Review

Leukemia (2008) 22, 240–248. doi:10.1038/sj.leu.2405078; published online 17 January 2008

Genetics of therapy-related myelodysplasia and acute myeloid leukemia

J Pedersen-Bjergaard1, M K Andersen1, M T Andersen1 and D H Christiansen1

1Department of Clinical Genetics, The Cytogenetic Laboratory, Rigshospitalet, Copenhagen, Denmark

Correspondence: Dr J Pedersen-Bjergaard, Department of Clinical Genetics, the Cytogenetic Laboratory, Section 4052, Rigshospitalet, Blegdamsvej 9, Copenhagen 2100, Denmark. E-mail: chromjpb@rh.dk

Received 19 November 2007; Accepted 27 November 2007; Published online 17 January 2008.

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Abstract

Myelodysplasia (MDS) and acute myeloid leukemia (AML) are heterogeneous, closely associated diseases arising de novo or following chemotherapy with alkylating agents, topoisomerase II inhibitors, or after radiotherapy. Whereas de novo MDS and AML are almost always subclassified according to cytogenetic characteristics, therapy-related MDS (t-MDS) and therapy-related AML (t-AML) are often considered as separate entities and are not subdivided. Alternative genetic pathways were previously proposed in t-MDS and t-AML based on cytogenetic characteristics. An increasing number of gene mutations are now observed to cluster differently in these pathways with an identical pattern in de novo and in t-MDS and t-AML. An association is observed between activating mutations of genes in the tyrosine kinase RAS–BRAF signal-transduction pathway (Class I mutations) and inactivating mutations of genes encoding hematopoietic transcription factors (Class II mutations). Point mutations of AML1 and RAS seem to cooperate and predispose to progression from t-MDS to t-AML. Recently, critical genetic effects underlying 5q-/-5 and 7q-/-7 have been proposed. Their association and cooperation with point mutations of p53 and AML1, respectively, extend the scenario of cooperating genetic abnormalities in MDS and AML. As de novo and t-MDS and t-AML are biologically identical diseases, they ought to be subclassified and treated similarly.

Keywords:

therapy-related myelodysplasia, therapy-related acute myeloid leukemia, 7q-/-7, 5q-/-5, Class I mutations, Class II mutations

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Introduction

For more than two decades, patients with myelodysplasia (MDS) or acute myeloid leukemia (AML) have been classified and treated according to their cytogenetic characteristics, which represent the most important prognostic factor of these diseases.1, 2, 3, 4, 5 Three major cytogenetic subgroups are considered. The first includes patients with the recurrent unbalanced chromosome aberrations. Loss of whole chromosome 5 or 7 (-5/-7) or various parts of the long arms of the two chromosomes (5q-/7q-) or gain of a whole chromosome 8 (+8) are the most common unbalanced aberrations. The abnormalities of chromosomes 5 and 7 are often associated with a complex karyotype, including other recurrent and non-recurrent chromosome aberrations. Such patients are often elderly, present as MDS and have a poor prognosis. The second subgroup comprises patients with recurrent balanced chromosome aberrations, mainly reciprocal translocations. These are often observed as sole abnormalities, in younger patients and in cases presenting as overt AML. Many balanced aberrations confer a favorable prognosis. Finally, the third subgroup includes patients with a normal karyotype. They present as either MDS with a favorable prognosis5 or as AML with an intermediate prognosis.1, 2, 3, 4

Whereas the critical genetic effects underlying 5q-/-5, 7q-/-7 and most other recurrent unbalanced aberrations until recently have remained unidentified, the recurrent balanced translocations and inversions have consistently been shown to result in chimeric rearrangement between genes encoding hematopoietic transcription factors, such as AML1, CBFB, MLL, RARA or EVI1 and their many alternative partner genes.6, 7 These changes characteristically result in a dominant loss of function of the transcription factor (Class II mutations) with defects in differentiation and increased self-renewal. Experiments in mice have shown that the chimeric genes may lead to development of MDS- or leukemia-like diseases.8

Patients with a normal karyotype were previously poorly characterized with respect to genetic changes. More recently, particularly in this subgroup of patients with AML, mutations of the FLT3 gene encoding a receptor tyrosine kinase,9, 10, 11, 12, 13, 14 of the CEBPA gene encoding a hematopoietic transcription factor15, 16, 17 and of the NPM1 transcription regulating gene18, 19, 20, 21, 22, 23 have been observed.

In leukemogenesis, a cooperation between two general types of gene mutations have been proposed (Figure 1).24, 25 Class I mutations result in constitutive activation of receptor tyrosine kinases or genes downstream in the RAS–BRAF–MEK–ERK signal-transduction pathway, thereby stimulating cell cycling and proliferation. Class II mutations, on the contrary, inactivate hematopoietic transcription factors and result in loss of differentiation.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Signal-transduction pathways and classification of mutations in MDS and AML.

Full figure and legend (154K)

Therapy-related MDS (t-MDS) and AML (t-AML) developing after chemotherapy or radiotherapy of a primary disease are of particular interest to study. First, these diseases represent the most serious long-term complication to cancer therapy. Second, as will be discussed below, they share cytogenetic abnormalities and gene mutations with de novo MDS and AML, allowing to extrapolate between observations in the two subtypes of disease. Third, they offer insight into the etiology of MDS and AML, as their cytogenetic abnormalities and gene mutations in many cases are directly related to specific cytotoxic exposures.26, 27, 28 Whereas alkylating agents characteristically induce t-MDS with the chromosome defects 5q/-5 or 7q-/-7 and associated genetic abnormalities, topoisomerase II inhibitors induce overt t-AML with one of the recurrent balanced translocations or inversions.28 Fourth, a close clinical follow-up after intensive therapy for the primary tumor results in a high diagnostic accuracy of t-MDS and allows to study the entire evolution from cytotoxic exposure to development of overt leukemia.

To obtain further insight into leukemogenesis, we have re-evaluated and summarized the results of our previous studies of chromosome abnormalities and mutations of 16 different genes in a cohort of 140 patients with t-MDS or t-AML from the Copenhagen series. In particular, associated, possibly cooperating mutations and their relations to stages of the disease are analyzed in the light of recent research disclosing critical genetic consequences of 5q-/5- and 7q-/7-. Finally, the results are compared to those of other studies of therapy-related and de novo MDS and AML.

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Patients and genes previously studied in the Copenhagen series

Cryopreserved bone marrow cells obtained at the time of diagnosis from 89 patients with t-MDS and 51 patients with t-AML were studied. The patients were unselected, as they represent all cases with the two diagnoses observed at our institution for more than 20 years, and material still available for examination. The detailed clinical and cytogenetic characteristics of 130 patients have been presented previously, whereas data for the remaining 10 cases are unreported.

The genes studied for mutations include the receptor tyrosine kinases FLT3, cKIT and cFMS and the intracellular non-receptor tyrosine kinase JAK2, together with KRAS, NRAS, BRAF and PTPN11 genes in the RASBRAFMEKERK signal-transduction pathway (Figure 1, Table 1). Furthermore, the transcription factors AML1, CBFB, MLL, RARA, EVI1 and CEBPA, the transcription regulatory NPM1 gene and the tumor suppressor gene p53 were studied. Methods used for mutation detection and primary data have been published elsewhere.29, 30, 31, 32, 33, 34, 35, 36 Mutations and internal tandem duplications were all confirmed by sequencing. Chimeric gene rearrangements in cases with the recurrent balanced chromosome aberrations were all confirmed by fluorescent in situ hybridization using breakpoint-specific probes and, in some cases, by supplementary sequencing.


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Frequencies and associations of gene mutations observed in the Copenhagen series of t-MDS and t-AML

Point mutations of p53

Point mutation of p53, often with loss of heterozygosity, was the most common genetic abnormality observed in 34/140 cases of t-MDS or t-AML (Table 1).29, 36 This mutation was highly significantly related to the cytogenetic defects 5q-/-5 (Table 2), as 26/34 patients with p53 mutations presented 5q-/-5, to previous therapy with alkylating agents29 and to complex karyotypes with highly rearranged chromosomes.37 Duplication or amplification of chromosome bands 11q23 and 21q22, including the unrearranged MLL and AML1 genes, were occasionally observed in t-MDS or t-AML38, 39 and closely associated with mutations of p53 (Figure 2).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Associated, possibly cooperating gene mutations observed in the Copenhagen studies of t-MDS and t-AML. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author, tyrosine kinases; Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author, RAS/BRAF signaling pathway; Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author, transcription factors; Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author, p53 tumor suppressor gene; square, number of cases with a Class I+a Class II mutation; circle, number of cases with either two Class I or two Class II mutations; cr, chimeric rearrangement; pm, point mutation; ITD, internal tandem duplication; dup, duplication; ampl, amplification; therapy-related MDS, t-MDS; therapy-related AML, t-AML.

Full figure and legend (131K)


Point mutations of AML1

These mutations were the second most frequent genetic abnormality detected in 22/140 patients with t-MDS or t-AML1 (Table 1).31 Mutations of AML1 were significantly related to previous therapy with alkylating agents, to presentation of the disease as t-MDS and to progression from t-MDS to t-AML. With high significance, mutations of AML1 were associated with the cytogenetic defects 7q-/-7 (Table 2),31 as 17/22 patients with AML1 point mutations presented 7q-/-7. Five patients with AML1 point mutations also presented a RAS mutation (Figure 2) similarly related to progression from t-MDS to t-AML.32 As shown in Table 2, there was no significant overlapping between the pathway defined by 5q-/-5+p53 mutations and the pathway defined by 7q-/-7+AML1 point mutations.

Mutations of genes encoding tyrosine kinases

Point mutations or internal duplications of such genes were observed in 15/140 patients (Table 1).30, 32, 33 They were mutually exclusive (Figure 2), except for one patient presenting two different FLT3 mutations simultaneously, possibly in different subclones. In our series, mutations of FLT3 were related to previous radiotherapy but not to chemotherapy and were often observed in patients with a normal karyotype.30, 32 FLT3 and cKIT mutations were related the to presentation of the disease as overt t-AML,32 whereas two patients with JAK2 mutations presented as t-MDS.33 Mutations of cFMS were not observed. Two patients with cKIT mutations presented as t-AML, in one case associated with a t(8;21). The two patients with JAK2 mutations were uncharacteristic cases of t-MDS disclosing a myeloproliferative pattern with splenomegaly.

Mutations of genes downstream in the RAS/BRAF signal-transduction pathway

Such mutations were observed in 20/140 patients (Table 1)32, 34 and were mutually exclusive except for one case presenting a KRAS and a BRAF mutations simultaneously (Figure 2) and another case presenting two different KRAS mutations.32 In both patients, the two mutations were observed in subclones. Mutations of RAS did not show associations to any specific type of previous therapy and were often observed in atypical cases with a normal karyotype, perhaps representing de novo MDS or AML.32

All three patients with BRAF mutations and 3/14 patients with RAS mutations presented as overt t-AML of FAB (French–American–British) subtypes M4 or M5 with chimeric rearrangement of the MLL gene (Figure 2). All four patients with mutations of PTPN11 presented rare balanced translocations with chimeric rearrangement of the EVI1 gene (two cases) or of the AML1 gene (two cases), all with unknown partners.34 Similar to point mutations of AML1, mutations of RAS were significantly related to progression from t-MDS to t-AML.32

Mutations of transcription factors

A total of 61 mutations of genes involved in hematopoietic transcription and differentiation were observed in 59 patients with t-MDS or t-AML, if classifying mutations of the NPM1 gene together with the mutations of transcription factors (Class II mutations; Table 1). Two patients presented a balanced t(3;21) with chimeric rearrangement between the AML1 and the EVI1 gene. Except for these two cases, mutations of transcription factors were mutually exclusive (Figure 2). Mutations of CEBPA were not observed.

The chimeric rearrangements of AML1, CBFB, MLL, RARA and EVI1 were significantly related to previous therapy with topoisomerase II inhibitors. Mutations of NPM1 were not related to any specific type of previous therapy and often seen in patients with a normal karyotype (7/10 cases).35

Patients with chimeric rearrangement of AML1, CBFB, MLL or RARA and patients with NPM1 mutations primarily presented as overt t-AML, whereas rearrangements of EVI1 and point mutations of AML1; as discussed above, were most common in t-MDS (Table 1).

Cooperation between Class I and Class II mutations

An association, possibly indicating cooperation, was observed between Class I and Class II mutations (Figure 2). In total, 35/140 patients with t-MDS or t-AML presented a Class I mutation, 59/140 patients presented a Class II mutation, whereas 25 patients disclosed a mutation of both classes of genes simultaneously (P=0.0001, Pearson chi2-test with Yates' correction). The associations between point mutations of AML1 and RAS, between mutations of NPM1 and FLT3, between mutations of MLL and RAS and between mutations of MLL and BRAF were most frequently identified. In addition, individual cases with many other combinations between mutated genes of the two classes were observed (Figure 2).

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CRITICAL GENETIC EFFECTS OF 5q-/-5, 7q-/-7, AND p53 mutations

New studies of the molecular effects

In a recent study, Dr Neal Young and his group at the National Cancer Institute observed a constitutive activation of the STAT1/STAT5 signal-transduction pathway in bone marrow cells from cases of MDS with monosomy 7 after GCSF stimulation.40 This effect was related to an overexpression of isotype 4 of the GCSF receptor, which failed to internalize following GCSF binding. No explanation was provided of the association between the cytogenetic defect and the shift in isoform of the receptor. If confirmed also in patients with MDS and 7q-, and in patients with AML and 7q-/-7, the critical lesion of 7q-/-7 is probably equivalent to a Class I activating mutation of a tyrosine kinase.

As far as the important genetic effects of 5q-/-5 are concerned, haploinsufficiency of the EGR1 gene was recently emphasized as a candidate abnormality.41 In another study, haploinsufficiency together with promoter methylation of the CTNNA1 gene was considered.42 Both genes are located within the commonly deleted region on chromosome band 5q31.2. Whether one of these changes, their combination or abnormalities of other genes located within this region is responsible for the decisive genetic effect of 5q-/-5 remains to be determined.

In solid tumors, p53 has repeatedly been demonstrated as a tumor suppressor gene of importance for genomic stability. Its roles in normal hematopoiesis and in leukemogenesis were previously almost unknown. A recent study, however, demonstrated p53 as mediating quiescence of normal hematopoietic stem cells.43 Despite this limited knowledge, the biological effects of p53 seem to differ markedly from those of the genes involved in Class I and Class II mutations in AML. Consequently, p53 mutations most likely represent a new Class III type of mutation in MDS and AML, to which also mutations of WT1 may belong.

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Re-evaluation of combinations of gene mutations in the Copenhagen Series

On the basis of the associations between 7q-/-7 and chimeric rearrangement or point mutation of AML1, as observed in many studies, we previously predicted 7q-/-7 to represent a Class I mutation-like abnormality in leukemogenesis.36 This now seems to be supported.40

In an attempt to characterize the genetic effects of 5q-/-5 and mutations of p53 in a similar way, we searched for their partner chromosome aberrations or partner mutations of Class I or Class II. In patients with 5q-/-5 plus mutated p53, the only recurrent partner abnormality was 7q-/-7, observed in 14/26 cases (Table 3, central column). This association is not significantly different from what could be expected by chance, as in total 63/140 patients with t-MDS or t-AML presented defects of chromosome arm 7q. Noteworthy, only one of the 14 cases with the combination 5q-/-5 + p53 mutation + 7q-/-7 presented an additional AML1 point mutation.


In the subgroup of 16 patients with 5q-/-5 but germline p53, or with mutated p53 but normal chromosomes 5 (Table 3, left + right columns), 8/10 cases with other abnormalities presented combinations between well-defined Class I and Class II mutation-like abnormalities. Taken together, these observations do not support 5q-/-5 or mutations of p53 to be classified as either Class I or Class II mutation equivalents in leukemogenesis.

In conclusion, two general types of mutations (Class I and Class II) predominate and possibly cooperate in MDS and AML. The cytogenetic defects 7q-/-7 seem to participate in leukemogenesis representing Class I-like types of abnormalities. 5q-/-5 and mutations of p53 seem to represent an alternative combination not interfering or overlapping with Class I or Class II abnormalities. If one of the partners 5q-/-5 or mutated p53 is lacking in the combination, it is often replaced by combined Class I and Class II mutations of other genes. The cooperation between different classes of genes may be much more extensive in MDS and AML than previously believed, if also considering chromosome aberrations such as 5q-/-5 and 7q-/-7 in the system.

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Other genetic abnormalities in leukemogenesis

In this review, we have focused on gene mutations and chromosome abnormalities in MDS and AML, and identification of novel genetic abnormalities will possibly in the future increase our understanding of leukemic transformation. Other phenomena, however, such as an abnormally high or low dose of normal regulatory proteins may play an important role. Particularly in t-MDS and t-AML, a decreased dose of the p15INK4B-63, the EGR1-41 or the CTNNA1-42 encoded proteins as a result of promoter methylation or haploinsufficiency must be considered. Also, an increased dose of the unrearranged MLL and AML1 gene products caused by chromosome duplication or amplification38, 39, 64, 65, 66 may represent examples of gene dose effects in AML.

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Conclusion

The identical pattern of cytogenetic abnormalities and gene mutations in de novo and in t-MDS and t-AML supports that these are indeed identical diseases. Consequently, they should be subclassified and treated similarly. Their biological similarity allows to extrapolate experience from one to the other subgroup of disease. Thus, three types of etiology must be considered in de novo MDS and AML. These include exposures to exogenous or endogenous metabolites with alkylating properties, illegitimate gene recombinations related to activities of topoisomerase II and spontaneous mutations or mutations induced by ionizing radiation. The pathogenesis of MDS and AML with cooperating mutations of at least two general classes of genes and chromosome abnormalities may preferentially be studied in therapy-related disease with follow-up from leukemogenic exposures to subsequent development of leukemia. Finally, response to various types of therapy is best studied in de novo MDS and AML. Thus, patients with therapy-related disease must, in many cases, be treated individually with less intensive regimens, as they are often elderly, present a poor performance status with decreased tolerance to intensive therapy and suffer from a primary malignancy, which is still active.

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Acknowledgements

The study was supported by grants from the Danish Cancer Society. The authors are indebted to Cand. Polit. Severin Olesen Larsen for help in the statistical calculations and to Mr Bent Børgesen for drawing the figures.

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