Williams Hematology




Cyclins and Cyclin-Dependent Kinases

Substrates and Inhibitors of Cyclin-Dependent Kinases
Tumor Suppressor Genes
Chapter References

Complex feedback pathways regulate the passage of cells through the G1, S, G2, and M phases of the growth cycle. Two key checkpoints control the commitment of cells to replicate DNA synthesis and to mitosis. Many oncogenes and tumor suppressor genes promote malignant change by stimulating cell cycle entry, or disrupting the checkpoint response to DNA damage. This chapter presents the pathways that regulate cell replication and tabulates the various oncogenes that have been shown to be involved in hematologic and some other malignancies.

Acronyms and abbreviations that appear in this chapter include: CDI, cyclin-dependent kinase inhibitors; CDK, cyclin-dependent kinases; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic leukemia; HIV, human immunodeficiency virus 1; MPF, M-phase promoting factor; RAR-a, retinoic acid receptor-a; rb, retinoblastoma; rPTK, receptor protein-tyrosine kinases; SPF, S-phase promoting factor; TAR, transactivation response element.

Cell mitosis is the final step of a defined program—the cell cycle—which can be separated into four phases: the G1-, S-, G2-, and M phases (Fig. 12-1). A number of surveillance systems (checkpoints) control the cell cycle and interrupt its progression when DNA damage occurs or when the cells have failed to complete a necessary event.1 These checkpoints have been given an empirical definition: When the occurrence of an event B is dependent on the completion of a prior event A, the dependence is due to a checkpoint if a loss-of-function mutation can be found that relieves the dependence.1 Three major cell cycle checkpoints have been discovered: the DNA damage checkpoint, the spindle checkpoint, and the spindle pole body duplication checkpoint.2,3 and 4

FIGURE 12-1 Cell cycle regulation in mammalian cells.

The functional consequence of cell cycle checkpoint failure is usually death by apoptosis. However, small numbers of genetically altered cells may survive. Cells with defective checkpoints have an advantage when selection favors multiple genetic changes. Cancer cells are often missing one or more checkpoints, which facilitates a greater rate of genomic evolution.5
Most of the basic principles of cell cycle regulation were worked out in yeast, but the underlying principles are equally applicable to the mammalian cell cycle. One must understand basic cell cycle regulation in order to understand the mechanisms that lead to hematological malignancies and the importance of tumor suppressor genes and oncogenes.


Early experiments on the control of mitosis in human cells provided evidence for the existence of factors called M-phase and S-phase promoting factors (MPF, SPF).6 The key element of SPF was thought to be cdc2. Experiments performed in Xenopus eggs showed that cdc2 is an M-phase-specific histone H1 kinase7 but is just one subunit of a regulatory complex. A second component is cyclin B, which is synthesized in interphase and degraded in mitosis. At least eight members of the mammalian cyclin family have been cloned to date (cyclins A-H). These cyclins all interact with a group of cdc2-related kinases called cyclin-dependent kinases (cdk).8,9 The cyclin/cdk complex is the mammalian counterpart of the cdc2/cdc13 complex in yeast. Phosphorylation of tyrosine 15 is the key event in regulating human cdc2 activity. Threonine 14 also is phosphorylated in G2 phase. Both phosphorylation sites are required for mitotic initiation. Cdc2 interacts with cyclin B in mitosis, whereas the cdc2/cyclin A complex is formed before mitosis and probably is required for progression through late G2 phase10 Thus, cyclins A and B are also called the mitotic cyclins, since they are upregulated in late G2 or G2/M and undergo proteolysis in M phase.
The exit from mitosis is characterized by the abrupt ubiquitination and subsequent degradation of cyclin B. Cells with a defective cyclin B degradation mechanism or without mitotic cyclin B easily become aneuploid. The exact role of the other mitotic cyclin, cyclin A, is still unclear. There is evidence that it both acts at the G2/M transition and binds cdk2 in S phase. Overexpression of cyclin A in G1 phase leads to an accelerated entry into S phase.11 Since cdc2 is able to interact with mitotic and G1 cyclins, it seems likely that one protein kinase potentially can fulfill several different functions in the cell cycle at various checkpoints. The redundancy of cyclin functions makes it difficult to ascertain the exact function of each protein in all cell types.
There are several cdc2-related protein kinases in humans that interact with the corresponding cyclins. Originally, three cdc2-related proteins were isolated which were able to replace deficient cdc28 function in budding yeast: cdk1, cdk2, and cdk3.12,13,14 and 15 Another group of cdks that bind to cyclin D (a G1 cyclin) have been named cdk4,16 cdk5,17 and cdk6.18 Cdk4 has been in the focus of tumor suppressor gene reseach for the last several years, since it complexes with cyclin D1. This complex is an important element in the p16INK4A-retinoblastoma (rb) gene pathway, which is commonly disrupted in cancer (see below). Three other cyclin-dependent kinases have been partially characterized: cdk7 (p40MO15) interacts with cyclin H and is responsible for phosphorylating pcdc2 on threonine 161.19,20 and 21 Cdk8 interacts with cyclin C and is associated with RNA polymerase II.22,23 and 24 Cdk9 binds cyclin T1 and displays a tissue-specific expression pattern.25,26 and 27 The fact that cdk9/cyclin T1 specifically interacts with the tat element of the human immunodeficiency virus 1 (HIV-1) links this cyclin-dependent kinase directly to the replication pathway of HIV, and circumstantially to HIV-1 related malignancies (e.g., Kaposi sarcoma).28,29 and 30
All cyclins share an approximately 150 amino acid region, called the cyclin box, which interacts with the cdks.31 The G1 cyclins (C, D, and E) and the mitotic cyclins (A and B)32 form distinct categories, although cyclin H and the type T cyclins (T1, T2a, and T2b) fall outside these two major groups.
Cyclin A binds and activates cdk2 mainly in S phase. However, microinjection of anticyclin A antibodies into cells causes cell cycle arrest just before S phase.10 The integration of the hepatitis B virus into the cellular genome is accompanied by the formation of a chimeric cyclin A, lacking the cyclin destruction box, and with a prolonged half-life.33 This observation, together with the finding that overexpression of cyclin A leads to accelerated S-phase entry, suggests that cyclin A is involved in transformation.11 The other cyclin that interacts with cdk2, cyclin E, may control the progression from G1 to S phase, but the exact timepoint when cdk2 “switches” from cyclin E to cyclin A binding is unknown. Cdk2/cyclin E activity peaks during late G1 phase, and declines in early S phase.34 Cells overexpressing cyclin E progress much faster through G1 into S phase, but the time required for DNA synthesis remains normal.35 Cyclin E levels also are regulated by environmental factors, including TGF-b and irradiation. These effects are, in part, mediated by small proteins, the cyclin-dependent kinase inhibitors (CDI). In addition to its role at the G1/S boundary, cyclin A acts in late G2 phase, where it complexes with cdk1. It has been suggested that this interaction might be necessary for the reorganization of the cytoskeleton prior to mitosis.36
The B-type cyclins associate with cdk1 and cdk2 to form the classical mitotic cyclin/cdk complexes.37 Cyclin B is synthesized in S phase and accumulates together with cdk2. Ubiquitin mediates the degradation of cyclin B, allowing the cell to exit from mitosis. The cyclin B/cdk2 checkpoint is very often defective in malignant cells, leading to uncontrolled M-phase entry and aneuploidy. The cellular localization of the cdk1-cyclin B complexes also is strictly cell-cycle–dependent. Although the complexes accumulate in the cytoplasm during G2 and S phase, they move to the nucleus in mitosis and bind to the mitotic spindle.38,39,40 and 41
The three different cyclin D molecules (D1, D2, and D3) function mainly in late G1 phase, where they bind cdk4 and cdk6. These complexes phosphorylate rb, restraining its inhibitory effects on E2F, and related transcription factors. Cyclin D1 is the major D cyclin in most cell types. All three cyclin D molecules act in late G phase, just before entry into S phase. Forced overexpression of cyclin D1 shortens the G1 phase. Many tumors have high cyclin D1 levels without amplification or mutation of the cyclin D1 structural gene. Instead, cycle D levels may be regulated by a feedback loop dependent on rb. Alterations of the retinoblastoma gene in cancer may secondarily cause upregulation of cyclin D transcription.
The most recently identified member of the cdk-family, cdk9, partners with cyclin T, an 87-kDa cyclin C type protein with three subunits.25 The cdk9/cyclin T complex is an essential component of the P-TEFb human transcription elongation factor.26 P-TEFb can hyperphosphorylate the C-terminal domain of RNA polymerase II, similar to the cyclin H/cdk7/MAT1 complex.28 In addition, P-TEFb forms a complex with the HIV tat protein that binds the transactivation response element (TAR). The modification of RNA polymerase II by cdk9/cyclin T facilitates the efficient multiplication of the viral genome.42,43 The fact that the cyclin T1/cdk9 complex is upregulated during T-cell activation enables the HIV to utilize this complex for replication.44 Another binding partner of cdk9 is a tumor necrosis factor signal transducer molecule, TRAF2.45
Many cyclin-cdk substrates have been identified by immunoprecipitation or two-hybrid assays, but only a few of them are thought to exert a direct function in cell cycle control. In G1 phase, the most important substrate of the cdk4-cyclin D and cdk6-cyclin D complexes is rb (Fig. 12-2). In its hypophosphorylated state, rb binds to and inhibits a class of transcription factors, of which the best characterized is the E2F transcription factor. Hyperphosphorylation causes rb to detach from its binding site, permitting transcriptional activation of genes necessary for DNA synthesis and cell division. This phosphorylation of rb is regulated in a cell-cycle–dependent manner.46,47 and 48 Interference with rb function impairs G1 checkpoint regulation, fosters unrestrained cell growth, and is a nearly universal characteristic of malignancy. Causes of reduced rb activity include changes in the structural gene, the sequestration and inactivation of the protein by viral oncogene products, and hyperphosphorylation of rb due to increased cdk4 and cyclin D activity or to deletion of the gene for the p16INK4A inhibitor of cdk4. Deletions, mutations, and translocations of rb are common in various malignancies, while homozygous deletions of the p16INK4A gene are even more frequent. Many different transforming viruses, such as papilloma virus and simian virus 40, produce proteins that interact with rb. Both cyclin D1/cdk4 and cyclin D1(D2, D3)/cdk6 complexes are able to phosphorylate the rb.49,50 The timepoint of rb-phosphorylation correlates strongly with the appearance of the cyclin D1/cdk4 complex. The link between rb and cyclin D is supported by the observation that loss of rb function leads to a decrease in the cellular cyclin D level.51,52 However, cyclin D may not be the only cyclin that is involved in the rb regulatory pathway.53,54 Ectopic expression of both cyclin A and cyclin E restores rb hyperphosphorylation and causes cell cycle arrest in cancer cell lines. Perhaps the cdk2-cyclin A complex contributes to additional phosphorylation of rb, whereas cdk2/cyclin E prolongs the phosphorylation time.53

FIGURE 12-2 Interactions between cyclin-dependent kinase inhibitors (p16, p14, p21), p53, and the retinoblastoma protein (rb).

Two rb-related proteins, p107 and p130, also form complexes with the transcription factor E2F,52,55,56 bind to the region of the adenovirus E1A protein required for transformation, and are able to induce G1 arrest when they are overexpressed in human malignant cell lines.57,58 and 59 Unlike the rb, the p107 and p130 proteins contain a so-called spacer region that interacts with cdk2/cyclin A and cdk2/cyclin E,60,61 although it seems to be unlikely that these two complexes regulate the activity of p107 and p130.53 Instead, p107 may bind and inactivate the cyclin A and cyclin E complexes. Thus, p107 may regulate the cell cycle by several different mechanisms. Since both p107 and p130 are regulated through phosphorylation, efficient cell cycle entry is accompanied by phosphorylation of all the rb-related proteins.
The cyclin-dependent kinases themselves are also controlled by several different mechanisms. Besides their regulation by phosphorylation, specific protein inhibitors of enzyme activity have been identified.62,63 The cyclin-dependent kinase inhibitors cause cells to arrest in G1 phase, followed by differentiation and/or senescence. The first cyclin-dependent kinase inhibitor identified was p21cip1.64 It binds to several cyclin/cdk complexes including cyclin A/cdk2, cyclin D/cdk4, and cyclin E/cdk2 (Fig. 12-2).46,47 and 48,65,66 and 67 Several different cell cycle regulatory pathways involve p21cip1. This molecule has a p53 binding site in its promoter, and an increase in p53 levels results in transcriptional activation of p21cip1, slowing down cell-cycle progression. The p21cip1 cyclin-dependent kinase inhibitor also plays a role in cellular differentiation in myoblasts.68 Other members of the p21cip1 family of cyclin-dependent kinase inhibitors include p27kip1 and p57kip2.49,50 High-level expression of p27kip2 leads to a cell cycle block in G1 phase after treatment of cells with TGF-b. One major difference between p21cip1 and p27kip1 is that the former binds predominantly to cdk2 whereas the latter binds cdk4.
The second group of cyclin-dependent kinase inhibitors belong to the inhibitor of kinase 4 (INK4) family and include p15INK4B, p16INK4A, p18, and p19.51,52,53,54,55 and 56 They all bind and inhibit the cyclin D1/cdk4 and/or cyclin D1/cdk6 complex, which regulates cell-cycle progression via the rb.51,54,55 TGF-b also is a potent inducer of p15INK4B.55 p16INK4A is probably the most important cyclin-dependent kinase inhibitor, since the p16INK4A gene is inactivated by several mechanisms in many different human cancers (see below).
Cyclin concentrations are regulated by ubiquitination and subsequent proteolysis. The formation of ubiquitin/protein complexes requires a ubiquitin-activating enzyme, a ubiquitin-conjugating enzyme, and a so-called specificity factor, which permits substrate recognition. Polyubiquitinated proteins are degraded by the 26S proteasome complex. There are two major ubiquitination systems in the cell, designated SCF and APC.57,58,59 and 60 SCF is named for three of its core components, Skp1, Cdc53, and an F-box containing protein. Important examples of SCF substrates are: Cln1, Sic1, Wee1 Cdc6/Cdc18, E2F, cyclin D1, cyclin E, p21cip1, p27kip1, and p57kip2.61 The APC complex regulates sister chromosome separation as well as exit from telophase into G1. APC substrates include cyclins A and B, Cdc20, Cdc5, Pds1, and Ase, a spindle protein.69 The exact mechanisms that precisely time substrate destruction are not fully understood. However, ubiquitination of distinct cell cycle proteins clearly plays an important role in cell-cycle regulation.


The complicated cell-cycle network has its parallel in the several different oncogenes and tumor suppressor genes that influence carcinogenesis and tumor progression. The products of oncogenes, the onco-proteins, lead to or faciltitate the transformation of a normal into a malignant cell. Oncogenes can be carried into the cell by viruses or they can arise from mutations in normal cellular genes. Oncoproteins can interact directly with cell-cycle regulatory proteins or control their activity by phosphorylation and dephosphorylation. Not all mutations in oncogenes lead to an altered function of the resulting product. The nomenclature in the oncogene tumor suppressor gene field is not always clear. As a general guideline, if a mutation causes a functional loss of the gene product, and the recessive loss of function leads directly to uncontrolled cell division, the underlying gene can be named a tumor suppressor gene. On the other hand, if the mutation leads to an altered gene product that interacts abnormally with other proteins to influence the cell cycle, this gene is an oncogene, acting in a dominant fashion. Mutations are found in both oncogenes and tumor suppressor genes. Translocations are typical of oncogenes, whereas homozygous deletions and hypermethylation of CpG-nucleotide repeats are characteristic features of tumor suppressor genes.
Probably more than 100 oncogenes and oncogene candidates have been described in the literature. The number of tumor suppressor genes is not much smaller. They are both involved in the pathogenesis and development of all kinds of tumors, especially the hematologic malignancies.
Mutant-activated receptor protein-tyrosine kinases (rPTK) comprise a family of very well characterized oncogenes. The constitutive activation of rPTK usually is achieved by mutations that lead to the dimerization and activation of their cytoplasmic cytalytic domains.70 Prominent examples include Neu/ERbB and CSF-1 oncogenes. NeuERbB2 is frequently mutated in breast cancer as well as in brain tumors.71,72 and 73 Another possible cause of rPTK dimerization is chromosomal translocations that create chimeric proteins. In the t(2;5) translocation, found in several anaplastic large cell lymphomas, N-terminal nucleophosmin sequences on the long arm of chromosome 5 are fused to the cytoplasmic domain of the Alk protein on chromosome 2.74,75 The characteristic translocation of chronic myelomonocytic leukemia (CMML), t(5;12), fuses sequences from the transcription factor Tel to the cytoplasmic domain of the platelet-derived growth factor-b receptor (PDGF-a rPTK), resulting in the formation of a Tel/PDGFbR fusion protein and the constitutive activation of the PTK.76 The chromosomal area surrounding the Tel gene is a fragile site, since the Tel gene is involved in several other translocations in human acute leukemias [e.g., t(12;9)]. The t(9;21) translocation, also called the Philadelphia chromosome, is a characteristic feature of chronic myelogenous leukemia (CML) and, less frequently, of other chronic myeloproliferative syndromes. It fuses the c-abl and bcl-2 oncogenes. Amplification of the fusion sequence is frequently used to detect minimal residual disease in patients under therapy with interferon-a and after bone marrow- or stem cell transplantation.77,78 and 79 Other oncogenes that belong to this family are Ret (mutations in Ret cause multiple endocrine neoplasia type 2A and type 2B)80, and c-Cbl, the homolog of the C. elegans gene Sli1.81
For several years, oncogene research focused on growth factor receptors because of the possibilities for therapeutic intervention. For example, the murine myeloproliferative leukemia virus protein (v-Mpl) is actually a mutant form of the human thrombopoietin receptor (c-Mpl). V-Mpl has part of the viral Env protein fused to the C-terminal end of c-Mpl and is activated through dimerization. This blocks normal differentiation and leads to uncontrolled cell growth. It has been suggested that one of the TGF-b receptors also is involved in oncogenesis, since mutations have been found frequently in colon cancer. TGF-b receptor signalling acts through the Smad family of transcription factors.
Two very important oncogene families encode the ras and rho family proteins. Ras itself is a G-protein, and activating mutations in H-Ras, K-Ras, and N-Ras have been found in nearly all kinds of human cancers. Several different Ras mutations are able to transform normal cells in tissue culture.82,83,84 and 85 Mutations in many different Ras family members have been identified in cancer (e.g., Raf1, p110 PI3 kinase, Rin1, Mekk1), but the exact downstream signalling effects of each mutation are still unclear. The Ras and the Rho family of oncoproteins are linked by a small G-protein called Rac, which is required for transformation by Ras.86,87 and 88 The Rho family of small G-proteins also regulates actin stress fiber formation.89 The regular formation of actin filaments is required for G1/S-phase entry. Thus, alterations in the Rho pathway may lead to premature entry into S phase by interference with cytoskeletal organization. The NF2 tumor suppressor gene also encodes a cytoskeletal protein.90 The two oncogenes BRCA1 and BRCA2 are frequently mutated in affected families with breast cancer.91,92 and 93 Their oncogenic activity might be associated with the transactivating property of the C-terminal ends of the genes, since mutations in this area inactivate this activity.94
Mitogen-activated protease kinases are potential downstream effectors of the Ras pathway.95,96 The three different MAP kinase cascades are the ERK-, JNK/SAPK-, and the p38 pathways. The MAP kinase pathways consist of three types of kinases in a series, MAPK, MAPKK, and MAPKKK. The MAP kinase cascades all transmit responses from several different surface receptors to the nucleus.97 Activation of the Ras-ERK pathway causes cyclin D overexpression and therefore promotes G1-phase progression.98
Several oncogene proteins are localized in the nucleus and include transcription factors and chromatin regulatory proteins. A characteristic feature of acute promyelocytic leukemia (APL) is a t(15;17) translocation that fuses the Pml protein to the retinoic acid receptor-a (RAR-a). The chimeric protein disrupts a nuclear structure called PODS in a retinoic acid reversible fashion.99,100 The detection and molecular characterization of the t(15;17) translocation, together with the development of retinoic acid therapy, was a direct result of oncogene research.101,102 and 103 A variant of this chromosomal translocation results in a fusion protein between RAR-a and the promyelocytic leukemia Kruppel-like zink finger (PLZF) protein, which is observed in a subset of patients with APL.104
Recent experiments on oncoproteins have focused on apoptosis, the lethal response of a cell to either DNA damage or to signaling through cell surface “death” receptors. Key regulators of apoptosis induced by DNA damage are the multiple members of the bcl family of proteins, which include bcl, bcl-XL, bax, and bad. Bcl-2 is involved in the t(14;18) chromosomal translocation, which is found in many leukemias and lymphomas of B-cell origin.105,106 and 107 The disruption of these loci increases expression of bcl, and results in the uncontrolled accumulation of malignant B cells, due to an impaired balance between growth and apoptosis.108,109 and 110 Apoptosis also is controlled by certain tumor suppressor genes, such as p53, that influence the cellular response to DNA damage. The nuclear histone deacetylase complex, which regulates the structural conformation of DNA and therefore the activation of several genes, is targeted by Eto, the fusion partner of the acute myelogenous leukemia AML1 gene. The t(8;21) translocation that occurs in acute myelogenous leukemia allows the formation of a stable complex between the histone deacetylase complex and Eto, with resultant leukemogenesis.111,112 and 113 Other ongogenes that target the histone deacetylase complex are PLZF, PLZF-RAR-a, and BCL-6.114,115 and 116 This implies that specific histone deacetylase inhibitors might be useful drugs in the treatment of myeloid leukemias. Recent reports provide evidence for this hypothesis (see below) and underline the important role of epigenetic phenomena in hematologic malignancies.


Almost every cancer harbors one or more abnormalities of tumor suppressor genes. These include mutations, translocations, and deletions. In addition, at least two epigenetic mechanisms, the hypermethylation of CpG islands in the promoter and the abberant acetylation of histones (especially histone H4), can silence tumor suppressor genes in a variety of human cancer cell lines and primary tumors.
It is remarkable that the products of the three most important tumor suppressor genes (rb, p53, and p16INK4A) are interconnected biochemically. The retinoblastoma gene maps to chromosome 13q14 and has several downstream effectors, among which the transcription factor E2F is the best characterized.117 The retinoblastoma gene family consists of three closely related proteins, rb, p107, and p130. All three proteins are able to interact with several E2F family members. Transcriptional activation and repression are mediated via complexes consisting of rb family members, E2F family members, and so-called DP proteins.118 Besides its role in cell cycle control, rb can modulate RNA polymerase activity, thus linking cell-cycle progression to transcriptional regulation. More than 30 separate cellular proteins have been identified that bind to rb. These proteins can be divided into different groups, including transcription factors, growth factors, protein kinases, protein phosphatases and nuclear matrix proteins. Mutations of rb are frequent in leukemias, soft tissue sarcomas, breast, esophagus, prostate, and renal carcinomas.119 Several viral or oncoproteins can bind to and inactivate rb.120
The p53 gene has been called a “guardian” of the genome because it transmits signals arising from various forms of DNA damage, leading to cell cycle arrest or apoptosis. The major regulator of p53 expression is MDM2. The MDM2 protein inhibits p53 transcription and stimulates p53 degradation.121,122 The MDM2 binding region includes several phosphorylation sites, although the exact mechanism by which MDM2 regulates p53 degradation is still not clear.121,122,123 and 124 The recently discovered p14ARF tumor suppressor gene, which is encoded within the p16INK4A locus by alternate splicing, controls MDM2 activity.125,126 The p14ARF gene shares exons 2 and 3 with p16INK4A but has a distinct exon 1. The discovery that two important tumor suppressor genes are encoded by the same chromosomal locus and share several exons was unexpected and is unique in human biology. The p16INK4A gene function depends on p53, since overexpression of p16INK4A causes cell cycle arrest in p53-wild type cells but not in p53-dependent cells.127 The transcription of p16INK4A is regulated by E2F, which is under the control of rb.128 This indicates the existence of yet another feedback loop, which links the rb pathway to p53.129 The Ras protein is another recently identified p16INK4A factor involved in MDM2-p53-p21-rb regulation.130,131 and 132
Abnormalities of p53 are found in slightly more than 50 percent of all human tumors and, surprisingly, even in some normal cells. It is unclear if these “normal” cells represent a pool of premalignant cells in an otherwise healthy body or if p53 changes are just one step in multistage tumorigenesis. Recently, a human p53 homologue, p73, has been described, which has DNA binding, transactivation, and oligomerization domains similar to p53. The p73 gene has been localized to chromosome 1p36, a common region of cytogenetic changes in cancer. If p73 is overexpressed, the pzl cyclin-dependent kinase inhibitor, a downstream element in the p53 pathway, is also upregulated.133 The p73 protein also can bind p53, inhibiting its transcriptional regulatory activity.134 Although p53 mutations are found in many cancers, p73 mutations apparently are much more rare. However, the p73 gene is inactivated by hypermethylation of CpG-islands in its promoter region in both leukemias and lymphomas.135 This finding supports the hypothesis that p73 is a tumor suppressor gene on chromosome 1p.
Homozygous deletions of the p16INK4A/p14ARF gene locus on human chromosome 9p21 have been detected in gliomas,56,136,137 primary cancers of the lung,56,138,139 bladder,140,141 and 142 head and neck,143,144 and 145 as well as in acute T-cell leukemias146,147 and 148 and mesotheliomas.149 Since inherited mutations of p16INK4A exon 2 may interfere with its expression and/or function, without causing an amino acid change in p14ARF, it is clear that p16INK4A inactivation alone is an important step in the evolution of malignant disease. However, in established tumor cell lines, nearly all chromosome 9p21 deletions disable the entire p16INK4A/p14ARF locus. The p15INK4B gene, also located on chromosome 9p21, about 20 kDa centromeric of p16INK4A, is deleted somewhat less frequently. Analyses of primary tumors, however, have shown that not all 9p21 deletions encompass these three tumor suppressor genes. One mechanism for disruption of the p15INK4B/p14ARF/p16INKA region in T-cell leukemias may be the action of an illegitimate V(D)J recombinase.150
Hypermethylation of CpG islands in the promoter areas of both p16INK4A and p15INK4B are frequently found in hematological malignancies.151,152,153,154 and 155 The availability of demethylating agents such as 5-aza-2′-deoxycytidine (decitabine) makes this phenomenon interesting for chemotherapy.156,157 Decitabine has been used to treat patients suffering from different hematological malignancies and was reported to have activity in advanced myelodysplastic syndrome, accompanied by demethylation of the p16INK4A promoter.158,159,160 and 161 Transcriptional regulation by methylation is mediated by a multiprotein complex consisting of a MeCP2, a methylcytosine-binding protein with a transcriptional repressor domain that binds the corepressor mSin3A, which is itself one element of a multiprotein complex that includes histone deacetylase HDAC1 and HDAC2.162,163 Therefore, reexpression of silenced genes can be achieved by demethylating DNA or by destabilizing histone deacetylases. A mammalian protein with specific demethylase activity for methylated CpG islands has been detected recently164 indicating that gene silencing by epigenetic mechanisms is highly regulated in vertebrate organisms. Histone deacetylase inhibitors and demethylating agents act synergistically to induce genes silenced in cancer by hypermethylation.165 Based on these findings, the MeCP2/SIN3A/HDAC1/2 complex may represent a new target for antineoplastic therapy.
In addition to the three major tumor suppressor gene pathways described above, several others have been identified. It is noteworthy that many different tumor suppressors can be inactivated by hypermethylation.

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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