Current Opinion in Hematology:
Myeloid disease: Edited by Martin S. Tallman
Advancements in the molecular pathogenesis of myelodysplastic syndrome
Epling-Burnette, Pearlie Ka,b,c; List, Alan Fb
aH. Lee Moffitt Cancer Center Immunology Program, Tampa, Florida, USA
bDepartment of Malignant Hematology, Tampa, Florida, USA
cJames A. Haley VA Hospital, Tampa, Florida, USA
Correspondence to P.K. Epling-Burnette, PharmD, PhD, H. Lee Moffitt Cancer Center; MRC 4 East, 12902 Magnolia Dr, Tampa, FL 33612, USA Tel: +1 813 745 6177; fax: +1 813 745 1720; e-mail: Pearlie.Burnette@moffitt.org
Purpose of review: Myelodysplastic syndrome is an important hematological malignancy affecting the expanding aged population. Our understanding of the biology of this disease has been limited by the heterogeneous clinicopathological features, difficulty in creating animal models, and paucity of evidence linking molecular abnormalities to disease pathogenesis. The importance of new advances in myelodysplastic syndrome will be discussed in this review.
Recent findings: Heightened awareness of the myelodysplastic syndrome burden has garnered rising interest in the development of new treatment strategies and investigation of the molecular basis of this complex disease. A multistep process explains the heterogeneity observed in myelodysplastic syndrome better than a single event, whereby multiple biological forces culminate in telomere erosion and genomic instability. Intrinsic genetic factors within myeloid progenitors along with extrinsic factors in the microenvironment may foster clonal selection. Specific targeted intervention at critical stages along this multistep pathway, prior to acute myeloid leukemia transformation, may produce the best clinical outcome.
Summary: Newly identified molecular defects, the creation of animal models, and several advancements in our understanding of the molecular pathogenesis have dramatically improved diagnostic and therapeutic potential of myelodysplastic syndrome.
Myelodysplastic syndrome (MDS) may occur through a multistage process that culminates in leukemia progression. As shown diagrammatically in Fig. 1, intrinsic defects within myeloid progenitors and extrinsic environmental factors in the bone marrow microenvironment may both contribute to abnormal apoptosis, accumulation of cells with mutated DNA, and then the conversion to acute myeloid leukaemia (AML).
Recently available data from the North American Association of Central Cancer Registries (NAACCR), which includes registries reporting to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, provided the first opportunity to investigate patterns in the incidence and survival of patients with MDS in the United States [1•,2,3]. The combined SEER and NAACCR registries encompass approximately 82% of the US population, capturing 25 000 reported cases of MDS in 2001–2003, the largest number of cases ever included in a single analysis [1•]. For the years 2001 through 2003, the average annual age-adjusted incidence rate for MDS in the United States was 3.3 per 100 000 and the results were similar whether based on SEER or NAACR registries. Reported by both Rollison et al. [1•] and Ma et al. , results confirmed positive trends in MDS incidence with increasing age and male sex similar to results from European-based cancer registries [4–6].
Importantly, incidence rates for MDS increased annually from 2001 to 2003 at a rate of 3.8 per 100 000 [1•]. Moreover, reporting practices identified in this study raised concern that strategies relying solely on hospital-based cancer registry capture underestimates the true incidence of MDS since cases diagnosed outside of a hospital setting are unreported.
From a study of 1049 adult MDS patients over an 11-year period from 1995–2006, Yue et al.  provided data supporting previous allegations that hypocellular MDS represents a distinct clinicopathological process [7–14]. From this large series of patients, bone marrow cellularity was based on age-adjusted criteria with hypocellularity less than 30% in patients under 70 years and less than 20% in patients over 70 years. Patients with hypocellular MDS were younger (P < 0.01) in age, less anemic (P = 0.02), more neutropenic (P < 0.001) and thrombocytopenic (P = 0.05) compared to normal/hypercellular MDS. Furthermore, follow-up of 52 months demonstrated a favorable overall survival in hypocellular MDS (56 months vs. 28 months) independent of other risk factors (Cox regression test, P = 0.01) compared to normal/hypercellular MDS. This survival benefit was not evident from a smaller study performed in 1995, in which bone marrow cellularity was not an important prognostic factor . Investigation of MDS incidence and survival by combining capture through population-based registries and alternate sources of diagnostic documentation are needed for an accurate assessment of the incidence and prevalence of the disease. The latter study highlights the notion that subsets of patients may have a distinct pathobiology with distinct prognostication.
Ribosomal processing in myelodysplastic syndrome
Of all the MDS subtypes, 5q- syndrome is the most homogenous with regard to clinical phenotype characterized by erythroid hypoplasia in association with severe macrocytic anemia, a normal or elevated platelet count associated with micromegakaryocytes, normal to reduced neutrophil count, and longer survival potential [15–17]. It was recently recognized that these patients and others harboring a chromosome 5q deletion are remarkably responsive to lenalidomide, suggesting that haplodeficiency of a gene contained on chromosome 5 within the interstitial region that is commonly deleted in 5q- syndrome (i.e. the common deleted region, or CDR) may be responsible for this unique phenotype and selective drug responsiveness [18,19]. Recent advancements have been made both in understanding the molecular defects underlying the pathogenesis of this disease and in predictive biomarkers associated with response to lenalidomide therapy.
The CDR in 5q spans 1.5 megabases and contains 40 genes. Because this region does not undergo biallelic deletion and there have been no reports of mutations in the remaining allele, haploinsufficiency of a critical gene was hypothesized to contribute to the homogenous clinical characteristics. To determine the critical haploinsufficient gene(s) involved in the 5q- syndrome, Ebert et al. [20••] employed a novel strategy to systematically incompletely suppress the expression of each 40 candidate genes located in the CDR of 5q in normal CD34+ cells by lentiviral transduction of short hairpin RNAs (shRNAs) to recapitulate allelic loss. The phenotypic consequence of each shRNA was determined by assessing the differentiation of erythroid and megakaryocytes in vitro by cell surface antigen analysis. Of the 40 genes investigated, only reduced expression of the RPS14 gene impaired erythroid differentiation and accelerated apoptosis while preserving megakaryocyte maturation. RPS14 is a component of the 40S ribosomal subunit. Reduction in expression impairs ribosomal biogenesis and leads to the accumulation of 30S pre-rRNA and reduction in formation of the 40S subunit. This finding was the first to provide a molecular link between MDS and the congenital disorder Diamond–Blackfan anemia that is associated with germline heterozygous mutations in RPS19 [21,22] and RPS24 . Other pediatric bone marrow failure syndromes such as Shwachman–Diamond syndrome, dyskeratosis congenital, and cartilage–hair hypoplasia are also associated with mutations affecting ribosomal processing [24,25]. The recent development of an animal model provided the first mechanistic insight into the cause of bone marrow failure resulting from abnormalities in ribosome biogenesis. McGowan and colleagues  showed that impaired ribosome integrity arising from allelic inactivation of the RPS19 and RPS20 genes triggered stabilization of p53, erythroid hypoplasia with accelerated apoptotic death of bone marrow progenitors, and macrocytic anemia. Reduced Trp53 gene dosage rescued the erythroid phenotype, confirming that p53 stabilization is the key effector of the hematologic manifestations. These novel findings have dramatically altered our view of 5q- syndrome and the pathogenesis of haploinsufficient mutations in cancer. Using this methodology, future experiments may identify the role of allelic insufficiency of other gene loci in MDS.
Although haploinsufficiency of RPS14 replicates the characteristic bone marrow findings in 5q- syndrome [20••], reduced dosage of this gene did not explain the karyotype-selective response to lenalidomide therapy. More than two-thirds of red blood cell transfusion-dependent patients with chromosome 5q deletion [del(5q)] as a single or more complex cytogenetic abnormality experience suppression of the clone with restoration of effective erythropoiesis and transfusion-independence after treatment with lenalidomide [18,26]. Patients without del(5q) are clearly less responsive to lenalidomide treatment, with only 56 of 214 (26%) patients achieving transfusion independence , however, with persistence of dysplasia and the underlying chromosome abnormality in responding patients. The results from these trials support mechanistically distinct drug actions on the basis of karyotype in which lenalidomide suppresses the del(5q) clone to restore erythropoiesis, whereas in nondel(5q) MDS it promotes erythropoiesis in the existing clone.
Ebert et al.  recently made a major contribution by defining a molecular signature, using genome-wide profiling, that defined a set of erythroid-specific genes whose expression is markedly diminished in nondel(5q) lenalidomide responders. These results not only represent a clinical breakthrough for patient selection but also indicate that lenalidomide-responsive patients share a common molecular profile that is characterized by profound impairment in erythroid maturation. Ebert and colleagues went on to show that lenalidomide directly restored erythroid maturation potential in vitro, thereby suggesting that lenalidomide acts to possibly modify one or more key regulators of the erythropoietin receptor transcriptional response.
Abnormalities in the bone marrow microenvironment in myelodysplastic syndrome
Tumor necrosis factor-alpha (TNF-α) is well recognized as a cytokine promoter of apoptosis in erythroid cells in early stages of MDS . Apoptosis and antiapoptotic mechanisms involved in MDS pathogenesis were recently reviewed by Kerbauy and Deeg . In addition to TNF-α, TNF-related apoptosis-inducing ligand (TRAIL) , caspase-8 , FAS-associated death-domain-like interleukin-1 (IL-1) beta-converting enzyme-inhibitory protein (FLIP) , and Fas  have all been identified through independent studies to be proteins linked to apoptosis sensitivity in MDS progenitors. In addition to intrinsic sensitivity to apoptosis induction, the stromal microenvironment has shown impaired ability to support differentiation [33–35]. TNF-α was shown recently to modulate gene expression in human bone marrow stroma of patients with MDS with the induction of proinflammatory cytokines including IL-6, IL-8, and IL-32 . IL-32 is a newly identified cytokine that was first identified in natural killer (NK) cells and T-cells that acts as a rheostat for proinflammatory chemokines and cytokines such as TNF-α, via the p38-MAPK and NF-kappaB signaling pathways [36–40]. IL-32 was expressed at a higher level in stromal cells from MDS patients but was lower in stromal cells from CMML patients compared to controls . TNF-α treatment of the stromal cell lines HS5 and HS27a increased IL-32 mRNA and protein suggesting that IL-32 and TNF-α cooperate in a positive feedback loop of paracrine regulation. Inhibition of IL-32 expression with siRNA protected bone marrow cells and bone marrow progenitors from apoptosis.
Because IL-32 was first discovered in NK cells, Marcondes et al.  explored the relationship between NK function and IL-32 expression. In an independent study, we recently demonstrated the regulation of NK cells during disease progression . NK cells from 48 MDS patients displayed impaired NK function against tumor targets that utilize distinct receptor–ligand interactions compared to healthy controls, implying global defects in NK receptor signaling. Reduced NK function was statistically associated with higher International Prognostic Score, abnormal karyotype, and higher bone marrow cellularity. Reduced expression of NKp30 and NKG2D activating receptors were associated with impaired NK function. In both studies, Marcondes et al.  and Epling-Burnette et al.  showed that NK cells from MDS patients fail to exhibit appropriate effector response and blunted response to IL-2 suggesting that abnormal myeloid progenitors may expand due at least in part to evasion of NK immunosurveillance. Based upon low levels of IL-32 in CMML and high levels in MDS but suppressed cytotoxicity function in both diseases, Mercondes et al.  concluded that the levels of IL-32 did not correlate with cytotoxic function. Whereas the mechanism is yet to be determined, abnormal stroma in MDS may play an inhibitory role in NK cell differentiation and development since close contact between these two cell populations are requisite for full differentiation. Loss of immunosurveillance may then lead to the accumulation of cells with DNA damage in the intermediate stages of MDS progression.
A distinct subset of MDS patients may possess CD8+ cytotoxic T-cells that suppress hematopoiesis [42–45] as intimated by hematological responses to immunosuppressive therapy (IST) [46–51]. Sloand et al.  recently summarized the long-term follow-up of the largest study of MDS patients treated with equine antithymocyte globulin (Atgam, Pfizer) with or without cyclosporine at the National Heart Lung Blood Institute (NHLBI). Of 129 patients treated with IST, 39 (30%) achieved a hematologic response with a median follow-up of 3 years (0.03–11.3 years). Compared to combined survival data from 816 patients in the International MDS Risk Analysis Workshop (IMRAW) matched for age and prognostic features, intermediate-1 risk MDS patients younger than 60 years of age treated with ATG had a significant survival advantage. Factors associated with response to ATG+/− CycA were age and HLA-DR15 expression with the strongest linkage to younger age [48,49]. Sloand et al. [50,51] also showed that ineffective hematopoiesis in trisomy 8 MDS was commonly mediated in part by T-cell autoreactive clones. Sorted T-cells of the expanded Vβ subfamilies, but not of the remaining subfamilies, suppressed trisomy 8 CD34+ cell growth in short-term colony formation assays by a Fas-dependent and contact-dependent pathway. Sixty-seven percent of MDS patients in this study with a sole trisomy 8 karyotypic abnormality achieved durable transfusion independence in response to ATG associated with normalization of the T-cell repertoire. Of particular interest, trisomy 8 clones persist and in fact expand in ATG responders. Using microarray analysis of CD34+ cells, Sloand et al.  found that trisomy 8 progenitors display up-regulation of survivin, c-myc, and CD1, and were resistant to apoptosis induced by gamma irradiation. Knock-down of survivin by siRNA resulted in preferential loss of trisomy 8 cells, indicating that survivin protects trisomy 8 cells from complete apoptotic cell death by autoreactive T-cells, allowing expansion following IST. The combined NHLBI results suggest that trisomy 8 patients with a younger age at onset of disease, and patients with an HLA-DR15+ class II HLA-phenotype may be candidates for IST. In patients without trisomy 8, the mechanism of response and pathology are currently unknown.
An increase in proinflammatory cytokines was shown to alter the expression of receptors and ligands involved in Notch signaling . Overexpression of transforming growth factor-beta (TGF-β)  and stromal cell-derived factor-1 (SDF-1)  modulate the proper localization and differentiation capacity of myeloid progenitors within the bone marrow microenvironment. Altered Notch signaling leads to activated immature myeloid cells associated with excessive release of reactive oxygen species (ROS) . Because ROS has been linked to an intermediate stage of MDS pathogenesis [56••], it is possible that this aggressive inflammatory response may impact early mutation events that culminate in genomic instability (shown diagrammatically in Fig. 1). Targeted interruption of selective abnormalities may provide options for individualized therapy in MDS prior to leukemia conversion.
Impaired chromosomal stability leads to successive acquisition of mutation
In the later stages of MDS, acquisition of somatic point mutations and deletions of critical genes has been demonstrated in MDS that is linked to AML progression [56••]. Genes encoding key cellular factors that control differentiation, stem cell survival, and proliferation are frequently mutated in de-novo [57,58] and treatment-related  MDS. The presence of repetitive chromosomal defects in MDS suggests that chromosomal instability may be related to defects in DNA repair mechanisms. On the basis of standard metaphase cytogenetics, 50–60% of MDS patients are considered to have a normal karyotype [16,60]. Metaphase cytogenetics is limited to deletions and changes in large sections of chromosomes and FISH is limited by the use of specific probes. Recent advancements using array-based comparative-genomic hybridization (a-CGH) [61–65], to test for copy number variants between normal and malignant clones, and genome-wide single nucleotide polymorphism (SNP) arrays [66–70] have led to improved sensitivity for detection of cryptic chromosomal changes not evident by metaphase karyotyping. SNP arrays were performed in samples from 174 patients with MDS, myeloproliferative disease, or AML compared to 76 controls . Using this method, karyotype aberrations were found in 59% of MDS patients along with unique lesions that were undetectable by metaphase karyotype analysis. The potential clinical significance of abnormalities detected by SNP array, which were not evident by metaphase karyotyping, was demonstrated by an adverse effect on overall survival.
Despite improved methods of detection, there is to date no correlation between re-occurring mutations and morphology or drug sensitivity. The AML1 gene, a member of the Runx-family of transcription factors located on chromosome 21, represents an important candidate gene mutation that may contribute to AML progression [71–76]. A high frequency (41%) of AML1 mutations was first noted in patients with radiation-associated and therapy-related MDS and AML . Furthermore, a germ line mutation of AML1 was found to occur in a rare autosomal dominant platelet disorder with predilection for AML transformation suggesting that mutations within this gene may lead to AML progression in MDS . Mutations in AML1 have been reported in both the C-terminal and the N-terminal region of the protein in patients with MDS, especially those with refractory anemia with excess blast (RAEB) and in patients with AML following MDS [78,79]. Although AML1 mutations were well documented in MDS, the link between those mutations had not been related directly to disease pathogenesis. To understand how AML1 mutations relate to MDS, investigators performed murine bone marrow transplantation (BMT) using bone marrow cells transduced with specific AML1 mutants [80••]. Most of the transplanted mice developed an MDS-like syndrome within 4–13 months after BMT. In addition to the direct effect of these AML1 mutations, the integration site provided increased pathogenic features and potentiated the phenotype. Specifically, the AML1 point mutation in the N-terminal Runt homology domain (D171N) integrated into an Evi1 site resulting in hepatosplenomegaly, myeloid dysplasia, leukocytosis, and biphenotypic surface markers. In contrast, a C-terminal truncated AML1 mutant developed a different phenotype associated with pancytopenia with erythroid dysplasia that lead to blast accumulation and AML transformation. These data confirm conclusively the role of AML1 mutations in MDS/AML transformation and demonstrates the usefulness of this BMT approach to link genetic abnormalities to phenotypic characteristics in MDS.
Ras signaling also represents an additional mutation and/or activation event associated with early stages of MDS to AML transformation (Fig. 1). Making use of a novel transplantable in-vivo animal model, Omidvar et al. [81••] demonstrated an intricate relationship between the antiapoptotic factor Bcl-2 and mutant NRas (NRASD12) in MDS progression. In this model, Bcl-2 was found to be the rate-limiting step required for leukemia development with expression controlled by the MMTVtTA transactivator under the control of doxycycline, which led to reduced transgene expression. Improvement or reversion of the neoplastic phenotype was based on the presence or absence of doxycycline, respectively. Making use of the same constitutive co-expression model of mutant NRas and Bcl-2, Rassool et al. [56••] demonstrated that mutant NRas/Bcl-2 overexpression led to genomic instability. Instability in chromosomal DNA is an abnormality, which is consistently observed in most forms of cancer. Pathways normally become activated upon DNA damage to repair this damage and prevent the mutation or deletion of genomic material (reviewed in ). Double-strand breaks from ionizing radiation and oxygen radicals closely align with cancer induction. There are two mechanisms for the repair of double-strand breaks including homologous recombination and nonhomologous end-joining (NHEJ) with the later one associated most commonly with errors in DNA repair. Rassool et al. [56••] proposed that myeloid progenitors in MDS may have increased NHEJ misrepair in response to increased generation of DNA damage that leads to genomic instability. Using the NRas/and Bcl2 mouse model, these investigators linked increased levels of ROS in vivo that were inhibited by N-acetylcysteine (NAC) antioxidant treatment, to abnormalities in DNA damage and increased double-strand breaks. This work links DNA damage repair mechanisms to the Ras-MAPK/RAC1 signaling pathway and suggests that antioxidant and interference with Ras-Rac1 signaling may prevent DNA damage and leukemia progression in MDS.
Emerging data suggest that the bone marrow microenvironment plays an important role in the early stages of MDS pathogenesis. Newly identified molecular defects act as key events that trigger the evolution of select clones with heightened survival benefit in the suppressive bone marrow environment. Our understanding of the transition phases of MDS progression has been advanced by the creation of animal models demonstrating a direct connection between molecular defects and the emergence of clonal populations with genomic instability that leads to leukemia progression. New discoveries have dramatically improved the diagnostic, mechanistic, and therapeutic potential of MDS. Future identification of predictors of therapeutic response and the molecular basis of these responses represent the challenging new frontier of MDS research.
Support for this work was provided by the National Cancer Center, R01CA11211201, and the Veterans' Administration Hospital.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 148–149).
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