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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Biol Blood Marrow Transplant. Author manuscript; available in PMC 2011 January 1.
Published in final edited form as:
PMCID: PMC2832708
NIHMSID: NIHMS154855

Therapy-related MDS: Models and Genetics

Introduction

Therapy-related myelodysplastic syndromes (t-MDS) occur in patients exposed to genotoxic chemotherapy, irradiation or both. About 20,000 cases of MDS were diagnosed in the US in 2008, of which approximately 10% were therapy-related. Since objective diagnostic criteria are lacking, this likely underestimates the true incidence. Cases are attributed to prior therapy based on circumstantial evidence, such as the following: 1) presence of typical clonal cytogenetic abnormalities, 2) significant exposure to leukemogenic therapy (e.g., at least one cycle), and 3) sufficient latency from exposure to diagnosis of t-MDS (e.g., at least six months).

Alkylating agents are the principal cause of t-MDS. The syndrome was first recognized in the treatment of Hodgkin Disease, where a relationship between alkylator dose and risk of t-MDS/AML was established [1, 2]. This thinking has been extrapolated to the autologous stem cell transplant population as a potential explanation for t-MDS rates as high as 10% [3]. There are several sources of bias in these retrospective reports, since transplant patients are often heavily pretreated and have increased survival after transplantation (and, therefore, have more years “at risk” for t-MDS). Indeed, there is evidence of clonal abnormalities at the time of transplant in some patients who subsequently develop t-MDS/AML [4, 5]. Nevertheless, at least one prospective, randomized trial in patients with follicular lymphoma demonstrated a higher rate of t-MDS/AML in the high dose vs. conventional dose chemotherapy arm (7% vs. 0%, p=0.014), suggesting that the transplant procedure contributes directly to leukemia risk [6]. In most series, higher rates of t-MDS/AML have been reported for patients conditioned with TBI-containing regimens [3].

Therapy-related leukemia is also caused by exposure to topoisomerase II inhibitors. These patients typically present with t-AML without a preceding MDS phase. As most patients receive combination chemotherapy, it is often impossible to assign blame to a particular agent. Regardless of the cause, t-MDS/AML has an inferior prognosis compared to de novo disease [7]. The only curative option is allogeneic stem cell transplantation [8]. In this sense, this disease is unique among hematopoietic malignancies in that hematopoietic stem cell transplantation is both an important cause and the only available cure.

Genetics

Recurring genetic abnormalities in t-MDS have been defined across the full spectrum of analytical platforms from cytogenetics to gene resequencing. Loss of material from chromosomes 5 and/or 7 is detectable in up to 70% of t-MDS/AML patients, often with other abnormalities in a complex karyotype [9]. The same pattern of cytogenetic abnormalities occur in de novo MDS, but at much lower frequency [10]. Through the work of many investigators, the minimally deleted regions on chromosomes 5 and 7 have been mapped, and the residual alleles have been examined for loss of heterozygosity. We performed a comprehensive analysis of the minimally deleted region on 5q31.2 using array comparative genomic hybridization, gene resequencing, and expression profiling. All 28 genes in the region on the unaffected chromosome were present in germline configuration in this cohort, with no gene consistently silenced [11]. This study and others suggests that multiple genes on 5q31.2 contribute to t-MDS by haploinsufficiency. Similarly, on 7q no single culprit has been identified, raising the possibility that a similar mechanism may apply.

Mutational profiling of individual candidate genes has revealed unique features of t-MDS. Point mutations in TP53, RUNX1, and K/NRAS are more common in t-MDS compared to de novo MDS (approximately 25% vs. 10%, 20% vs. 10%, and 5-10% vs. 5%, respectively), whereas mutations in FLT3 are relatively under-represented in t-MDS [1216]. Ongoing studies using transcriptome, whole exome, and whole genome sequencing approaches will provide an unbiased comparison of the genetic landscape in t-MDS vs. de novo MDS.

There may be a genetic component to t-MDS susceptibility. Rare familial cancer predisposition syndromes provide proof of principle that inherited genetic variants can influence t-MDS/AML susceptibility. For example, children with NF1 are at 200–500 fold risk for developing myeloid malignancies [17], and t-MDS can occur as a second malignancy in adult NF patients exposed to alkylators [18]. In sporadic t-MDS/AML, candidate gene association studies have focused on genes involved in drug detoxification and DNA repair. More than 30 published studies have examined the role of variants in the conjugating enzymes involved in phase II metabolism. A meta-analysis criticized most of these studies for inadequate sample size and population heterogeneity [19]. Associations with the deleted genotypes of glutathione S-transferase GSTM1 and GSTT1 are mostly null. Heterozygosity of the codon 105 polymorphism in GSTP1 does appear to increase risk of t-MDS/AML (OR=2.66, 95% CI 1.39–5.09) [20]. In phase I metabolism, the poor metabolizer genotypes of CYP2C19 or CYP2D6 do not appear to be associated with t-MDS/AML risk [21], whereas reduced risk (OR=0.07) was associated with the variant allele in the 5’-promoter of CYP3A4 [22]. Common polymorphisms in genes involved in the response to drug-induced DNA damage have also been implicated as risk factors for t-MDS/AML. Like changes in genes involved in drug detoxification, the relative risks associated with these variations are small, but their high prevalence implies a potentially significant attributable risk of t-MDS/AML. Increased risk of t-MDS/AML has been demonstrated with the Lys751Gln variant of ERCC2 (XPD) [23], a SNP in exon 13 of MSH2 [24], and a protective effect of proline at codon 399 of XRCC1 [25]. Many of these associations have been difficult to replicate, as is often the case in under-powered gene association studies. Sample size is an even greater constraint in genome-wide association studies, although one recent publication reported significantly more SNP associations in t-MDS/AML than would be expected by chance [26].

Models

Animal models of t-MDS provide platform both for identifying recurring mutations relevant for human t-MDS and germline alleles that affect susceptibility. Heterozygous Nf1 mutant mice are susceptible to a spectrum of spontaneous and therapy-induced myeloid malignancies that resembles the pattern seen in humans with germline NF1 mutations [27]. To identify novel genes associated with t-MDS susceptibility, we performed a genome-wide screen in mice. We exposed a large panel of inbred strains to the prototypical alkylator, N-nitroso-N-ethylurea (ENU). Myeloid malignancies (MDS, AML, granulocytic sarcoma) were induced in a strain-dependent manner, supporting the notion that there is a genetic component to susceptibility [28]. An F2 intercross between susceptible and resistant strains identified loci associated with leukemia-free survival after ENU [29]. Fine-mapping these intervals has identified candidate genes that are being tested for their importance in t-MDS/AML susceptibility.

Several other mouse models of human MDS have been generated using transgenic, gene targeting, and retroviral transduction/transplantation approaches (reviewed in [30]). Although these models recapitulate (to varying degrees) the phenotype of human MDS, they are defined by single genetic events and, therefore, do not capture the complexity of t-MDS. Similarly, other animal models of MDS exist [30] that have not yet been exploited to study t-MDS.

Bench to Bedside

Ongoing genomic studies in patients and animal models of t-MDS will provide new information that could be translated into strategies for improved treatment and prevention of t-MDS. Identification of recurring mutations may provide new targets for therapy. Translating knowledge of susceptibility alleles into prevention and control strategies for t-MDS may prove more challenging. One approach would be to identify patients with high risk genotypes and tailor their therapy accordingly. Many caveats apply here: the effect size of the genotype must be relatively large, the prevalence of variant alleles in the population must be relatively high, and equipotent chemotherapy must be available. Providing suboptimal chemotherapy to a relatively large group of patients with potentially curable malignancies in order to prevent a rare (albeit, serious) complication is an unacceptable tradeoff. A second strategy would be to offer intensive surveillance for t-MDS after alkylator exposure in patients with high genotype-specific relative risk. This effort would only be justified if there was evidence that chemotherapy delays progression from t-MDS to t-AML or that early transplant improved overall survival in t-MDS. A final concept that is more speculative at this stage may prove most useful in the long term. It is predicated on understanding the biochemical events relevant for t-MDS initiation. If key regulatory factors can be identified, it may be possible to perturb them during alkylator exposure in such a way as to preserve antitumor efficacy while reducing hematologic toxicity. These approaches all require additional work in animal models before clinical trials can be initiated. Since patients undergoing autologous stem cell transplantation are at high risk, they may be an ideal population to recruit to these trials. A successful outcome will certainly depend on broad support from the transplant community.

Footnotes

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