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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Myeloproliferative Disorders

, MD, PhD, , MD, , MD, DSc, and , MD.

Chronic Myeloid Leukemia

The first consistent chromosome abnormality in any malignant disease was the Philadelphia or Ph chromosome (now called the Ph chromosome) identified in chronic myeloid leukemia (CML).14 This abnormality was thought to be a deletion of chromosome 22 (22q-) but was later shown to be a translocation involving chromosome 9 and 22 [t (9;22)(q34;q11)] (see Figure 8-2).15

The Philadelphia chromosome occurs in a pluripotential stem cell that gives rise to cells of both lymphoid and myeloid lineage. The reciprocal nature of the translocation was established in 1982, when the Abelson proto-oncogene, ABL, which is normally on chromosome 9, was identified on the Ph chromosome.16 This ultimately led to cloning of the breakpoint involved in the t(9;22).17 The site on the Ph chromosome was called bcr, for breakpoint cluster region, in which the majority of translocations cluster within a small, 5.8-kb region.17 In contrast, the breaks on chromosome 9 occur over an incredible distance of more than 200 kb.18 The genetic consequence of the t(9;22) is to move the ABL gene, a non-receptor tyrosine kinase on chromosome 9, next to the BCR gene on chromosome 22. This translocation creates two new genes, BCR-ABL on the 22q- or Phi chromosome, and the reciprocal ABL-BCR on the derivative 9q+. Whether the latter fusion gene, although transcriptionally active, plays a role in the disease remains controversial. Depending on the breakpoint in the BCR gene, three main types of BCR-ABL gene can be formed.19 The predominant hybrid gene in classic CML is derived from a disruption in the major breakpoint cluster region (M-bcr). Transcription from this gene yields chimeric mRNA molecules. The final product of this genetic rearrangement is a 210kDa cytoplasmic fusion protein or p210BCR-ABL, the transforming protein responsible for most, if not all, phenotypic abnormalities of chronic phase CML. The leukemogenic nature of the BCR-ABL protein results from the fact that its ABL-derived tyrosine kinase function is constitutively activated, presumably through dimerization of the BCR portion of the fusion protein.20

Knowledge of the molecular consequence of the consistent chromosome abnormality seen in CML, together with the availability of sophisticated biochemical and biophysical technology, has led to the exciting development of the first molecularly targeted therapy based on a recurrent cytogenetic rearrangement. Imatinib mesylate, marketed as Gleevec in the US, and formerly referred to as STI-571, prevents BCR-ABL mediated transfer of phosphate to its substrates. Druker and colleagues established the safety and efficacy of imatinib in patients with chronic-phase CML in a Phase I clinical trial.21 Within the group of 54 patients who received oral doses of at least 300mg per day, 53 (98 %) had normalization of leukocyte and platelet counts. Even more dramatically, cytogenetic responses occurred in 29 patients (54 %), with 7 (13 %) having complete responses. Side effects were generally mild to moderate and included nausea, abdominal cramping, diarrhea, as well as cytopenias. All were generally reversible with cessation of therapy. Accrual to three multi-institutional Phase II studies including over 1,000 patients with chronic and blast phase CML occurred rapidly. Over 90% of patients with interferon resistant chronic phase CML enjoyed a complete hematologic response, and nearly half had a major cytogenetic response.22 Response rates were more modest in one recently reported Phase II study by Kantarjian and coworkers, which enrolled 75 patients with blast- phase CML. Approximately 16% had a complete hematologic response, 11% had a cytologic response, with 6% having a complete cytogenetic reponse.23 Imatinib mesylate is now FDA approved for the treatment of patients with CML in blast crisis, accelerated phase, or in chronic phase after failure of interfeon-α (IFN-α).

The appearance of new abnormalities in the karyotype of a patient with CML often signals a change in the pace of the disease, usually to a more aggressive disorder. While the majority of patients with chronic phase CML have t(9;22), or a related variant, as their sole chromosomal abnormality, additional genetic changes are seen in 60 to 80% of CML patients in blast crisis. During the acute phase of CML, different chromosomal abnormalities occur either singly or in combination, in a distinctly nonrandom pattern. In patients with secondary chromosomal changes, the most common abnormalities are +8 (34% of cases with additional changes), +Ph(30%), i(17q) (20%), +19 (13%), -Y(8% of males), +21(7%), +17(5%), and monosomy 7(5%).24 The frequency of secondary cytogenetic abnormalities has been shown to vary in relation to the therapy given during chronic phase. Examples include a higher incidence of trisomy 8 in CML treated with busulfan as compared to treatment with hydroxyurea, and a higher incidence of anomalies involving 13q in patients with relapsed disease after bone marrow transplantation.25,26 Similarly, frequencies of secondary chromosomal abnormalities also vary in relation to the morphology of the blast crisis cells. A higher incidence of i(17q) is seen with myeloid blast crisis, and higher frequencies of monosomy 7, and hypodiploidy are seen in lymphoid blast crisis.24

Marrow cells from some patients who appear to have CML on both clinical and morphologic grounds lack a Ph chromosome. Most of these patients had a normal karyotype, and, somewhat surprisingly, their survival was substantially shorter than those whose cells were Ph+.27 Reviews of two series of such patients showed they did not have CML, but rather some form of myelodysplasia, most commonly chronic myelomonocytic leukemia or refractory anemia with excess blasts, leading to their shorter survival.28,29 The situation has become more complex, however, because molecular analysis has shown that some patients with clinically typical CML who lack a Ph chromosome cytogenetically have evidence for the insertion of ABL sequences into the BCR gene.28,30 Thus, it is clear that the sine qua non of CML is the juxtaposition of BCR and ABL with the formation of a fusion transcript BCR-ABL.30–32

Acute Myeloid Leukemia De Novo

At present, at least 80% of patients with acute myeloid leukemia (AML) have an abnormal karyotype. Specific rearrangements are closely associated with particular subtypes of AML as defined by the French-American-British Cooperative Group (FAB classification) (Figure 8-3).33 This association has been incorporated into the recent WHO classification.34 The chromosomal abnormalities associated with each subtype and their frequency are summarized in Table 8-2.

Table 8-2. Nonrandom Chromosome Abnormalities in Malignant Myeloid Diseases.

Table 8-2

Nonrandom Chromosome Abnormalities in Malignant Myeloid Diseases.

Over the past decade, the explosion of molecular biology research and improvement in molecular techniques has led to the identification of and study of genes involved in recurring chromosomal translocations in cancer. Although a large number of translocations have been cloned, many of the genes identified have been found to be common to certain pathways that are now postulated as being important in malignant transformation.

Chromosomal Rearrangements Involving Core Binding Factor

Core binding factor (CBF) is a heterodimeric transcription factor. It was named for its ability to bind to a core enhancer sequence of the Moloney leukemia virus LTR.35 It is comprised of CBFα (also called AML1, and more recently RUNXI), which binds DNA, and CBFβ, which increases the binding affinity for DNA. CBF has been shown to be important in the transcriptional activation of genes crucial for hematopoiesis. These include, but are not limited to, the cytokines interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF); cytokine receptors such as macrophage colony-stimulating factor (M-CSF); and genes involved in T-cell maturation such as T-cell receptor β enhancer, TCRβ. Given the role of CBF in normal hematopoiesis, it is reasonable to question whether disruption of function of the CBF would result in impaired differentiation of hematopoietic cells or frank leukemogenesis. In fact several chromosomal rearrangements involving CBF have been seen in patients with acute myeloid leukemia and include the t(8;21)(q22;q22), t(3;21)(q26;q22), inv(16)(p13q22) and t(16;16)(p13;q22). The t(12;21)(p13;q22) also involves CBF, but the phenotype of the leukemia that results is acute lymphoblastic leukemia (ALL), and this will therefore be discussed in the section on lymphoid malignancies. CBFα or, AML1, has been identified in 12 different translocations, of which seven have been cloned.

The translocation between chromosomes 8 and 21 [t(8;21) (q22;q22)] was first identified in 1972 and was the first translocation to be discovered (see Figure 8-3).36 The translocation is seen primarily in patients with AML-M2 (acute myeloblastic leukemia with maturation). The t(8;21) is one of the most frequent chromosomal abnormalities in AML and is found in up to 15% of patients. The majority of patients exhibit an FAB M2 morphology and have a favorable response to chemotherapy.37 In fact, the t(8;21) is a distinct category in AML-M2.36 The translocation results in fusion of the AML1 gene (also known as RUNXI or CBFA2) on chromosome 21 to the ETO gene on chromosome 8. The fusion of these genes on the der(8) chromosome produces a chimeric AML1/ETO gene. The AML1/ETO fusion transcript is consistently detected in patients with the t(8;21) by RT-PCR even as long as 10 years after attaining a complete cytogenetic and morphologic remission.38

The AML1 gene encodes a sequence-specific DNA-binding protein that demonstrates 69% identity over a central 128 residues domain with the Drosophila pair-rule gene runt. DNA binding is mediated through the runt-homology domain. AML1 binds DNA as a heterodimeric complex. This complex, also known as CBF, consists of the AML1 DNA binding subunit and a second subunit, CBFβ, which increases the DNA binding affinity of AML1. As discussed earlier, CBF has been shown to be important in the transcriptional activation of genes crucial for hematopoiesis. Murine models in which the AML1 gene has been targeted by homologous recombination have been constructed. Mice heterozygous for the mutation were phenotypically normal. Homozygous mutation of the gene (ie, deletion of both copies of the murine AML1 gene) is an embryonic lethal mutation. The embryos lack fetal liver hematopoiesis and die of central nervous system hemorrhage at day 12.5.39 Furthermore, embryonic stem (ES) cells with deletion of the gene do not contribute to hematopoiesis in chimeric animals, underscoring the importance of AML1 target genes in normal hematopoiesis.40

The mechanism of malignant transformation by AML1/ETO has not been fully elucidated, but the fusion product has dominant inhibitory activity of transcriptional activation by AML1.41 Recent studies have shown that the AML1/ETO fusion is associated with a histone deacetylase complex that inhibits normal AML1 function.42 It therefore appears that the AML1-ETO fusion protein acts as a dominant negative inhibitor of wild-type AML1 gene function. This has been further demonstrated in AML1/ETO “knock-in” mice experiments, in which mice heterozygous for the AML1/ETO allele and wild-type AML1 gene are generated by homologous recombination. These animals have the same phenotype as mice with deletion of the AML1 gene (ie, embryonic lethality), suggesting that the fusion gene blocks normal transcription of wild-type AML1.43 An inducible transgenic model was subsequently developed by Rhoades and colleagues, in which the expression of AML1/ETO is under the control of a tetracycline-inducible system. In the mice expressing AML1/ETO, abnormal maturation and proliferation of progenitor cells was noted, but throughout the normal murine lifespan of 24 months none developed leukemia.44 This may suggest that either additional genetic changes must be introduced, or that expression of AML1/ETO must occur at a particular stage of hematopoietic differentiation to create an animal model for studying the pathogenesis of this translocation.

The t(3;21)(q26;q22) has been detected in patients with MDS and CML blast crisis. The genes cloned at this translocation breakpoint have been AML1, on band 21q22 fused to EAP, MDS1, or EVI1 on band 3q26. The fusion transcripts retain the AML1 DNA-binding domain and can therefore dimerize with CBFβ, possibly inhibiting transcription of wild-type AML1. In addition, there is evidence that the EVI1 portion of the fusion may be equally important for malignant transformation.45 Establishing that the CBF subunit fusion proteins directly induce leukemia in vivo has been difficult because of the essential nature of the genes involved. Previous knock-in mice experiments, mentioned above, have resulted in embryonic lethality. To circumvent this problem, a recent study has employed a bone marrow retroviral transduction/transplantation approach to study the effects of the t(3;21) AML1/MDS1/EVI1 (AME) fusion gene on leukemogenesis. Expression of the AME fusion protein in mouse bone marrow cells induced a disease similar to human acute myelomonocytic leukemia.46

Another clinical-cytogenetic association that has been identified involves acute myelomonocytic leukemia with abnormal eosinophils that have unique morphologic changes (AMML Eo). Associated chromosomal abnormalities are inv(16)(p13q22) or t(16;16)(p13;q22) and are incorporated in the new WHO classification.34 The strong correlation between abnormal eosinophils and structural rearrangements of chromosome 16 was confirmed at the Fourth International Workshop on Chromosomes in Leukemia (IWCL).47 This chromosomal abnormality, which is present in approximately 25% of patients with AMMoL M4, is associated with a favorable prognosis.37,48

In both the inversion and translocation, the critical genetic event is the fusion of the CBFB gene at 16q22 to the smooth muscle myosin heavy chain (MYH11) at 16p13.49 The fusion transcript can be detected by FISH and RT-PCR.50 The fusion protein retains its ability to interact with AML1(CBFα) and is thought to act as a dominant negative inhibitor of wild-type AML1 function. CBFB-MYH11 knock-in mice have been developed that have a phenotype identical to that of AML1/ETO knock-in mice and to mice with homozygous mutation of AML1, thus supporting this hypothesis.51

Translocations Involving RAR α

A structural rearrangement involving chromosomes 15 and 17 in acute promyelocytic leukemia (APL) was first recognized in 1977 [t(15;17)(q22;q12–21)] (see Figure 8-3).49 This rearrangement is unique to APL, or to the hypogranular variant. The translocation has been cloned. The gene at the breakpoint on chromosome 17 is the α chain of the retinoic acid receptor (RARA), whereas that on chromosome 15 is called PML.52,53 The critical junction is located on the der(15) chromosome and consists of the 5′ portion of PML fused to virtually all of the RARA gene. The fusion transcript can be detected with RT-PCR.53 Other less common variant translocations involving RARA include the t(11;17)(q23;q12–21), t(5;17)(q35;q12–21), t(11;17)(q13;q12–21), t(17;17)(q11;q21).54–56 These translocations fuse the RARA gene on 17q12 to the PLZF and NPM, NUMA, and STAT5b genes, respectively.

The t(15;17) that results in the PML-RARA fusion gene is the most common and best studied to date.53 Patients have classic APL with characteristic AML-M3 morphology, which includes a dramatic accumulation of promyelocytes in the bone marrow and presence of Auer rods within the cytoplasm of the promyelocytic blasts. This is accompanied clinically by hemorrhagic diathesis. These patients have a dramatic response to all-trans retinoic acid (ATRA) therapy that tends to be short-lived unless it is followed by conventional chemotherapy. The RARA gene encodes the retinoic acid receptor alpha protein that belongs to the nuclear steroid/thyroid hormone receptor superfamily. It is a transcriptionally active protein that contains two zinc finger DNA-binding domains and a ligand-binding domain that interacts with retinoic acid receptor X (RXR). The PML-RARA fusion gene is thought to interfere with wild-type RARA function in a dominant manner.

Murine models have been created that underscore the importance of the fusion gene in leukemogenesis. When placed under the control of the human myeloid/promyelocytic specific cathepsin-G (hCG) gene or the human migration inhibitory factor related protein (hMRP8) expression cassette, the fusion gene results in development of acute leukemia in transgenic mice. However, only approximately 10% to 20% of the mice developed leukemia over a variable latency period (as long as 1 year), although all of the mice developed a preceeding myeloproliferative disorder.57 This suggests that PML-RARA is necessary but not sufficient to cause full-blown APL. Additional mutations are needed for the expression of the fully malignant phenotype.

As previously mentioned, the APL blasts with a t(15;17) are exquisitely sensitive to the differentiating action of ATRA. ATRA is thought to override the dominant negative inhibition of wild-type RARA by PML-RARA (similar to the AML1-ETO fusion). The PML-RARα fusion protein interacts with a complex of molecules known as nuclear co-repressors and histone deacetylase. This complex binds to the fusion protein and blocks the transcription of target genes. ATRA interacts with the RARα portion of the complex to cause release of the co-repressor complex. This allows transcription of these target genes to proceed and allows expression of genes required for hematopoietic differentiation.58–60 However, APL associated with the PLZF-RARA fusion shows no response to ATRA, a poor response to chemotherapy and therefore, a distinctly worse prognosis. This may be explained by the fact that PLZF can recruit the nuclear co-repressor histone deacetylase complex and therefore is not ATRA sensitive.60 It can also independently block transcription of target genes involved in normal hematopoietic differentiation.

Translocations involving 11q23

The human chromosome band 11q23 is associated with an astonishing number of recurrent chromosomal abnormalities including translocations, insertions, and deletions. It is involved in over 20% of acute leukemias. The cloning of the 11q23 breakpoint region revealed the MLL (Myeloid-Lymphoid Leukemia or Mixed-Lineage Leukemia) gene, named for its involvement in myeloid (usually monoblastic) and lymphoblastic leukemia, and less commonly in lymphoma.61 It is also involved in myelodysplastic syndrome, biphenotypic leukemia, and therapy-induced AML (particularly following treatment with topoisomerase II inhibitors).62 This gene (also known as ALL1, HRX, and HTRX-1) spans 100 kb and encodes a large and complex protein with several regions of homology to Drosophila trithorax(trx) protein.63,64 Leukemias involving the MLL gene have a poor prognosis, although recent data suggest that the t(9;11) may respond better than other MLL translocations.37,65

The MLL protein comprises 3,968 amino acids and contains several domains.64,66 These include the AT-hook DNA-binding domain near the amino terminus, which binds AT-rich cruciform DNA recognizing structure, rather than a specific sequence.66 This region is similar to the AT-hook of high-mobility group (HMG)I(Y) proteins. HMG proteins bind AT-rich regions of the minor grove of DNA, and do not directly activate transcription but facilitate action of other factors such as NF-KB. It also has a region of homology to mammalian DNA methyl transferases, transcriptional activation, and repression domains, as well as a cysteine-rich region that forms three zinc fingers or plant homeodomains (PHD) (also called LAP for leukemia-associated protein domain).66 The PHD domain and the SET domain located at the carboxyl terminus are the regions most conserved with the Drosophila trx protein. The TRX gene is required to maintain the proper expression of homeotic genes of the Bithorax and Antennapedia complexes in Drosophila.

MLL has been targeted in mice by homologous recombination in ES cells to assess its role in development. MLL heterozygous mice had retarded growth and displayed bidirectional homeotic transformation of the axial skeletion as well as sternal malformations. These mice also displayed hematopoietic abnormalities including anemia and decreased platelets, although morphology of the hematopoietic cells was normal. This suggests that MLL haploinsufficiency, on its own, is inadequate for leukemic transformation. In contrast, mice with homozygous deletions die by embryonic day 10.5. MLL has been shown to positively regulate homeobox (Hox) gene expression. Anterior boundaries of Hoxa-7 and Hoxc-9 expression were shifted posteriorly in heterozygous mice, whereas embryos with homozygous deficiency of MLL failed to maintain expression of representative Hox genes. Hox genes, in general, are important determinants of the mammalian body plan and are also differentially expressed in subsets of hematopoietic cells. These data suggest that the MLL gene is important for axial organization and hematopoietic differentiation.67 More recent studies have shown that MLL and BMI1 (a member of the polycomb family) have opposing functions. Mice that lack both genes develop normally.68

MLL is involved in translocations with at least 57 different partner genes, 33 of which have been cloned thus far (Figure 8-4).1 In spite of the large size of the gene, the translocation breakpoints in MLL cluster around an 8.3-kb region just 5′ of the PHD domain. The clustering of the breaks makes it possible to detect virtually all MLL rearrangements with a 0.74-kb complementary DNA (cDNA) probe on Southern blot analysis. The fusion genes that result consist of 5′ MLL and 3′ partner gene. The reciprocal fusion transcript (3′ partner gene and 5′ MLL) is also frequently expressed. The role of the partner genes in leukemogenesis has been the subject of much debate. The fact that they lack a common motif and are so varied suggests that they may be interchangeable and have only a minor role in leukemogenesis. However, the observation that the leukemia phenotype generated usually correlates with the specific MLL-partner gene fusion protein expressed argues against this hypothesis. For example, a common MLL translocation, t(4;11)(q21;q23), which generates the MLL-AF4 fusion is found predominantly in 2% to 7% of all cases of ALL and more than 80% of acute lymphoblastic leukemia in infants. The t(11;19)(q23;p13.3) results in the MLL-ENL fusion transcript and is also found in ALL. In AML, the most common MLL rearrangements are the t(9;11)(q22;q23) involving MLL and AF9, the t(6;11)(q27;q23) involving MLL and AF6 and the t(11;19) (q23;p13.1) involving MLL and ELL.1,69

Formal proof that the MLL/partner gene fusion products created by these translocations are important in hematologic malignancies has been provided by Mll-AF9 knock-in mice. The chimeric, as well as heterozygous, mice carrying the fusion gene developed AML. In contrast, MLL-myc chimeras (carrying a truncated myc allele) did not develop leukemia, or did so after a long latent period. However, Mll-AF9 mice developed leukemia only after a latency period of over 2 months, suggesting that secondary mutations in other genes are necessary for overt malignant transformation.70

Other groups have also performed studies that reinforce the importance of the partner genes in leukemogenesis. MLL-ENL fusion cDNA, when transduced by retroviral gene transfer into cell populations enriched in hematopoietic stem cells, was capable of immortalizing early myelomonocytic cells. The immortalized cells, as well as freshly infected bone marrow cells enriched for hematopoietic stem and progenitor cells, were capable of inducing leukemias in 100% of recipients when transplanted into syngeneic recipients. In contrast, wild-type ENL or a deletion mutant of MLL-ENL lacking the ENL component did not demonstrate any in vitro transforming abilities.71 Similar experiments using MLL fused to CBP or ELL also produced leukemia, but with a longer latent period.72,73

A two-hit model of oncogenesis for MLL chromosomal aberrations has been proposed. The first “hit” is the MLL translocation which creates an MLL fusion with a partner gene that could confer a gain-of-function activity. The second hit, MLL haploinsufficiency, due to loss of this normal functioning allele, would also contribute to the malignant phenotype.74 However, it is clear that alterations in other genes are also required.

Chromosomal Abnormalities Involving Transcriptional Coactivators

Transcriptional coactivators interact with the basal transcription machinery and with transcription factors such as the cAMP response element binding protein (CREB) and nuclear hormone receptors. Many of these coactivators also have histone acetyl transferase (HAT) activity, which is important in chromatin remodeling. A number of coactivators have recently been cloned at translocation breakpoints in leukemia. These include the CREB binding protein (CBP) gene, which is involved in both the t(11;16)(q23;p13.3) and the t(8;16)(p11;p13), which result in MLL/CBP and MOZ/CBP fusion transcripts, respectively.75,76 P300, located on chromosome 22, is a functional homolog of CBP. It is involved in the t(11;22)(q23;q13), which gives rise to the MLL/P300 fusion transcript.77 Another coactivator that is potentially important in leukemogenesis is TIF2, which has been cloned in the inv(8)(p11q13) translocation that generates the MOZ/TIF2 fusion.78

CBP is one of the best studied of these co-activators to date. It is located on chromosome band 16p13.3 and binds to the phosphorylated form of CREB. It also interacts directly with TFIIB and RNA polymerase II (basal transcription machinery). It functions as a global transcriptional co-activator by interacting with many DNA-binding transcription factors. These proteins are often discussed as CBP/P300 because they are functional homologs. Both have intrinsic HAT activity.79

Cloning of the t(8;16) led to the discovery of a novel gene MOZ and identification of CBP as its translocation partner.75 Patients with the t(8;16) are classified as AML-M4 patients or M5, with pronounced erythrophagocytosis by the blast cells in the majority of cases. Both de novo and therapy related AML cases have been reported. This is very similar to patients with inv(8) involving MOZ and TIF2, who also have AML-M5 with an erythrophagocytic picture.

In contrast to most patients with MLL translocations, almost all patients with t(11;16) involving MLL and CBP that have been reported to date have therapy-related leukemia, with a significant percentage having therapy-related myelodysplasia (t-MDS). CBP is also the gene responsible for the Rubinstein-Taybi syndrome, in which loss of one functional allele results in a well-defined syndrome characterized by facial abnormalities, broad thumbs, and mental retardation, as well as the propensity for malignancy.80

Besides the CREB binding domain and HAT domain, the CBP protein also has other important domains, including the PHD domain found in many other proteins including MLL and some of MLL's other partner genes (AF10, AF17). This domain is also present in trithorax and polycomb-like proteins in Drosophila, as well as in MOZ. The exact function of this domain is unknown, but it is postulated to be important in protein-protein interactions. CBP also contains a bromodomain, which is a motif that is conserved in humans, Drosophila (brahma), and the yeast SWI2/SNF2 complex. Several bromodomain-containing proteins including CBP, SWI2/SNF2, TAF250 and GCN5 are involved in transcriptional regulation as mediators or co-activators. Several of these proteins also have HAT activity, are present in large multi-protein complexes, and are important in chromatin modification. It has therefore been proposed that the bromodomain is important for protein-protein interaction and may influence the assembly or activity of these complexes.81 It may also be important in chromatin interaction.81 Recent structure-function studies of the HAT co-activator P/CAF(P300/CBP-associated factor) bromodomain revealed interaction with acetylated lysine in a manner similar to the interaction of acetyl-CoA with histone acetyltransferases, suggesting that it may be important in regulation of HAT activity.82 CBP retains several of these domains, including the bromodomain and HAT domain (which includes the PHD domain) in the t(11;16). These domains have also been shown to be retained in the t(8;16).75

In summary, the exact mechanism by which these transcriptional co-activators contribute to leukemogenesis is unknown. Many of them have been postulated or demonstrated to have HAT activity.75 Chromatin remodelling through histone acetylation plays a major role in transcriptional activation by co-activators, and disruption of this process may be important in leukemogenesis.

Other Chromosomal Abnormalities

Gains and losses of a part of or whole chromosomes frequently occur in AML, both as solitary changes usually found at diagnosis or as additions in later disease stages. Most of the structural translocations occur in younger patients, with a median age in the thirties, whereas some of the numeric abnormalities and other structural rearrangements, such as -5 or loss of the long arm [del(5q)] or -7 or del(7q), occur in patients with a median age of over 50. Many of these latter patients have a history of working in environments that might have exposed them to mutagenic agents such as chemicals that include solvents, petroleum products, or pesticides.83,84 Secondary chromosome changes, such as del(20q), del(9p), and i(17q), occur in AML and also are associated with other diseases; these changes sometimes are found as the sole aberrations. Although it appears that CDKN2 (p16) may be the target for 9p21 deletion, despite intensive efforts the genes involved in other deletions such as 5q, 7q, and 20q are unknown. This has been a very difficult problem because there are no homozygous deletions and each of these is a very gene-rich region.85

Other Myeloproliferative Diseases

In polycythemia vera, an abnormal clone is present in about 15% of untreated patients. This number increases to 40% overall because the frequency with which abnormalities are seen is as high as 80% in the later phases of the disease.86 The five most common aberrations are, in descending order of frequency, 20q-, + 8, +9, gains of 1q and 13q-. Two-thirds of the cytogenetically abnormal cases have at least one of these aberrations.5 The presence of chromosomal abnormalities at diagnosis is not predictive of clinical outcome, but a change in karyotype, as with CML, is an ominous sign.86 In the terminal leukemic phase, -7 (20% of patients) and del(5q) (40%) have been observed. It is not clear whether these abnormalities are related to the therapy these patients may have received.

Approximately one-third of patients with agnogenic myeloid metaplasia have clonal abnormalities, commonly -7, 18, del(11q), or del(20q).5

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Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK12465


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