effect, which can compensate for haploinsufficiency of p19ARF.
When wild type p16INK4A was introduced into the p16INK4A-deficient hematopoietic cell lines BV173 (Lewis et al., 2001), K562 (Quesnel et al., 1996; Gombart et al., 1997; Lewis et al., 2001), CEM (Quesnel et al., 1996; Gombart et al., 1997), JURKAT (Quesnel et al., 1996), Granta 519 (Jadayel et al., 1997), NB4 (Gombart et al., 1997) or JKB (Urashima et al., 1997), their growth was retarded and they partially underwent differentiation, suggesting that p16INK4A-deficiency might contribute to the malignant phenotype. No effect of introduction of wild type p16INK4A was observed in the p16INK4A-deficient HL-60 (Quesnel et al., 1996) and HSB-2 cells (Gombart et al., 1997), but HSB-2 cells also lack wild type Rb, a downstream target of p16INK4A (Figure 1). Of future interest will be to express ectopically the wild type p14ARF in cell lines with inactivated p16INK4A/p14ARF locus and wild type expression of p53, to determine whether reintroduction of p14ARF will cause a growth inhibitory effect either alone or in combination with p16INK4A.
The p18INK4C and p19INK4D genes are two other INK4 family member. Alterations of these genes rarely are found in hematological malignancies (reviewed in Drexler, 1998).
p53 is considered the ‘guardian of the genome’ and halts the cell cycle upon DNA damage. In addition, it is also a key regulator of apoptosis (reviewed in Wang, 1999). Since the first detection of alterations of p53 in human tumors (Masuda et al., 1987), it has become clear that p53 is the most frequently altered tumor suppressor in human non-hematopoietic malignancies. More than 50% of solid tumors have loss of wild type p53 expression due to deletions or point mutations (Hollstein et al., 1991; Hainaut et al., 1998). In contrast, hematopoietic malignancies are less likely to home a p53 alteration. In the version R5 of the database of p53 mutations at the International Agency for Research on Cancer (Hernandez-Boussard et al., 1999), only 14% of 672 hematological malignancies had p53 mutations.
In AML and MDS, alterations of p53 occur most frequently in therapy-related AML and MDS, and AML and MDS carrying a deletion of chromosome 17p at the p53 locus. Studies of therapy-related AML/MDS found p53 mutations in 30% of cases, with the majority of the mutated samples showing a loss of the wild type p53 allele (Horiike et al., 1999; Christiansen et al., 2001). In two studies involving 351 patient samples of AML and MDS (Fenaux et al., 1991; Lai et al., 1995), 38 of 59 samples (64%) that showed a deletion of chromosome 17p had a point mutation of the remaining p53 allele. On the other hand, only nine out of 292 patients (3%) without a chromosome 17p deletion had a p53 mutation (Fenaux et al., 1991; Lai et al., 1995). Similarly, point mutations of p53 were found in all four of four samples of chronic lymphocytic leukemia (CLL) with a chromosome 17p monosomy, and no p53 mutations were detected in the remaining 35 CLL samples that had a cytogenetically normal chromosome 17 (Fenaux et al., 1992b). In unselected CLL samples, the frequency of p53 mutations was 15% (Table 2). One study found a significantly worse response to chemotherapy and a significantly shorter survival in AML, MDS and CLL patients whose abnormal cells had a p53 mutation (Wattel et al., 1994). But, this was shown only in a univariate analysis and has to be interpreted with caution, since therapy-related AML and MDS, which show a higher frequency of p53 mutations, have a worse prognosis per se.
CML frequently shows a loss of the short arm of chromosome 17, often through the formation of an isochromosome 17, i(17q), and acquires a p53 mutation in the progression towards blast crisis (reviewed in Di Bacco et al., 2000). This occurs especially during the progression to myeloid blast crisis (Ahuja et al., 1991a). Two animal studies illustrate the role p53 inactivations might have in blastic progression of CML. Bone marrow cells from p53-deficient (p53−/−) and p53 Wt (p53+/+) mice were transfected with a retroviral expression vector for BCR/ABL p210 (Skorski et al., 1996). p53+/+/p210 transgenic cells showed a differentiated phenotype and formed a CML-like myeloproliferative syndrome when injected into lethally irradiated wild type mice. In contrast, p53−/−/p210 transgenic cells showed a blastic phenotype and formed an acute myelogenous leukemia when injected into lethally irradiated wild type mice. Mice heterozygous for p53 (p53+/−) and transgenic for BCR/ABL p210 rapidly developed acute myeloid leukemias (Honda et al., 2000). The myeloblasts in the majority of these mice lost the remaining wild type p53 allele, again illustrating the importance that loss of p53 can have on disease progression.
Similarly, small studies also suggest an involvement of p53 mutations in the acceleration of Philadelphia chromosome negative chronic myeloproliferative disorders (Ph− MPD). p53 mutations were detected in 37% of Ph− MPD in blast crisis and 2% of Ph− MPD in the chronic phase (Gaidano et al., 1993, 1997; Neri et al., 1996).
p53 mutations in ALL is restricted to a small subset of cases. In unselected cases, the frequency of p53 mutations is 5% (Table 2). Nevertheless, presence of p53 mutation was correlated with a poor clinical outcome (Marks et al., 1997; Kornblau et al., 1998). An increased incidence of p53 mutations occurs in relapsed childhood ALL (Marks et al., 1997), childhood T-ALL (Hsiao et al., 1994; Diccianni et al., 1994; Kawamura et al., 1999) and childhood ALL carrying the t(1;19) translocation (Kawamura et al., 1995). However, two studies did not find a correlation between p53 mutations and outcome in adult ALL (Fenaux et al., 1992a; Tsai et al., 1996).
Mutations of p53 have been detected in 29% of ATL (Nagai et al., 1991; Sakashita et al., 1992; Cesarman et al., 1992; Nishimura et al., 1995) and our group found loss of heterozygosity (LOH) at chromosome 17p, the locus of p53, in almost 50% of ATL samples (Hatta et al., 1998). One study found a higher rate of p53 mutations in aggressive subtypes of ATL compared to chronic ATL (Nishimura et al., 1995), and our group found the acquisition of a p53 mutation in an individual as he progressed from a chronic to acute stage of ATL (Sakashita et al., 1992).
In NHL, alterations of p53 were found in 12% of low grade and 20% of high grade NHL cases in studies looking at nucleotide changes in the ‘mutational hot spots’ in exons 5–8 (Table 2). p53 inactivations were frequent in transformed follicular lymphomas (80%) (Lo et al., 1993) and Burkitt's lymphoma (28%) (Gaidano et al., 1991; Bhatia et al., 1992; Preudhomme et al., 1995; Kaneko et al., 1996). One extensive study detected three out of a total of 10 mutations in high grade non-Hodgkins lymphomas outside of the ‘mutational hot spots’ (Kocialkowski et al., 1995), suggesting that the true frequency of p53 mutations in non-Hodgkins lymphomas might be higher.
Detection of p53 mutations was carried out in some of the studies by staining for p53 protein rather than looking at the nucleotide sequence. p53 mutations usually stabilize the half life of the protein resulting in abundant cellular levels. However, three studies (Nakamura et al., 1993; Kocialkowski et al., 1995; Adamson et al., 1995b) found major discrepancies between the immuno-detection of p53 protein and p53 mutations; 70% of the samples were false-positives and 26% false-negatives, respectively. Therefore, studies utilizing antibody-based techniques for the detection of p53 mutations are not included in Table 2. The data suggest a tendency towards a poor clinical outcome in NHL (Nieder et al., 2001) and CLL (Dohner et al., 1995) when the malignant cells have a p53 mutation.
p73 is a recently cloned gene homologous to p53, located on chromosome 1p36, a locus frequently deleted in neuroblastomas (Kaghad et al., 1997). The locus is also frequently deleted in blast crisis of CML (Mori et al., 1998) and in 13% of MDS (Hofmann et al., 2001a). It has overlapping functions with p53, i.e. it induces some, but not all of the p53 target genes, like p21CIP1 and MDM-2 (Zhu et al., 1998), and its overexpression in p53-deficient tumor cells causes apoptosis and growth arrest (Fang et al., 1999). Therefore, investigators have considered it as a potential tumor suppressor. However, mice with a targeted disruption of p73 do not have an increased susceptibility to develop cancer (Yang et al., 2000). Three studies showed loss of p73 expression due to methylation of CpG islands in about 30% of lymphoid malignancies, namely ALL, Burkitt's lymphomas and various other NHL (Corn et al., 1999; Kawano et al., 1999; Liu et al., 2001). No mutations or deletions of the p73 gene have been found in hematological malignancies to date (Corn et al., 1999; Kawano et al., 1999), but not a large number of cases have been examined so far.
Other ways to disrupt the p53 pathway in cancer includes either overexpression of MDM-2, inactivation of p14ARF (see below and Figure 1), or inactivation of p53-activating enzymes like ATM, Chk1 or Chk2. Overexpression of MDM-2 as a mechanism of p53 inactivation was initially described in human sarcomas as a result of gene amplification (Oliner et al., 1992). Gene amplification of MDM-2 was not detected in leukemias and NHL (Bueso-Ramos et al., 1993; Schottelius et al., 1994; Ridge et al., 1994), advanced MDS (Preudhomme et al., 1993) or NHL (Kawamata et al., 1996), but a recent report described MDM-2 gene amplification in four out of six cases of Hodgkin's lymphoma (Kupper et al., 2001). Overexpression due to hitherto unknown reasons might play a role in some hematopoietic malignancies. MDM-2 has been documented to be highly expressed in 40% cases of AML (Faderl et al.; Bueso-Ramos et al., 1993; Quesnel et al., 1994; Seliger et al., 1996). A small study of MDS found MDM-2 to be highly expressed in five out of seven samples (Bueso-Ramos et al., 1993), a large study found normal levels of the protein in 21 cases of MDS (Quesnel et al., 1994). MDM-2 was reported to be frequently (>50%) overexpressed in multiple myeloma (Lai et al., 1998) and high grade NHL (Finnegan et al., 1994; Moller et al., 1999) and moderately frequently in low grade NHL, CLL (Bueso-Ramos et al., 1993; Quesnel et al., 1994; Watanabe et al., 1994) and childhood ALL (Zhou et al., 1995; Marks et al., 1997; Gustafsson and Stal, 1998). In childhood ALL, high expression of MDM-2 was associated with a poor outcome (Marks et al., 1996, 1997; Gustafsson and Stal, 1998; Zhou et al., 2000), similar to what was found for samples with p53 mutations. One frequently unaddressed problem is proper controls. For example, CD34 positive AML cells may have prominent expression of MDM-2, but CD34 positive normal blast cells also might have high expression of MDM-2. Nevertheless, about 65% of transgenic mice overexpressing MDM-2 develop lymphomas (Jones et al., 1998).
A tumor suppressor gene acting upstream of p53 is the mutated in ataxia teleangiectasia (ATM) gene. Upon DNA damage, this kinase is activated and in turn activates several target proteins by phosphorylation, including p53 (Banin et al., 1998; Canman et al., 1998) and MDM-2 (Khosravi et al., 1999). It is homozygously mutated in ataxia teleangiectasia, a hereditary disease characterized by cerebellar ataxia, oculocutaneous teleangiectasia, immune deficiency, genomic instability and a predisposition to neoplasias including lymphoid malignancies (Gatti et al., 1991), especially T-ALL, T-prolymphocytic leukemia (T-PLL) and B-CLL (Taylor et al., 1996). ATM is located on chromosome 11q22-23, a locus which is frequently deleted in lymphoid malignancies (Stilgenbauer et al., 1996). Several groups have investigated the incidence of alterations of the ATM gene in sporadic tumors. In sporadic T-PLL, the ATM gene was mutated in the leukemic cells in about 45% of the cases (Vorechovsky et al., 1997; Stilgenbauer et al., 1997; Stoppa-Lyonnet et al., 1998), but no mutations were detected in childhood T-ALL (Takeuchi et al., 1998a). For B-CLL, 21% had a mutated ATM gene (Schaffner et al., 1999; Bullrich et al., 1999; Pettitt et al., 2001). Two of these mutations were of somatic origin and the remaining two were germline mutations, showing a carrier frequency of 5.5% (two out of 36) among all B-CLL samples tested. This is consistent with another study finding a heterozygous ATM germline mutation in two out of 32 B-CLL patients (6.3%) (Stankovic et al., 1999). Considering the frequency of being a carrier of a heterozygous ATM germline mutation in the Caucasian population is 0.2 to 1% (Bullrich et al., 1999), perhaps the heterozygous carrier of inactivating ATM mutations are predisposed to B-CLL. However, given the small numbers in these two studies, further investigations are required to address this question.
Analysis of the expression of ATM protein in B-CLL found an at least 50% decrease compared to normal lymphoid cells in 34% of the samples (Starostik et al., 1998). Those cases with decreased ATM expression had a significantly shorter survival time.
Assuming that alterations of the ATM gene disrupt the same pathway as alterations of p53, these alterations might be expected to be mutually exclusive. For example, a recent study (Pettitt et al., 2001) found that the p53 pathway was not functioning correctly in thirteen of 43 individuals with B-CLL, as assessed by the ability of their leukemic cells to upregulate expression of p21CIP1 upon irradiation. Six of these samples harbored p53 mutations and the remaining seven samples had mutations of the ATM gene.
Another lymphoid malignancy with alterations of the ATM gene is mantle cell lymphoma (MCL). LOH of the ATM gene was detected in almost 50% of the samples (Stilgenbauer et al., 1999). When further examining seven cases with and five cases without LOH, all seven samples with LOH had mutations of the remaining allele and two cases without LOH of the ATM locus displayed biallelic mutations of the ATM gene (Schaffner et al., 2000). Normal tissue was available in three cases and no ATM mutations was found in this tissue.
Two checkpoint kinases, Chk1 and Chk2, phosphorylate and stabilize p53 upon DNA damage (Shieh et al., 2000) (Figure 1). One allele of Chk2 is mutated in some cases of Li-Fraumeni Syndrome having a wild type p53. The individuals with this syndrome have an increased cancer predisposition usually associated with inherited p53 mutations (Bell et al., 1999). However, we found that Chk2 mutations were rare events in AML, MDS (Hofmann et al., 2001b) childhood ALL, ATL and Non-Hodgkin lymphomas (Tavor et al., 2001).
CREB binding protein (CBP) and its close relative p300 are coactivators of a large variety of transcription factors (Shikama et al., 1999). These two proteins act as cofactors for transcription through various mechanisms: First, they acetylate histones, which makes adjacent DNA accessible for transcription factors. Second, they alter function of transcription factors by acetylation. Third, they physically link different transcription factors together; and fourth, they recruit proteins from the basal transcription machinery (reviewed in Giles et al., 1998 and Blobel, 2000).
CBP was suggested to be a tumor suppressor due to the constellation of abnormalities found in individuals with the Rubinstein–Taybi-Syndrome (RTS), which is caused by monoallelic CBP (Petrij et al., 1995). This syndrome is characterized by craniofacial, skeletal, and cardiac defects, growth and mental retardation, and affected individuals have an increased rate of malignancies, including leukemias (Siraganian et al., 1989; Miller and Rubinstein, 1995).
In mice, a monoallelic inactivation of the CBP gene leads to a phenotype very similar to RTS with a low number of B-lymphocytes in their peripheral blood, a decreased bone marrow cellularity and presence of extramedullary hematopoiesis (Kung et al., 2000). At the age of >1 year, four of 18 mice developed histiocytomas or lymphocytic or myeloid leukemias. Additionally, three of 10 lethally irradiated wild type mice transplanted with bone marrow or spleen cells from older CBP+/− mice without malignancies, also developed histiocytomas and multiple myeloma. Further analysis revealed loss of the wild type CBP allele in the tumors of these mice. These murine models with the onset of leukemia after inactivation of CBP suggest that loss of CBP function contributes to leukemogenesis.
However, other data suggest that CBP can be involved in leukemogenesis through a gain of function instead of a loss of function. For example, rearrangements of the CBP locus occur in a large variety of translocations involving chromosome 16 which is where CBP is located. CBP is fused to the gene (monocytic leukemia zinc finger) MOZ in the t(8;16) translocation. This is associated with an AML M4 or M5 according to the FAB-classification characterized by prominent erythrophagocytosis of the blastic cells (Borrow et al., 1996). Another partner is the MLL (mixed lineage leukemia) gene caused by a t(11;16) translocation which is associated with either AML or MDS developing after previous therapy with topoisomerase II-inhibitors (Rowley et al., 1997). MORF (monocytic leukemia zinc finger protein-related factor) is also a partner of CBP in childhood AML M5 with t(10;16) (Panagopoulos et al., 2001).
Of note, most of the interaction domain of CBP remains intact in all three fusion proteins, suggesting that the function of the CBP part of these fusions is altered rather than inactivated. Also, lethally irradiated wild type mice transplanted with bone marrow progenitor cells overexpressing the MLL-CBP develop leukemia after a preleukemic phase, and in vitro transforming studies with deletional mutants of the fusion protein revealed that the histone acetyltransferase (HAT) domain and the Bromodomain of the CBP part of the fusion protein are indispensable for the transforming capacity (Lavau et al., 2000).
Also of interest, two of the identified fusion partners of CBP, MOZ and MORF, also possess HAT domains (Borrow et al., 1996; Champagne et al., 1999) and MLL may serve as a chromatin-binding protein through its SET domain (Redner et al., 1999). Possibly as a result of the fusion of CBP to other chromatin-remodelling proteins, the HAT-domain of CBP is localized to inappropriate DNA sites which might alter the expression of genes that provide these cells a growth advantage over the normal cells.
Overall, these results suggest that the mechanism of leukemogenesis by a rearrangement of CBP might be different from the mechanism of leukemogenesis in RTS-patients. In the case of translocations, the resulting CBP fusion protein might locate the HAT-activity to promoters of genes with either proliferative or antiapoptotic function; whereas in RTS-related malignancies, CBP might act as a ‘classic’ tumor suppressor. To verify this hypothesis, mutational and LOH analyses of the CBP locus in patients with RTS-related malignancies would be of great interest, as one would anticipate the inactivation of the wild type CBP locus in tumors according to the Knudson's ‘two hit’ model of tumor suppressors.
Neurofibromin, the protein encoded by the NF1 gene, is involved in the Ras pathway (O'Marcaigh and Shannon, 1997). Upon growth factor receptor signalling, small GTPases of the p21ras family (H-, K- and N-Ras) bind guanosine triphosphate (GTP), which results in activation of Ras and a proliferation signal for the cell. Inactivation of Ras is mediated by substituting GTP with guanosine diphosphate (GDP), a process mediated by Neurofibromin (O'Marcaigh and Shannon, 1997). The most common disruption of this pathway with a resulting high proliferative signal in human cancer is mutation of Ras, resulting in constitutively active, oncogenic Ras (reviewed in Adjei, 2001).
Another disruption of this pathway is by inactivation of Neurofibromin, resulting in a higher proportion of GTP-bound, active Ras. Monoallelic germline inactivation of NF1, the gene encoding Neurofibromin, leads to Neurofibromatosis von Recklinghausen, an autosomal-dominant genetic disease characterized by a pigment disorder, high incidence of benign neurofibromas and a reduced life expectancy due to a high incidence of malignancies (Rasmussen and Friedman, 2000). Hematological diseases associated with this syndrome include juvenile myelomonocytic leukemia (JMML) (Stiller et al., 1994), and probably ALL, NHL (Stiller et al., 1994) and MPD with monosomy 7 (Shannon et al., 1992). For example, two studies (Shannon et al., 1994; Side et al., 1997) found the loss of the wild type NF1 allele in the malignant cells of nine out of 18 patients with Neurofibromatosis and myeloid malignancies (five JMML, two CML, one AML and one MPD with monosomy 7). Strikingly, mice heterozygous for a targeted disruption of the NF1 gene do not resemble the human phenotype with regard to either pigment disorders or neurofibromas, but they are susceptible to malignancies (Jacks et al., 1994), consistent with a tumor suppressor function of NF1. In the study, seven out of 62 heterozygous mice developed myeloid leukemias. The malignant cells in all of the leukemias lost their wild type NF1 allele.
In 295 samples of sporadic AML and MDS, only one NF1 mutation was detected in a case of chronic myelomonocytic leukemia (CMML) (Ludwig et al., 1993; Quesnel et al., 1994; Kaneko et al., 1995; Lee et al., 1995; Misawa et al., 1997). Thus, mutations of NF1 do not seem to play a significant role in sporadic AML or MDS not associated with Neurofibromatosis.
The core binding factor (CBF), or polyomavirus enhancer binding protein 2 (PEBP2), is a transcription factor consisting of two subunits. A DNA-binding alpha subunit of the runt domain family (CBFα1/PEBP2A/AML3/Runt related transcription factor 2 (RUNX2)/osteoblast specific factor 2 (OSF2), CBFα2/AML1/RUNX1 and CBFα3/AML2/RUNX3) heterodimerizes with the non-DNA-binding beta subunit (CBFβ/PEBP2B). Translocations involving the genes coding for the subunits AML1 and CBFβ are among the most frequent alterations associated with acute leukemias. For example, the t(8;21) translocation results in an AML1-ETO fusion protein; the inversion 16 causes a CBFβ-MYH11 fusion protein and the t(3;21) results in AML1-EV11, AML1-MDS1 or AML1-EAP fusions. Any of these changes can be found in up to 20% of all AML samples (Nucifora and Rowley, 1995), whereas a translocation t(12;21) resulting in the AML1-ETV6 chimeric protein occurs in approximately 20% of childhood ALL, especially B-ALL (Romana et al., 1995; Shurtleff et al., 1995; Liang et al., 1996; McLean et al., 1996; Cave et al., 1997). AML1 and CBFβ both are critical for hematopoiesis. Mice with homozygous targeted disruption of either of them lack hematopoiesis and die in utero around day 12 of embryogenesis (Okuda et al., 1996; Wang et al., 1996a,b; Niki et al., 1997). Mice with a transgenic overexpression of either the CBFβ-MYH11 or the AML1-ETO fusion protein manifested a phenotype very similar to the AML1- or CBFβ-knockout mice (Castilla et al., 1996; Okuda et al., 1998), suggesting a dominant-negative effect of both of these fusion proteins.
Further support for the hypothesis that loss of AML1 is associated with leukemogenesis comes from recent findings that a monoallelic loss of AML1 due to a nonsense mutation or intragenic deletion resulted in an inherited familial platelet disorder with the predisposition to AML (FPD/AML) (Song et al., 1999). This disease is inherited in an autosomal dominant fashion; patients with FPD/AML retain one wild type AML1 allele, suggesting that haploinsufficiency of the AML1 locus is sufficient to cause the disease. When this disease progresses to AML, additional genetic changes occur which are not necessarily associated with the normal AML1 allele. Interestingly, another family with autosomal dominant inherited AML has been observed which was linked to an LOH at chromosome 16q22, the locus of CBFβ (Horwitz et al., 1997). Possibly, haploinsufficiency of CBFβ might play a causative role in this syndrome.
In addition to the described germline mutations, somatic mutations in the AML1 gene have been detected in around 5% of sporadic myeloid leukemia samples, with a high incidence occurring in those which are M0 subtype or myeloid malignancies with an acquired trisomy 21 (Osato et al., 1999; Preudhomme et al., 2000), and in a small subset of MDS and pediatric ALL samples (Song et al., 1999; Imai et al., 2000). As opposed to the FPD/AML syndrome, most mutations effected both alleles in the M0 subtype of AML. This suggests that haploinsufficiency of AML1 alone is not sufficient to be leukemogenic, but that other secondary events are necessary to cause the malignant phenotype.
CCAAT enhancer binding protein alpha (C/EBPα) is a member of the C/EBP family of transcription factors. It is involved in liver function (Rana et al., 1994) and the differentiation of various tissues, i.e. adipocyte tissue (Lane et al., 1996) and keratinocytes (Maytin and Habener, 1998). C/EBPα is also essential for myelopoiesis; mice lacking C/EBPα have a block in granulocytic differentiation at the myeloblast stage (Zhang et al., 1997). Myeloid-specific genes like granulocyte colony-stimulating factor receptor have been shown to be regulated by C/EBPα (Zhang et al., 1998). In addition to acting as a transcription factor, C/EBPα may also be involved in cell cycle control: C/EBPα binds to and stabilizes p21CIP, interacts with CDK2 and represses transcription of E2F (Timchenko et al., 1996, 1997; Harris et al., 2001; Porse et al., 2001). Recently, our group (Gombart et al., 2002) and others (Pabst et al., 2001) found mutations of C/EBPα in about 8% of AML and 2% of MDS samples. Evidence for a causative role of this mutations comes from observations with KCL-22, a Philadelphia chromosome positive myeloid blast crisis cell line with mutations of C/EBPα and no normal allele. Ectopic expression of C/EBPα in these cells results in their dramatic granulocytic differentiation within 3 days (Tavor et al., manuscript submitted).
The Wilms' Tumor gene (WT-1) encodes several isoforms of protein having four zinc finger domains. It acts as a transcriptional repressor of genes that enhance proliferation, i.e. early growth response (Madden et al., 1991), granulocyte colony-stimulating factor (Harrington et al., 1993), insulin-like growth factor II (Drummond et al., 1992), insulin-like growth factor I receptor (Werner et al., 1993), platelet-derived growth factor A chain (Gashler et al., 1992; Wang et al., 1992), transforming growth factor β-1 (Dey et al., 1994), bcl-2 and c-myc (Hewitt et al., 1995). In addition, it can also enhance transcription of growth inhibitory genes, i.e. p21CIP (Englert et al., 1997), retinoblastoma suppressor (Rb)-associated protein 46 (Guan et al., 1998), Syndecan-1 (Cook et al., 1996) and amphiregulin (Lee et al., 1999). WT-1 has two main isoforms, the +KTS form with a stretch of three amino acids, Lys-Thr-Ser, inserted between the third and fourth zinc finger, while the −KTS form does not have this insertion (Davies et al., 1999). The −KTS form associates with transcription factors and presumably regulates transcription. The +KTS form, on the other hand, colocalizes with splicing proteins and therefore might be involved in the splicing process (Davies et al., 1999).
WT-1 behaving as a tumor suppressor was first suggested from the analysis of Wilms' tumors, malignant nephroblastomas occurring during infancy, arising from individuals with the WAGR syndrome. This is an autosomal recessive syndrome associated with the occurrence of Wilms tumors (30% of all patients), aniridia, abnormalities of the genito-urinary tract and mental retardation. This syndrome has a hemizygous germline deletion of 11q13 including the WT-1 locus. Some of the Wilms' tumors arising in these individuals have inactivation of the remaining WT-1 allele, consistent with the ‘two hit’ hypothesis (Gessler et al., 1990, 1993; Pelletier et al., 1991; Brown et al., 1992; Baird et al., 1992; Gessler et al., 1993; Santos et al., 1993). On the other hand, the Denys–Drash syndrome is characterized by a higher incidence of Wilms' tumors (>90%), intersexual disorders, and nephropathy. Wilms' tumors arising in this syndrome retain their wild type allele (reviewed in Coppes et al., 1994). Therefore, the WT-1 mutations associated with this syndrome behave in a dominant negative fashion, inactivating the function of the remaining wild type allele. In sporadic Wilms' tumors, the frequency of inactivations of the WT-1 gene is around 10%, and these tumors have either homozygous or dominant negative hemizygous mutations (Little et al., 1999).
The first hint of involvement of WT-1 in leukemogenesis resulted from a patient with the WAGR syndrome who developed AML as a secondary malignancy after therapy for a Wilms' tumor. The leukemic cells of this patient showed a mutation in both alleles of WT-1 (Pritchard-Jones et al., 1994). However, the role of WT-1 in leukemogenesis is far from clear; sometimes it appears to behave as a tumor suppressor gene and at other times as an oncogene.
The role of WT-1 as a tumor suppressor in leukemia is supported by several studies: HL-60 (WT-1 expressing AML cell line), U937 (AML cell line lacking endogenous WT-1 expression) and M1 (murine AML cell line) had arrest of growth and underwent differentiation and/or apoptosis (Murata et al., 1997), when transfected with the −KTS, but not with the +KTS isoform of WT-1 (Ellisen et al., 2001). In contrast, a +KTS, but not a −KTS isoform of WT-1, induced macrophage differentiation of M1 in another study (Smith et al., 1998), and overexpression of +KTS WT-1 reduced the tumorigenicity of these cells in SCID mice (Smith et al., 2000). Mutations of the WT-1 gene has been detected in 10% of de novo AML (Pritchard-Jones et al., 1994; Algar et al., 1997; Carapeti et al., 1997; King-Underwood and Pritchard-Jones, 1998; Miyagawa et al., 1999) and in two of 10 acute undifferentiated leukemias (AUL) (King-Underwood et al., 1998). Mutations were very infrequent in MDS or AML secondary to MDS (Hosoya et al., 1998; Miyagawa et al., 1999; Mori et al., 1999), ALL (Algar et al., 1997; Carapeti et al., 1997; King-Underwood et al., 1998) or blast crisis of CML (Carapeti et al., 1997). In most cases, these mutations were hemizygous, and some were identical or similar to those existing in the Denys–Drash syndrome (Mori et al., 1999) or in sporadic Wilms' tumors with hemizygous inactivations of the WT-1 gene (King-Underwood et al., 1996; Carapeti et al., 1997), suggesting a dominant-negative effect of this mutations.
In contradistinction, another series of studies suggest that WT-1 is associated with proliferation of normal and leukemic progenitor cells: WT-1 expression was detected in the very immature CD34+ CD38− myeloid progenitors, but not in CD34−, more mature myeloid cells (Baird and Simmons, 1997). Both HL-60 cells (Sekiya et al., 1994) and normal CD34+ cells (Maurer et al., 1997) decrease their expression of WT-1 during granulocytic differentiation. Furthermore, overexpression of WT-1 retarded induction of differentiation of the HL-60 (Deuel et al., 1999) and U937 (Svedberg et al., 1998) AML cell lines and 32D cl3, a murine myeloblast cell line (Inoue et al., 1998). Also, high levels of WT-1 were detected in 68% of 600 AML and ALL samples (Miwa et al., 1992; Miyagi et al., 1993; Patmasiriwat et al., 1996; Schmid et al., 1997; Bergmann et al., 1997; Inoue et al., 1997; Im et al., 1999; Gaiger et al., 1999; Niegemann et al., 1999) and approximately 60% of MDS samples which were associated with advanced stages of the disease (Patmasiriwat et al., 1999; Tamaki et al., 1999).
In summary, WT-1 is mutated in less than 10% of leukemia samples. It is robustly expressed in normal myeloid progenitor cells. The fall scope of WT-1 activities requires further study.
Conclusions and future directions
Over the last decade, the study of tumor suppressor genes has grown enormously. This review only focuses on selected genes. Many other genes deserve to be mentioned. For example, the methylthioadenosine phosphorylase (MTAP) locus is located near the p16INK4A, p15INK4B and p14ARF cluster of genes on 9q21, and it is on occasions encompassed in the chromosomal deletion that inactivates these INK4 family proteins in the lymphoid and myeloid malignancies mentioned earlier (Nobori et al., 1996; Batova et al., 1996, 1999; Dreyling et al., 1998; Batova et al., 1999). The inactivation of the inhibitor of kappa B alpha gene (IκBα) may be important in Hodgkin's disease (Emmerich et al., 1999; Jungnickel et al., 2000). Decreased expression of the deleted in colorectal cancer (DCC) gene may have a role in AML, ALL, CML or NHL (Miyake et al., 1993; Younes et al., 1995; Inokuchi et al., 1996). The DNA mismatch repair gene MSH2 may have importance in AML (Zhu et al., 1999). Inactivations of PTEN have been observed in a small subset of cutaneous T-cell lymphomas (Scarisbrick et al., 2000) and other NHL (Nakahara et al., 1998). Disruption of the TGFβ signalling pathway by mutations of the SMA- and MAD-related protein 4 (SMAD4) can be found in AML (Imai et al., 2001). Apoptotic pathways may be disrupted by mutations of CD95 (Fas/APO-1) in NHL (Xerri et al., 1995; Gronbaek et al., 1998; Straus et al., 2001; Seeberger et al., 2001), T-ALL (Beltinger et al., 1998) and multiple myeloma (Landowski et al., 1997) or by mutations of B-cell leukemia 2 associated X protein (BAX) in various leukemia and lymphoma cell lines (Meijerink et al., 1998; Inoue et al., 2000). Also, genes of the checkpoint of the G2 to M transition of the cell cycle might play a role in malignant transformation, as mutations of mitotic checkpoint genes budding uninhibited by benzimidazoles 1 (BUB1) and BUB related 1 (BUBR1) in ATL and B-NHL (Ohshima et al., 2000) and of mitotic arrested-deficient 1 yeast homologue-like 1 (MAD1L1) in a single case of B-NHL (Tsukasaki et al., 2001) might suggest.
Frequent LOH for many other loci has been identified for a variety of hematological malignancies, indicating that many other tumor suppressor genes are yet to be discovered. A summary of recurrent LOH in hematological diseases harboring putative tumor suppressor genes is provided in Table 3. The continuous development of more powerful molecular biology techniques should allow us to identify and study them.
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U Krug thanks Catrin Sperveslage for continuous support. U Krug is a recipient of a grant of the Lymphoma Research Foundation of America, Inc. HP Koeffler holds the Mark Goodson endowed Chair of Oncology Research. This work was supported in part by NIH, Parker Hughes Trust, C and H Koeffler Fund, Ko-So Foundational, Joseph Troy trust and the Horn Fund.
For a review of this complexity, excellent contributions to the field could not be discussed because of space limitations.
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