LEADING ARTICLE Causality of myelodysplasia and acute ... - Nature

Leukemia (2002) 16, 2177–2184  2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu

LEADING ARTICLE Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities J Pedersen-Bjergaard, DH Christiansen, MK Andersen and F Skovby Cytogenetic Laboratory, Section of Hematology/Oncology, Department of Clinical Genetics, Juliane Marie Center, University Hospital, Rigshospitalet, Copenhagen, Denmark

New insights into causative factors for the development of myelodysplasia (MDS) and acute myeloid leukemia (AML), with associations to specific cytogenetic and genetic abnormalities have been obtained primarily from studies of patients with the therapy-related subsets of the two diseases. Current knowledge now makes it possible to distinguish between at least seven major genetic subgroups of MDS and AML, and has directed research towards more specific causative factors also for de novo MDS and AML. Leukemia (2002) 16, 2177–2184. doi:10.1038/sj.leu.2402764 Keywords: myelodysplasia; acute myeloid leukemia; therapy related leukemia; epidemiology; chromosome abnormalities; alkylating agents; topoisomerase II inhibitors

Introduction In most malignant diseases little is known of the etiological factors and the way they induce the genetic abnormalities resulting in neoplastic transformation. Examples of tumors with a specific etiology are lung cancer induced by smoking, pleural mesothelioma induced by inhalation of asbestos particles, and hepatocellular carcinoma following ingestion of aflatoxin. Myelodysplasia (MDS) and acute myeloid leukemia (AML) most often develop de novo without knowledge of previous mutagenic exposures. A subset of 10–15%, however, have a history of chemotherapy, of high voltage radiotherapy, or of combined modality therapy for another tumor. These therapyrelated cases of MDS (t-MDS) and AML (t-AML) are unique diseases, because in most cases they are induced by chemically well-defined drugs associated with specific genetic pathways of the disease. Because the pathology, the cytogenetics and the molecular biology of therapy-related and of de novo MDS and AML are almost indistinguishable, we propose hypotheses of the origin also of de novo disease. The risk of MDS and AML in patients treated intensively with chemotherapy has been shown to be increased 100 times or more as compared to the risk in the general population.1–7 This indicates that at least 99% of such cases of t-MDS or tAML must be considered as drug-induced. For this reason it is appropriate to relate their cytogenetic and genetic abnormalities to the mechanisms of action of the two types of leukemogenic drugs: alkylating agents and topoisomerase II inhibitors.

Correspondence: J Pedersen-Bjergaard, Section 4052, Rigshospitalet, Blegdamsvej 9, DK 2100 Copenhagen ⭋, Denmark; Fax: +45 3545 2577 Received 19 April 2002; accepted 26 July 2002

The ‘alkylator types’ of MDS and AML The first cytostatic drugs shown to be leukemogenic were alkylating agents, administered as single agents1,2,4,5,8–10 or included in combination chemotherapy regimens,3,7,11 primarily for multiple myeloma1,3,10 and Hodgkin’s disease.6,12–14 Many of these studies showed that the risk of t-MDS and tAML increases with the cumulative dose of drug4,5,7,9,10,13,14 and with patient age.3,6,13,14 After the first reports of t-AML it was realized that in most of these patients the disease presents in a preleukemic stage as t-MDS with abrupt thrombocytopenia 2–5 years after start of therapy with alkylating agents. Characteristically, the karyotypes, even early in the course of the disease, show loss of whole chromosomes 5 or 7 or loss of various parts of the long arms of these two chromosomes, often with many additional chromosome abnormalities.15–20 Most patients with t-MDS die of refractory cytopenia before developing t-AML.16–20 Alkylating agents are known to induce interstrand crosslinking of DNA preventing transcription and replication, to form adducts with DNA bases resulting in gene mutations, and to induce various types of chromosome damage.21,22 These effects are not restricted to specific genes or chromosome regions, and the predominance of cases of t-MDS and t-AML with loss of various parts of the long arms of chromosomes 5 and 7 possibly reflects a selection of cells with these abnormalities due to a proliferative advantage. Chromosome damage which may lead to deletions or total chromosomal loss is frequent following chemotherapy with alkylating agents, and because two different deletions of the long arm of a chromosome 5 or a chromosome 7 are sometimes observed in cytogenetically unrelated clones in the same patient, the chromosome defects most likely are secondary and potentiate or activate the effects of other more important preclinical genetic changes23 (Figure 1a and c). Inactivated recessive genes on the remaining normal chromosome 5 or 7 have been searched for, so far without success,24–28 for which reason haploinsufficiency must also be considered. Two subgroups of the alkylator type of t-MDS and t-AML with deletion or loss of the long arms or complete loss of chromosomes 5 and 7 were recently identified (Figure 1).29,30 The first subgroup includes patients with abnormalities of chromosome 7 but normal chromosome 5. These patients generally have few other cytogenetic abnormalities, but often have mutations of the RAS genes and methylation of the p15 gene promotor. If loss of a whole chromosome 7 is the only cytogenetic abnormality observed, the patient may survive for long periods of time with a more indolent type of t-MDS. The second subgroup includes patients with t-MDS and tAML and deletion or loss of the long arm of chromosome 5,

Causality of genetic changes in MDS and AML J Pedersen-Bjergaard et al

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Figure 1 Genetic changes in different types of myelodysplasia and acute myeloid leukemia. (a) and (c) Putatitively inactivated recessive genes on the long arms of chromosome 5 and 7; (e) genetic abnormality specific for the 5q- syndrome; (f) genetic abnormality specific for juvenile myelomonocytic leukemia; (h–k) genetic abnormalities supplementing the dominant oncogenic effect of the transcripts of the recurrent balanced chromosome aberrations; (l) and (n) primary genetic changes in MDS with a normal karyotype or with +8; (b) (d) (g) (m) and (o) genetic changes involved in transformation from myelodysplasia to overt leukemia. Many of the genetic changes may be complex or identical for different types of MDS and AML.

with or without abnormalities of chromosome 7.29,30 These patients characteristically have a complex karyotype with many additional abnormalities and their prognosis is extremely poor.29 Mutations of p53 have been observed in 77% of such patients, often with loss of heterozygosity of the gene.29,31,32 The mutational spectrum seems to vary with the type of alkylating agent or cisplatin used, possibly due to different preferences for alkylation of the individual drugs at specific bases in the minor or in the major groove of DNA.29 These results support the notion that the p53 mutations are directly induced by the cytostatic agents. Many of the previously unidentified chromosome abnormalities of t-MDS and t-AML following therapy with alkylating agents have recently been identified by FISH as dicentric chroLeukemia

mosomes involving chromosomes 5 or 7,33 or as unbalanced translocations to their long arms, both type of abnormality resulting in loss of different but overlapping parts of 5q or 7q.34 In other cases, previously unidentified abnormalities have now been disclosed as duplications or amplifications of varying parts of the long arm of chromosome 11, including the 11q23 band and the unrearranged MLL gene, a phenomenon significantly associated with mutations of p53.35 Experimental research indicates that the entire scenario of multiple chromosome aberrations and amplifications could result directly from p53 mutations.36–38 As suggested for de novo AML,39 deleted genes at 5q and acquired mutations of p53 possibly cooperate in leukemogenesis, also in t-MDS and t-AML.29 In de novo MDS and AML similar deletions or loss of the


long arms of chromosomes 5 and 7 are observed, although less frequently than in therapy-related diseases.40–42 With some exceptions, most cases of de novo MDS or AML with the characteristic defects of chromosomes 5 or 7 show a striking similarity to cases of t-MDS and t-AML after the use of alkylating agents. In particular, cases with deletions or loss of 5q often present mutations of p53 and a complex karyotype,43– 45 and they all respond poorly to intensive antileukemic chemotherapy. De novo AML with abnormal chromosomes 5 and 7 has repeatedly been associated with previous exposure to chemicals, organic solvents and pesticides.46–48 Although referred to as a well-established fact, such an association has not been confirmed or rejected by larger prospective studies. The 5q- syndrome and juvenile myelomonocytic leukemia with monosomy 7 Cases of de novo MDS with interstitial deletion of the long arm of chromosome 5 as a sole abnormality, refractory anemia, and without an excess of blasts in the bone marrow represent a specific entity: ‘the 5q- syndrome’ (Figure 1).49,50 The commonly deleted region on 5q seems in these cases to be located more telomeric than in other cases of MDS and AML. These patients have normal platelet counts and an extremely good prognosis with a very low risk of leukemic transformation. They thereby differ completely, possibly also at the molecular level (Figure 1, genetic abnormality e), from other patients with MDS and an increased percentage of myeloblasts in the bone marrow or with t-AML and deletions of the long arm of chromosome 5. Monosomy 7 is frequently observed in children with MDS,51 and is characteristic of juvenile myelomonocytic leukemia.51,52 Although the specific genetic background of this disease entity remains to be identified, the molecular biology (Figure 1, genetic abnormality f) most likely differs from that of adult cases of MDS or AML with monosomy 7. The ‘topoisomerase II-related types’ of MDS and AML Anthracyclines, epipodophyllotoxins, mitoxantrone and the bisdioxopiperazine derivatives, all cytostatic drugs belonging to the group of topoisomerase II inhibitors, have recently been demonstrated as leukemogenic.53–63 Leukemic complications following therapy with these drugs characteristically present as overt t-AML rather than t-MDS, often with a latent period of only 1–2 years or less.11 Cytogenetic abnormalities include balanced reciprocal translocations, involving chromosome bands 11q23 or 21q22,53–55,58,59,64–67 more rarely inv(16)66,68 or t(15;17).61,63,66,69 These recurrent aberrations have been shown to generate fusions between the MLL, AML1, CBFB or RARA genes and various partner genes (Figure 1), and the new chimeric genes are supposed to act as dominant oncogenes.70–72 Although the molecular biology of the disease in this group of patients with t-MDS and t-AML is heterogeneous, they all present chimeric gene fusions and a common ethiology: therapy with topoisomerase II inhibitors. Indirect evidence now supports the notion that the balanced chromosome aberrations observed in t-MDS and t-AML are directly induced by cytostatic drugs.73 Topoisomerase II is a major component of the chromosomal scaffold,74 and as a part of its normal function the enzymes induce transient, 4 base pair staggered double strand breaks of DNA for strand passage and unwinding. Induction of double strand breaks of

DNA is a potent initiator of translocations,75 and topoisomerase II interacts preferentially with DNA crossovers.76 The enzyme has been associated with illegitimate gene recombinations at matrix-associated regions.77 Many cytostatic drugs, as an important mechanism of action, inhibit religation of the topoisomerase II-induced double strand breaks of DNA78,79 and this effect may enhance the risk of illegitimate chromosome recombinations. Etoposide has been shown to induce illegitimate gene recombinations,80 and etoposide and doxorubicin to induce site-specific cleavage within the MLL and the AML1 genes,81,82 a prerequisite for development of translocations and new fusion genes. A topoisomerase II cleavage site83 and a Dnase hypersensitive site have been shown to colocalize near exon 9 in the MLL breakpoint cluster region.84 Furthermore, a 4 base pair microduplication has been demonstrated at the translocation site between the NUP98 and the TOP1 genes in two cases of t-MDS with a t(11;20)(p15;q11) after treatment with topoisomerase II inhibitors.85 These results, if evaluated together, strongly support a direct role of topoisomerase II and its inhibition by cytostatic drugs in the development of balanced chromosome aberrations and fusion genes in therapy-related leukemia. Patients with de novo AML and recurrent balanced chromosome aberrations, like their therapy-related counterpart, are most often younger than patients with deletions or loss of 5q and 7q, and their initial response to chemotherapy is favorable.41,42 The long-term survival, however, of patients with translocations to chromosome band 11q23 is worse than the long-term survival of patients with other common balanced chromosome aberrations due to a high risk of relapse of the disease.86 Previously, no specific external exposures were suspected to play a role in the development of such de novo leukemias. Recently, a significantly increased maternal intake of agricultural products such as beans, fresh vegetables and fruit, all rich in bioflavonoids, has been demonstrated in cases of infant acute leukemia.87 These bioflavonoids are topoisomerase II inhibitors, pass the placental barrier and induce a cleavage of the MLL gene within the break point cluster region similarly to etoposide and doxorubicin.88 Thus, in one particular subgroup of de novo acute leukemias, an association between specific external exposures and definite cytogenetic abnormalities has now been established. In knock-in experiments in mice with the different fusion genes from the most common recurrent balanced chromosome aberrations, for instance the AML1-ETO gene of the t(8;21),89 it has been shown that additional cooperating mutations (Figure 1h–k) are required for development of overt leukemia. The fact that the AML1-ETO transcript can still be detected by the sensitive RT-PCR technique in many cases of AML with t(8;21) in long-term remission90 supports the idea that cooperating, additional mutations are also required for the development of human AML.

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The ‘non-mutagenic type’ of MDS and AML A normal karyotype has been observed consistently in 40– 50% of patients with de novo MDS and AML.40–42 New techniques such as RT-PCR and Southern blotting for detection of the rearranged genes of the recurrent balanced translocations, and multicolor fluorescence in situ hybrization (M-FISH) for detection of cryptic chromosome rearrangements, have disclosed abnormalities in only a smaller fraction of patients with a normal karyotype. Other genetic changes (Figure 1l and m) Leukemia


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are supposed to play a role, and recently internal tandem duplications of the MLL and the FLT3 genes have been demonstrated in 6–9% and 28–36%, respectively, of such patients (Figure 1).45,91–97 Classification of cases of AML de novo with a normal karyotype as a single entity is now supported by a characteristic gene expression profile of such cases,98 different from the profile of normal CD34-positive cells and different from the profile of AML cells with trisomy 8. In patients with t-MDS and t-AML only 10–15% have a normal karyotype.16–21 It has not been possible in these cases to relate the disease to any specific type of chemotherapy or radiotherapy. Recently, internal tandem duplications of the MLL and the FLT3 genes were also observed in patients with tAML and a normal karyotype.99 Even these duplications were unrelated to any type of therapy. As the junction points for duplications of the MLL gene consistently occur within Alurepeats,96,97,99 these duplications have been supposed to arise as spontaneous homologous recombinations. As the genetic changes of t-MDS and t-AML with a normal karyotype seem to arise unrelated to exposure to cytostatic drugs or irradiation, the genetic changes of de novo MDS and AML with a normal karyotype could perhaps likewise arise without any external leukemogenic exposures. Other general types of MDS and AML The three major types of MDS and AML discussed above include more than 80% of patients with therapy-related and de novo MDS and AML. At least two other types must be considered. The first type includes patients with de novo or therapy-related MDS or AML and trisomy 8, the second comprises patients with t-MDS and t-AML after radiotherapy only. Trisomy 8 with or without other chromosome aberrations is present in 5% and 9% of patients with de novo MDS and AML, respectively,40–42 and is associated with an intermediate or poor prognosis depending on the number of additional aberrations. In de novo AML trisomy 8 has been related to previous exposure to organic solvents.100 In t-MDS and t-AML trisomy 8 is less common than in de novo disease,19,20 and is often observed in only a subclone of cells or as an evolutionary event during the course of the disease,101 unrelated to any specific type of previous therapy. For these reasons trisomy 8 has been considered a secondary phenomenon.20,30 Recently, however, a distinct gene expression profile was demonstrated in patients with de novo AML and trisomy 8 as the sole abnormality.98 Leukemic cells with trisomy 8 showed down-regulation of several apoptosis-related genes and a moderate overexpression of many genes located to chromosome 8 as compared to leukemic cells with a normal karyotype and to normal cells. The results suggest a simple gene-dosage effect of the supernumerary chromosome 8 and support trisomy 8 as well as a normal karyotype to represent specific genetic entities of leukemia (Figure 1). Cytogenetic investigations of t-MDS and t-AML following radiotherapy only have been published for single cases or small series of patients.16–20 Karyotypes have not differed markedly from those of de novo MDS and AML, taking the often advanced age of patients receiving radiotherapy into consideration. Other very extensive studies have consistently reported a much lower risk of t-AML following high voltage radiotherapy only than following intensive chemotherapy. Irradiation confers relative risks of AML in the order of 1.3– 2.4 as compared to the risk of AML in the general popu-

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lation.102–104 Consequently, only about half of the radiotherapy-related cases can be considered as radiation-induced, whereas the other half represents incidental cases of de novo MDS or AML. The fact that some of these leukemias have been observed only a few months after radiotherapy, and others after more than 10 years, supports the assumption that far from all radiotherapy-related cases are radiation-induced. In our own series of 19 consecutive cases of t-MDS or tAML after radiotherapy only,105 eight patients presented deletion or loss of 7q whereas six patients had a normal karyotype. These findings are in agreement with data from Felix Mitelman’s Catalog of Chromosome Aberrations in Cancer,106 according to which deletions or loss of the long arm of chromosome 5 are also common in radiotherapy-related leukemias. It is still an open question whether radiotherapy-induced cases of t-MDS and t-AML show characteristic chromosome aberrations, or whether the aberrations observed merely relate to an advanced age of most of these patients. If characteristic abnormalities exist, these include deletions or loss of 5q and 7q or loss of the whole chromosomes.

Epidemiologic studies of de novo MDS and AML Many studies have searched for etiologic factors in malignancy including MDS and AML as previously reviewed.107 Apart from chemotherapy or radiotherapy, only few other exposures have consistently been verified as leukemogenic. These include inhalation of benzene vapor at high concentrations108–111 and smoking.112–114 There may be several reasons for this lack of success. First, many cases of MDS and AML may develop as the result of spontaneous gene mutations or recombinations, unrelated to external mutagenic exposures, as suggested for the ‘non-mutagenic type’ of MDS and AML with a normal karyotype. Second, many environmental exposures are difficult to quantify or even to verify, and the low incidence of MDS and AML makes it difficult to gather large numbers of patients for study. Third, only a few out of numerous potential gene mutations or rearrangements are present in each case. If only some of these are associated with a specific external exposure, it may be impossible to identify such an exposure as leukemogenic by epidemiologic methods.

t-MDS and t-AML as a model of leukemic transformation The induction by chemically well-defined substances with a known mechanism of action, administered in exact doses and at a known time, make t-MDS and t-AML following chemotherapy exceptional diseases. Further studies may be able to relate chemical structure and reactivity to specific genetic changes more precisely. In the closely followed cohorts of patients treated intensively it may be possible to study a stepwise accumulation, alternatively a ‘one hit’ development, of the genetic changes required for leukemic transformation. Experience from chemotherapy-related MDS and AML may also help in identifying new important chemical exposures, as exemplified by recent studies suggesting that consumption of natural products and medicines,115 and absorption of phenol and hydroquinone from the gastrointestinal tract,116 may be responsible for some cases of de novo MDS and AML.


Acknowledgements Supported by grants from the Danish Cancer Society and HS Forskningspulje 1997.

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