Skip Navigation LinksHome > March 2009 - Volume 16 - Issue 2 > Advancements in the molecular pathogenesis of myelodysplasti...
Current Opinion in Hematology:
doi: 10.1097/MOH.0b013e3283257ac7
Myeloid disease: Edited by Martin S. Tallman

Advancements in the molecular pathogenesis of myelodysplastic syndrome

Epling-Burnette, Pearlie Ka,b,c; List, Alan Fb

Free Access
Article Outline
Collapse Box

Author Information

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

Collapse Box

Abstract

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.

Back to Top | Article Outline

Introduction

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).

Figure 1
Figure 1
Image Tools
Back to Top | Article Outline

Epidemiology

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. [2], 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. [7] 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 [12]. 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.

Back to Top | Article Outline

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 [23]. 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 [25] 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 [26], 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. [27] 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.

Back to Top | Article Outline

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 [13]. Apoptosis and antiapoptotic mechanisms involved in MDS pathogenesis were recently reviewed by Kerbauy and Deeg [28]. In addition to TNF-α, TNF-related apoptosis-inducing ligand (TRAIL) [29], caspase-8 [30], FAS-associated death-domain-like interleukin-1 (IL-1) beta-converting enzyme-inhibitory protein (FLIP) [31], and Fas [32] 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 [34]. 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 [36]. 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. [36] 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 [41]. 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. [36] and Epling-Burnette et al. [41] 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. [36] 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. [49] 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. [51] 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 [52]. Overexpression of transforming growth factor-beta (TGF-β) [53] and stromal cell-derived factor-1 (SDF-1) [54] 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) [55]. 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.

Back to Top | Article Outline

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 [59] 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 [66]. 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 [76]. 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 [77]. 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 [82]). 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.

Back to Top | Article Outline

Conclusion

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.

Back to Top | Article Outline

Acknowledgements

Support for this work was provided by the National Cancer Center, R01CA11211201, and the Veterans' Administration Hospital.

Back to Top | Article Outline

References and recommended reading

Back to Top | Article Outline

Papers of particular interest, published within the annual period of review, have been highlighted as:

Back to Top | Article Outline

• of special interest

Back to Top | Article Outline

•• of outstanding interest

Back to Top | Article Outline

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 148–149).

1• Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001–2004, using data from the NAACCR and SEER programs. Blood 2008; 112:45–52. This article reports the incidence of MDS and chronic myeloproliferative disorders (CMDs) on the basis of population-based cancer registries in the United States. Representing approximately 82% of the US population with more than 40 000 observations reported, this study represents the largest ever reported in MDS.

2 Ma X, Does M, Raza A, et al. Myelodysplastic syndromes: incidence and survival in the United States. Cancer 2007; 109:1536–1542.

3 De Roos AJ, Deeg HJ, Davis S. A population-based study of survival in patients with secondary myelodysplastic syndromes (MDS): impact of type and treatment of primary cancers. Cancer Causes Control 2007; 18:1199–1208.

4 Aul C, Giagounidis A, Germing U, et al. Myelodysplastic syndromes. Diagnosis and therapeutic strategies. Med Klin (Munich) 2002; 97:666–676.

5 Radlund A, Thiede T, Hansen S, et al. Incidence of myelodysplastic syndromes in a Swedish population. Eur J Haematol 1995; 54:153–156.

6 Maynadie M, Verret C, Moskovtchenko P, et al. Epidemiological characteristics of myelodysplastic syndrome in a well defined French population. Br J Cancer 1996; 74:288–290.

7 Yue G, Hao S, Fadare O, et al. Hypocellularity in myelodysplastic syndrome is an independent factor which predicts a favorable outcome. Leuk Res 2008; 32:553–558.

8 Killick SB, Mufti G, Cavenagh JD, et al. A pilot study of antithymocyte globulin (ATG) in the treatment of patients with ‘low-risk’ myelodysplasia. Br J Haematol 2003; 120:679–684.

9 Ganser A, Passweg J, Stadler M, et al. Immunosuppressive treatment strategies in low-risk MDS. Cancer Treat Rev 2007; 33(Suppl 1):S11–S14.

10 Barrett J, Saunthararajah Y, Molldrem J. Myelodysplastic syndrome and aplastic anemia: distinct entities or diseases linked by a common pathophysiology? Semin Hematol 2000; 37:15–29.

11 Saad ST, Vassallo J, Arruda VA, et al. The role of bone marrow study in diagnosis and prognosis of myelodysplastic syndrome. Pathologica 1994; 86:47–51.

12 Tuzuner N, Cox C, Rowe JM, et al. Hypocellular myelodysplastic syndromes (MDS): new proposals. Br J Haematol 1995; 91:612–617.

13 Goyal R, Qawi H, Ali I, et al. Biologic characteristics of patients with hypocellular myelodysplastic syndromes. Leuk Res 1999; 23:357–364.

14 Marisavljevic D, Cemerikic V, Rolovic Z, et al. Hypocellular myelodysplastic syndromes: clinical and biological significance. Med Oncol 2005; 22:169–175.

15 Cermak J, Michalova K, Brezinova J, et al. A prognostic impact of separation of refractory cytopenia with multilineage dysplasia and 5q- syndrome from refractory anemia in primary myelodysplastic syndrome. Leuk Res 2003; 27:221–229.

16 Mohamedali A, Gaken J, Twine NA. Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes. Blood 2007; 110:3365–3373.

17 Sokal G, Michaux JL, Van Den Berghe H, et al. A new hematologic syndrome with a distinct karyotype: the 5q chromosome. Blood 1975; 46:519–533.

18 List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352:549–557.

19 List AF. Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS). Semin Oncol 2005; 32:S31–S35.

20•• Ebert BL, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 2008; 451:335–339.

21 Willig TN, Draptchinskaia N, Dianzani I, et al. Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression. Blood 1999; 94:4294–4306.

22 Draptchinskaia N, Gustavsson P, Andersson B, et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet 1999; 21:169–175.

23 Gazda HT, Grabowska A, Merida-Long LB, et al. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet 2006; 79:1110–1118.

24 Liu JM, Ellis SR. Ribosomes and marrow failure: coincidental association or molecular paradigm? Blood 2006; 107:4583–4588.

25 McGowan KA, Li JZ, Park CY, et al. Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects. Nat Genet 2008; 40:963–970.

26 Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008; 111:86–93.

27 Ebert BL, Galili N, Tamayo P. An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome. PLoS Med 2008; 5:e35.

28 Kerbauy DB, Deeg HJ. Apoptosis and antiapoptotic mechanisms in the progression of myelodysplastic syndrome. Exp Hematol 2007; 35:1739–1746.

29 Zang DY, Goodwin RG, Loken MR, et al. Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and its receptors in myelodysplastic syndrome: effects on in vitro hemopoiesis. Blood 2001; 98:3058–3065.

30 Claessens YE, Park S, Dubart-Kupperschmitt A, et al. Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD. Blood 2005; 105:4035–4042.

31 Benesch M, Platzbecker U, Ward J, et al. Expression of FLIP(Long) and FLIP(Short) in bone marrow mononuclear and CD34+ cells in patients with myelodysplastic syndrome: correlation with apoptosis. Leukemia 2003; 17:2460–2466.

32 Gersuk GM, Beckham C, Loken MR, et al. A role for tumour necrosis factor-alpha, Fas and Fas-ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol 1998; 103:176–188.

33 Aizawa S, Nakano M, Iwase O, et al. Bone marrow stroma from refractory anemia of myelodysplastic syndrome is defective in its ability to support normal CD34-positive cell proliferation and differentiation in vitro. Leuk Res 1999; 23:239–246.

34 Deeg HJ, Beckham C, Loken MR, et al. Negative regulators of hemopoiesis and stroma function in patients with myelodysplastic syndrome. Leuk Lymphoma 2000; 37:405–414.

35 Cortelezzi A, Fracchiolla NS, Mazzeo LM, et al. Endothelial precursors and mature endothelial cells are increased in the peripheral blood of myelodysplastic syndromes. Leuk Lymphoma 2005; 46:1345–1351.

36 Marcondes AM, Mhyre AJ, Stirewalt DL, et al. Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function. Proc Natl Acad Sci U S A 2008; 105:2865–2870.

37 Stirewalt DL, Mhyre AJ, Marcondes M, et al. Tumour necrosis factor-induced gene expression in human marrow stroma: clues to the pathophysiology of MDS? Br J Haematol 2008; 140:444–453.

38 Kim SH, Han SY, Azam T, et al. Interleukin-32: a cytokine and inducer of TNFalpha. Immunity 2005; 22:131–142.

39 Goda C, Kanaji T, Kanaji S, et al. Involvement of IL-32 in activation-induced cell death in T cells. Int Immunol 2006; 18:233–240.

40 Conti P, Youinou P, Theoharides TC. Modulation of autoimmunity by the latest interleukins (with special emphasis on IL-32). Autoimmun Rev 2007; 6:131–137.

41 Epling-Burnette PK, Bai F, Painter JS, et al. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood 2007; 109:4816–4824.

42 Saunthararajah Y, Molldrem JL, Rivera M, et al. Coincident myelodysplastic syndrome and T-cell large granular lymphocytic disease: clinical and pathophysiological features. Br J Haematol 2001; 112:195–200.

43 Sloand EM, Kim S, Fuhrer M, et al. Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities. Blood 2002; 100:4427–4432.

44 Kook H, Zeng W, Guibin C, et al. Increased cytotoxic T cells with effector phenotype in aplastic anemia and myelodysplasia. Exp Hematol 2001; 29:1270–1277.

45 Epling-Burnette PK, Painter JS, Rollison DE, et al. Prevalence and clinical association of clonal T-cell expansions in myelodysplastic syndrome. Leukemia 2007; 21:659–667.

46 Saunthararajah Y, Nakamura R, Wesley R, et al. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood 2003; 102:3025–3027.

47 Molldrem JJ, Caples M, Mavroudis D, et al. Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol 1997; 99:699–705.

48 Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood 2002; 100:1570–1574.

49 Sloand EM, Wu CO, Greenberg P, et al. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 2008; 26:2505–2511.

50 Sloand EM, Mainwaring L, Fuhrer M, et al. Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome. Blood 2005; 106:841–851.

51 Sloand EM, Pfannes L, Chen G, et al. CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins. Blood 2007; 109:2399–2405.

52 Varga G, Kiss J, Varkonyi J, et al. Inappropriate Notch activity and limited mesenchymal stem cell plasticity in the bone marrow of patients with myelodysplastic syndromes. Pathol Oncol Res 2007; 13:311–319.

53 Powers MP, Nishino H, Luo Y, et al. Polymorphisms in TGFbeta and TNFalpha are associated with the myelodysplastic syndrome phenotype. Arch Pathol Lab Med 2007; 131:1789–1793.

54 Fuhler GM, Drayer AL, Olthof SG, et al. Reduced activation of protein kinase B, Rac, and F-actin polymerization contributes to an impairment of stromal cell derived factor-1 induced migration of CD34+ cells from patients with myelodysplasia. Blood 2008; 111:359–368.

55 Fuhler GM, Hooijenga F, Drayer AL, Vellenga E. Reduced expression of flavocytochrome b558, a component of the NADPH oxidase complex, in neutrophils from patients with myelodysplasia. Exp Hematol 2003; 31:752–759.

56•• Rassool FV, Gaymes TJ, Omidvar N, et al. Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia? Cancer Res 2007; 67:8762–8771. This study describes a two-step mouse model of leukemic progression serving as the molecular basis of MDS pathogenesis. Mutant NRAS and BCL2 genes increased the frequency of DNA damage leading to an increased frequency of error-prone repair of double-strand breaks and an increase in reactive oxygen species.

57 Maciejewski JP, Mufti GJ. Whole genome scanning as a cytogenetic tool in hematologic malignancies. Blood 2008; 112:965–974.

58 Haase D. Cytogenetic features in myelodysplastic syndromes. Ann Hematol 2008; 87:515–526.

59 Guillem V, Tormo M. Influence of DNA damage and repair upon the risk of treatment related leukemia. Leuk Lymphoma 2008; 49:204–217.

60 Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108:419–425.

61 Starczynowski DT, Vercauteren S, Telenius A, et al. High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival. Blood 2008; 112:3412–3424.

62 Suela J, Alvarez S, Cigudosa JC. DNA profiling by arrayCGH in acute myeloid leukemia and myelodysplastic syndromes. Cytogenet Genome Res 2007; 118:304–309.

63 Evers C, Beier M, Poelitz A, et al. Molecular definition of chromosome arm 5q deletion end points and detection of hidden aberrations in patients with myelodysplastic syndromes and isolated del(5q) using oligonucleotide array CGH. Genes Chromosomes Cancer 2007; 46:1119–1128.

64 Gohring G, Karow A, Steinemann D, et al. Chromosomal aberrations in congenital bone marrow failure disorders: an early indicator for leukemogenesis? Ann Hematol 2007; 86:733–739.

65 Paulsson K, Heidenblad M, Strombeck B, et al. High-resolution genome-wide array-based comparative genome hybridization reveals cryptic chromosome changes in AML and MDS cases with trisomy 8 as the sole cytogenetic aberration. Leukemia 2006; 20:840–846.

66 Gondek LP, Dunbar AJ, Szpurka H, et al. SNP array karyotyping allows for the detection of uniparental disomy and cryptic chromosomal abnormalities in MDS/MPD-U and MPD. PLoS ONE 2007; 2:e1225.

67 Gondek LP, Tiu R, O'Keefe CL, et al. Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood 2008; 111:1534–1542.

68 Gondek LP, Haddad AS, O'Keefe CL, et al. Detection of cryptic chromosomal lesions including acquired segmental uniparental disomy in advanced and low-risk myelodysplastic syndromes. Exp Hematol 2007; 35:1728–1738.

69 Mohamedali A, Gaken J, Twine NA, et al. Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes. Blood 2007; 110:3365–3373.

70 Tiu R, Gondek L, O'Keefe C, Maciejewski JP. Clonality of the stem cell compartment during evolution of myelodysplastic syndromes and other bone marrow failure syndromes. Leukemia 2007; 21:1648–1657.

71 Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation. Blood 2004; 104:1474–1481.

72 Nucifora G, Begy CR, Kobayashi H, et al. Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations. Proc Natl Acad Sci U S A 1994; 91:4004–4008.

73 Robinson L, Robson L, Sharma P, et al. A novel dicentric deleted chromosome 21 arising from tandem translocation. Cancer Genet Cytogenet 2000; 121:208–211.

74 Imai O, Kurokawa M, Izutsu K, et al. Mutational analyses of the AML1 gene in patients with myelodysplastic syndrome. Leuk Lymphoma 2002; 43:617–621.

75 Harada H, Harada Y, Niimi H, et al. High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 2004; 103:2316–2324.

76 Nucifora G, Birn DJ, Espinosa R 3rd, et al. Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. Blood 1993; 81:2728–2734.

77 Osato M. Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. Oncogene 2004; 23:4284–4296.

78 Kirschnerova G, Tothova A, Babusikova O. Amplification of AML1 gene in association with karyotype, age and diagnosis in acute leukemia patients. Neoplasma 2006; 53:150–154.

79 Niimi H, Harada H, Harada Y, et al. Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations. Leukemia 2006; 20:635–644.

80•• Watanabe-Okochi N, Kitaura J, Ono R, et al. AML1 mutations induced MDS and MDS/AML in a mouse BMT model. Blood 2008; 111:4297–4308. This study describes a murine bone marrow transplantation model expressing mutations of the transcription factor AML1/RUNX1 that are commonly associated with MDS/AML. Depending on the integration site of the AML1 mutant and the specific mutation, some mice developed pancytopenia and erythroid dysplasia, whereas others developed an AML-like phenotype. This manuscript therefore demonstrates the molecular basis of the heterogeneous phenotype observed in MDS and provides a mechanism for leukemia progression.

81•• Omidvar N, Kogan S, Beurlet S, et al. BCL-2 and mutant NRAS interact physically and functionally in a mouse model of progressive myelodysplasia. Cancer Res 2007; 67:11657–11667.

82 Zhang Y, Rowley JD. Chromatin structural elements and chromosomal translocations in leukemia. DNA Repair (Amst) 2006; 5:1282–1297.

Cited By:

This article has been cited 3 time(s).

Hematology-Oncology Clinics of North America
Lenalidomide for Treatment of Myelodysplastic Syndromes: Current Status and Future Directions
Komrokji, RS; List, AF
Hematology-Oncology Clinics of North America, 24(2): 377-+.
10.1016/j.hoc.2010.02.013
CrossRef
Critical Reviews in Oncology Hematology
The immunomodulatory agents lenalidomide and thalidomide for treatment of the myelodysplastic syndromes: A clinical practice guideline
Leitch, HA; Buckstein, R; Shamy, A; Storring, JM
Critical Reviews in Oncology Hematology, 85(2): 162-192.
10.1016/j.critrevonc.2012.07.003
CrossRef
Oncoimmunology
Effector memory regulatory T-cell expansion marks a pivotal point of immune escape in myelodysplastic syndromes
Mailloux, AW; Epling-Burnette, PK
Oncoimmunology, 2(2): -.
ARTN e22654
CrossRef
Back to Top | Article Outline
Keywords:

aging; DNA repair; genetic instability; microenvironment; myelodysplasia

© 2009 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.