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Myelodysplastic syndromes

The myelodysplastic syndromes (MDS, formerly known as "preleukemia") are a diverse collection of haematological conditions united by ineffective production of blood cells and varying risks of transformation to acute myelogenous leukemia. Anemia requiring chronic blood transfusion is frequently present. more...

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Signs and symptoms

Abnormalities include:

  • neutropenia, anemia and thrombocytopenia (low cell counts of white & red blood cells and platelets, respectively)
  • abnormal granules in cells, abnormal nuclear shape and size
  • chromosomal abnormalities, including chromosomal translocations.

Symptoms of myelodysplastic conditions:

  • Anemia - chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
  • Neutropenia (low white cell count) - increased susceptibility to infection
  • Thrombocytopenia (low platelet count) - increased susceptibility to bleeding

All these conditions have an increased risk of developing acute leukaemia, which is notoriously resistant to treatment ("secondary leukaemia").

Diagnosis

Investigation:

  • Full blood count and examination of blood film
  • Bone marrow aspirate and biopsy with examination by an experience hematopathologist
  • Cytogenetics or chromosomal studies. This is performed on the bone marrow aspirate.

Pathophysiology

MDS is due to genetic defects in the multi-potent blood stem cell of the bone marrow. Most of these are not yet described. Differentiation of the abnormal cells is impaired. Clonal expansion of the abnormal cells lead to production of abnormal cells and decreased production of normal bone marrow products.

Bleeding (due to lack of platelets) or infection (due to lack of white blood cells) is common in the majority of MDS patients. In about 25-35% of patients there is a further genetic mutation in one of the abnormal blood stem cells which eventually results in acute leukemia. The progression of MDS to leukemia is a good example of the multi-step theory of carcinogenesis in which a series of mutations occur in an initially normal cell and transform it into a cancer cell.

Types and classification

French-American-British (FAB) classification

In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This French-American-British (FAB) classification was published in 1976 and revised in 1982. Cases were classified into 5 categories: (ICD-O codes are provided where available)

  • (M9980/3) Refractory anemia (RA) - characterized by less than 5% primitive blood cells (myeloblasts) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
  • (M9982/3) Refractory anemia with ringed sideroblasts (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
  • (M9983/3) Refractory anemia with excess blasts (RAEB) - characterized by 5-19% myeloblasts in the marrow;
  • (M9984/3) Refractory anemia with excess blasts in transformation (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
  • (M9945/3) Chronic myelomonocytic leukaemia (CMML) - not to be confused with chronic myelogenous leukemia or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 109/uL monocytes (a type of white blood cell) circulating in the peripheral blood.

A table comparing these is available from the Cleveland Clinic.

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Myelodysplastic Syndromes: Clinicopathologic Features, Pathobiology, and Molecular Pathogenesis
From Archives of Pathology & Laboratory Medicine, 10/1/05 by Nishino, Ha Thanh

Context.-Myelodysplastic syndromes (MDSs) are clonal stem cell diseases characterized by ineffective hematopoiesis, multilineage dysplasia, and peripheral cytopenias with normocellular or hypercellular marrow. They represent a heterogeneous group of disorders with a varied spectrum of clinical, morphologic, biologic, and genetic characteristics. This heterogeneity in disease characterization has led to evolving classification systems, developing prognostic models, and continuing research efforts to elucidate its pathobiology and pathogenesis.

Objective.-To summarize updated information and provide a general overview of the clinicopathologic features, pathobiology, and cytogenetic and molecular pathogenesis of MDSs.

Data Sources.-Relevant articles indexed in PubMed (National Library of Medicine) between 1982 and 2005 and reference medical texts.

Conclusions.-Although MDSs remain a relatively poorly defined disease entity, recent advancements in cytogenetic and molecular studies have significantly contributed to our present knowledge of MDSs. Novel strategies for studying the pathogenesis and evolution of MDSs continue to shape our understanding of this disease and guide our approaches to diagnosis and treatment.

(Arch Pathol Lab Med. 2005;129:1299-1310)

Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders of hematopoietic stem cells that are characterized by ineffective hematopoiesis, multilineage dysplasia, peripheral cytopenias, and susceptibility to leukemic transformation. The heterogeneity of the clinical, morphologic, biologic, and genetic characteristics of MDSs has led to evolving classification systems and continuing research proposed to elucidate its pathobiology and disease mechanisms. Although it remains an inadequately characterized disorder, our understanding and treatment of MDSs continue to be enhanced by our growing knowledge of the processes that contribute to the disease pathogenesis.

This review is divided into 3 major sections: (1) summary of the clinicopathologic features of MDSs, including classification (French-American-British [FAB], World Health Organization [WHO]) and prognostic stratification (International Prognostic Scoring System [IPSS]); (2) overview of the pathobiology of MDSs, including clonality, multistep disease development, derangements in cell proliferation and differentiation, and apoptosis; and (3) consideration of the cytogenetics and molecular pathogenesis of MDSs, including data from recent complementary DNA (cDNA) microarray technology.

CLINICOPATHOLOGIC FEATURES

Demonstrating a varied spectrum of biologic, genetic, morphologic, and clinical characteristics, MDSs have a natural history that ranges from indolent disease that lasts for years to accelerated progression toward acute leukemia within months. Clinical features of MDSs often stern from manifestations of bone marrow failure and resultant cytopenias (anemia, neutropenia, thrombocytopenia). Although common presenting symptoms include fatigue, pallor, infection, bruising, and/or bleeding, patients may be asymptomatic at diagnosis. Currently, the diagnosis of MDSs is minimally based on a combination of peripheral blood cell counts and morphologic examination of peripheral blood and bone marrow. Additional studies useful in establishing diagnosis include cytogenetic analysis, immunophenotyping, in vitro colony growth assays, and molecular genetic tests.

Primary or de novo MDSs predominantly affect older populations, with a median age of onset of 60 to 70 years. Although actual epidemiologic statistics are unknown, MDSs have an estimated annual incidence of approximately 3.5 to 10 per 100000 in the general population and 12 to 50 per 100000 in the elderly population.1 The rising frequency and incidence of MDSs in the US population may be attributed to the growing aging population and increasing disease recognition and diagnosis.1,2 Although largely affecting older adults, MDSs have been documented in younger people at a lower incidence.3-5 Predisposing factors with variable relative risks for developing MDSs include occupational exposure to benzene, pesticides, organic solvents, and other cytotoxic agents or environmental carcinogens.

The wide variability in prognosis of MDSs is accompanied by heterogeneous diagnostic criteria and classification systems. Disease classification systems for MDSs have been developed and modified during the past several decades. Introduced in 1982, the FAB Classification provided the initial framework for morphologic classification and diagnostic evaluation of MDSs.6 This system defined 5 major subtypes of MDSs characterized by percentage of blasts, the presence of ringed sideroblasts, and the extent of monocytosis. Table 1 summarizes the criteria for peripheral blood and bone marrow findings for these FAB subtypes of refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia. Since its introduction, the FAB Classification has realized widespread use and clinical utility despite its prognostic limitations.

In 1999, the WHO established a modified scheme for the categorization of hematopoietic neoplasms that proposed to improve the prognostic significance of MDS classification.7 With incorporation of biologic and genetic features of disease to morphologic findings, the WHO guidelines offer refinements to subgroup designations. These changes include classifying chronic myelomonocytic leukemia into a distinct category of myelodysplastic/myeloproliferative diseases due to its potential for disease presentation that bridges the spectrum of MDSs and myeloproliferative disorders and eliminates the FAB definition of RAEB-t by reducing the defining threshold of blasts for acute myeloid leukemia (AML) to 20%. Also, cytogenetic data are incorporated with the addition of the subtype 5q-syndrome. Furthermore, the WHO proposals introduce an additional category designated as refractory cytopenia with multilineage dysplasia; this subtype comprises cases that demonstrate significant cytopenia and dysplasia but do not meet minimum blast criterion for the classification of RAEB. This group of patients has been shown to have slightly more favorable prognosis compared with patients with RAEB classification but worse prognosis than patients with unilineage dysplasia (RA, RARS).8 Although some revisions to the former organization of MDSs and AML remain controversial, the WHO recommendations for MDS classification generally are continuing to gain increasing acceptance. The WHO classification and criteria for MDSs along with corresponding FAB designations are presented in Table 2.

As a complement to morphologic classification, the IPSS was devised as a risk-based classification system for prognostic stratification of newly diagnosed, untreated primary MDSs.9 Based on independent prognostic variables of percentage of bone marrow blasts, degree of cytopenia, and chromosomal pattern, the IPSS defines 4 distinctive risk groups with variable probability for survival and evo- lution to acute leukemia. In the prognostic model by Greenberg et al,9 median overall survival times for MDS patients based on IPSS risk categories are as follows: low risk, approximately 5.7 years; intermediate 1 risk, approximately 3.5 years; intermediate 2 risk, approximately 1.2 years; and high risk, approximately 0.4 years (Table 3). Similarly, by stratified risk groups, median intervals for 25% of patients to transform to AML are as follows: low risk, approximately 9.4 years; intermediate 1 risk, approximately 3.3 years; intermediate 2 risk, approximately 1.1 years; and high risk, approximately 0.2 year. Data on survival and AML evolution of MDS patients subgrouped according to the WHO classification system alone and in combination with IPSS risk stratification are summarized in Table 4. The IPSS model of MDSs proposes to be a valuable tool in the practical approach to evaluating disease prognosis.

Currently, the only curative treatment available to MDS patients is bone marrow or peripheral stem cell transplantation. With improving characterization of pathophysiologic pathways and potential molecular targets in MDSs, recent therapies have been developed, including DNA methyltransferase inhibitors, vascular endothelial growth factor (VEGF) inhibitors, farnesyl transferase inhibitors, thalidomide, arsenic trioxide, and anti-tumor necrosis factor α (anti-TNF-α).10-15 Greater insight into the underlying molecular mechanisms that lead to marrow failure and progression to acute leukemia may identify additional strategies and targets for diagnostic and therapeutic approaches.

PATHOBIOLOGY

The etiology and pathogenesis of MDSs remain poorly characterized. Underlying the marrow failure and peripheral cytopenias common in MDSs is deranged clonal proliferation of hematopoietic progenitor cells with inherited or acquired genetic mutation. Although its characterization continues to be controversial, clonality in MDSs has been supported by cytogenetics, fluorescence in situ hybridization analysis, and X-chromosome inactivation studies.2-16"22 These various studies strongly suggest clonal involvement of the myeloid lineages; however, the clonal character of the lymphoid lineage remains unclear. Importantly, the effect of this primary clonal mutation that involves pluripotent or multipotent hematopoietic cells may establish the MDS phenotype and its natural disease course.

Development of MDSs presumably occurs through multiple evolutionary stages. Likely representing an early-stage event in the multistep pathogenesis of MDSs, the initial genetic insult to hematopoietic stem cells leads to emergence of an aberrant clone that exhibits morphologic dysplasia, cellular dysfunction, and disparate proliferative advantage. Although the mechanisms that promote the initiation of MDSs are not well defined, events implicated in this process include somatic DNA injury, defective DNA repair, impaired immunologie surveillance, and dysregulated cell signal transduction.2,23-25 Furthermore, the initiating clonal defect is believed to promote genomic instability and heightened susceptibility to acquisition of additional genetic lesions. Subsequent evolution of this mutant clone is associated with progressive cellular dysfunction and ineffective hematopoiesis characterized by excessive apoptosis. Impaired cellular differentiation and maturation accompanying the dysregulated apoptosis contributes to the peripheral cytopenias characteristic of the MDS phenotype. Ultimately, as a potential final stage in its multistep pathogenesis, continued expansion of this abnormal clone with accumulated genetic damage and alteration of critical targets may result in neoplastic transformation to acute leukemia.

Derangements in hematopoietic cell proliferation and differentiation that characterize MDSs are associated with complex changes in biology. The early proliferative advantage of MDS clones may be represented by increased cellular proliferation particularly in the myeloid lineage and potentially all hematopoietic lineages.26 Accumulating multiple alterations that may affect cycle regulation, transcription factors, growth factor receptors, and tumor suppressors, these clonal cells further expand with abnormal maturation and increased rates of apoptosis. Opposing forces of increased cell proliferation and excessive cell death in concert with impaired differentiation of hematopoietic progenitor cells result in the ineffective marrow hematopoiesis and peripheral cytopenias observed in MDSs, often in the setting of normal to hypercellular bone marrow.

Particularly, the mechanism, of programmed cell death (apoptosis) has been hypothesized as a possible explanation for the apparent paradoxical MDS phenotype of peripheral cytopenia alongside marrow cellularity. Excessive apoptosis of hematopoietic progenitor cells may contribute to the defining features of MDSs, including dysplastic morphologie features, ineffective hematopoiesis, and marr row failure.27-32 Studies have demonstrated morphologic evidence of increased apoptotic cell death in MDSs, particularly in less advanced disease.33-36 Alongside this observation, some studies suggest that disease progression may be accompanied by decreased rates of apoptosis, because susceptibility to intramedullary cell death changes with changing cellular phenotype.33,34,36-38 These studies offer evidence for increasing levels of antiapoptotic Bcl-2 marrow blasts with advancing MDS subtype.33,37,38 These observations are consistent with other reports of shifting ratios of proapoptotic and antiapoptotic proteins with the progression of MDS disease.39,40 Although increased programmed cell death in MDSs may occur as an early rescue or compensatory response to dysregulated clonal proliferation, it may also represent a pathophysiologic consequence of the epigenetic changes associated with the dis ease biology of MDSs. Possible mechanisms that contribute to excessive apoptosis in MDSs include essential genetic damage and a perturbed marrow microenvironment.23,41 Whether by direct injury to critical gene targets or complex downstream effects of elaborated cytokines and altered cellular milieu, diverse apoptotic stimuli may activate various signal transduction pathways for apoptosis that culminate in a common cell death program. The interesting relationship of cell death with dysregulated cellular proliferation and differentiation suggests a unique role for apoptosis in MDSs. The significance of apoptosis and other key mechanisms in the molecular pathogenesis of MDSs continues to be investigated as the complex biologic features of such hematologic diseases are further recognized.

CYTOCENETICS AND MOLECULAR PATHOGENESIS

The heterogeneity of the clinical and morphologic pictures of MDSs reflects the fundamentally complex genetic and biologic abnormalities manifested in its pathogenesis. Important aspects of this disease that can be investigated at the molecular level include the cytogenetic abnormalities and dysregulated gene pathways common to MDSs. Elucidating the pathogenetic processes and molecular mechanisms underlying MDSs is central to our understanding of disease biology and prognosis.

Clonal cytogenetic abnormalities are important in the characterization of MDSs. The presence of chromosomal abnormalities can be identified in approximately 30% to 50% of primary MDSs and in more than 80% of secondary or therapy-related MDSs.42 Karyotyping is particularly valuable in the clinical evaluation of MDSs and is integrated into the IPSS model for risk stratification for survival and AML evolution. Representing stages of the multistep pathogenesis of MDSs, single or complex cytogenetic abnormalities may manifest in early MDSs and persist or evolve with disease progression. More complex cytogenetics tend to be associated with disease progression and therapy-related MDSs. Structural and/or numerical chromosomal aberrations may be present. Unlike the chromosomal translocations frequently observed in AML, unbalanced chromosomal changes that consist of partial or complete losses are common in MDSs. Characteristic chromosomal deletions involve chromosome 5 [del(5q),-5], chromosome 11 [del(11q)], chromosome 12 [del(12q)], chromosome 20 [del(20q)], chromosome 7 [del(7q),-7], chromosome 17 [del(17p)J, and chromosome 13 [del(13q)]. Other frequent chromosomal abnormalities include trisomy 8, trisomy 21, and inversion 3(q21q26). Rare reciprocal translocations include t(l;7)(qlO;plO), t(l; 3)(p36;q21), t(3;3)(q21;q26), t(6;9)(p23;q34), and t(5; 12)(q33;p13); t(5;7)(q33;11.2).

The incidence of these cytogenetic aberrations may reflect the genomic instability of affected MDS clones and their susceptibility for acquisition of additional genetic lesions. In particular, chromosomal deletions in MDSs suggest aberrations of genes involved in tumor suppression or DNA repair. As the most common chromosomal aberrations in MDSs, abnormalities in chromosomes 5 and 7 have been investigated extensively. Partial or complete deletion of chromosome 5 is estimated to occur in 10% to 15% of MDSs that arise de novo and 50% of therapy-related disease.43,44 The critical region of interstitial deletion within chromosome 5[5q31-5q33] has been associated with genes that encode hematopoietic cytokines (colony-stimulating factor [CSF] 2, interleukin [IL] 3, IL-4, IL-5, IL-9), hormone and growth factor receptors (CSFlR, α^sub 1^,-adrenergic receptor [ADRA1], β^sub 2^-adrenergic receptor [ADRB2], glucocorticoid receptor 1 [GRL1]), and proteins active in transcription and signal transduction (epidermal growth factor [EGF] 1, interferon regulatory factor 1 [IRF1]).45-46 Chromosomal 7 abnormalities associated with complete or partial deletions may occur in 10% of cases of primary MDS and AML and 50% to 75% in therapy-related MDSs and AML.47,48 Presumably involving tumor suppressor genes, critical deletions of the long arm have been localized to 7q22 and 7q32-34.47,49 Characterization of the genes associated with these and other recurrent chromosomal aberrations will contribute to our understanding of their normal physiology and role in the pathogenesis of MDSs.

Molecular abnormalities derived from genetic mutations likely mediate the development and progression of MDSs. Active research efforts in this area have led to the identification and characterization of important genes and molecular pathways.

To date, numerous genes have been implicated in the molecular pathogenesis of MDSs (Figure). These targets of interest include oncogenes, cell cycle regulatory genes, apoptotic genes, growth factor or angiogenesis genes, genes that regulate DNA methylation and histone deacetylation (epigenetic gene silencing), and immunomodulatory cytokine genes.

Oncogenes

The RAS gene family and its signaling transduction pathway are among the most widely investigated molecular targets in oncogenesis. Activated by ligand binding to cell surface receptors such as tyrosine kinases, RAS proteins function in intracellular signaling pathways to promote cellular proliferation and differentiation. The mutated RAS gene product features constitutive activity in its persistent guanosine triphosphate-bound form to promote continuous kinase activity and signal transduction. Point mutations of the n-ras oncogene that demonstrate this dysregulated signal transduction have been reported in 10% to 40% of MDSs.50-53 Furthermore, n-ras mutations have been associated with decreased survival and higher incidence of leukemic progression.51,54 Many studies suggest that mutations of the ras oncogene in initial or advanced stages of disease may contribute to the pathogenesis of MDSs by stimulating early progressive clonal expansion or late leukemic transformation.51,55,56

The FMS gene encodes the cell surface receptor of CSF-1 or macrophage CSF. Expressing ligand-dependent tyrosine kinase activity, this gene product bound to CSF-I promotes the proliferation and differentiation of hematopoietic cells of the monocyte-macrophage series.57,58 Mutation in the c-fms gene results in an altered gene product, with conformational change supporting constitutive receptor transduction. Mapped to chromosome 5q33, the FMS gene region has been implicated in the pathogenesis of hematopoietic diseases, including MDSs.47,52,59,60 Point mutation at codon 969 has been reported with increased incidence in association with more advanced MDS subtypes.52,61

Cell Cycle Regulatory Genes

Dysregulation of normal cell growth through the cell cycle may contribute to leukemogenesis and the pathogenesis of MDSs. Epigenetic alteration of the cyclin-dependent kinase inhibitor gene p15^sup INK4B^ has been observed in hematopoietic progenitor cells in MDSs. Recent studies suggest that hypermethylation of CpG islands in the promoter region of cell cycle inhibitor p15^sup INK4B^ may be associated with disease progression and leukemic transformation in MDSs.62-64 This mechanism for inactivation of regulatory genes such as p15^sup INK4B^ suggests a process by which leukemic cells may evade the inhibitory signals imposed by the milieu.

EVl-I is another gene that encodes for a complex transcription factor involved in myeloid maturation through interaction with multiple cell cycle regulators.65 Overexpression of the proto-oncogene EW-2 has been documented in chronic myeloid leukemia and AML transformed from MDSs.66"68 Furthermore, data suggest that a fused AML1/EVI-1 chimeric gene product produced by the reciprocal t(3;21)(q26;q22) translocation may inhibit terminal hematopoietic progenitor cell differentiation in erythroid and granulocytic lineages.69-72

Additional mutations that involve other genes, including CHK2, p53, and MLL, have been implicated in altered checkpoint controls or other cell cycle abnormalities that may contribute to the pathogenetic processes in MDSs.73-76

Apoptotic Genes

Dysregulated genes responsible for the transcription of cytokines and growth factors that regulate apoptosis likely contribute to the ineffective hematopoiesis characteristic of MDSs. In addition to the direct effect of abnormal elaboration of apoptotic factors, the resulting disordered cellular-stromal microenvironment associated with altered levels of these gene products further potentiate cellular susceptibility to apoptosis and disrupt hematopoietic cell capacity for proliferation and survival in MDSs.23,77 Elevated levels of various cytokines have been associated with increased apoptotic cell death in MDSs, including TNF-α receptor, transforming growth factor β (TGF-β), IL-1β, IL-6, interferon-γ (IFN-γ), VEGF, and Fas/Fas ligand.26,28-78-80 Particularly, gene products for bcl-2 proto-oncogene, c-myc, and p53 have been implicated as key regulators in the apoptotic pathway. Bcl-2 represents the prototypical negative regulator of apoptosis from the Bcl-2 family of proapoptotic and antiapoptotic proteins. It primarily functions through dimerizations with family members and through interactions with other regulators, such as p53 and RAS. With subcellular localization to mitochondrial membrane, endoplasmic reticulum, and nuclear envelope, Bcl-2 has been reported to participate in ion channel formation and the alteration of membrane permeability necessary for the initiation of apoptosis.81,82 Increased bcl-2 expression has been correlated with MDS progression, with the highest bcl-2 overexpression observed in more advanced subtypes (RAEB and RAEB-t by FAB classification).37-38-83 c-myc and p53 are proapoptotic regulators that have also been shown to be abnormally expressed in hematopoietic cells of MDSs. c-Myc presumably accelerates apoptosis in hematopoietic cells through its association with designated growth factors and apoptotic regulators such as Bcl-2.84-85 Increased levels of c-myc relative to bcl-2 expression have been reported in MDS subtypes RA and RARS.39 p53 promotes apoptosis in various cell lineages, including the myeloid line, and functions through its interactions with numerous regulators of the apoptotic pathway. Enhanced p53 expression has been associated with MDS evolution to leukemia.38-86

Growth Factor and Angiogenesis Genes

Dysregulation of genes that encode angiogenic factors involved in the growth of endothelial or hematopoietic cells87-88 may play an important role in the pathophysiology of hematologic malignancies such as MDSs. Reported mediators of angiogenesis include VEGF, basic fibroblast growth factor, angiogenin, angiotropin, angiopoietin-1, platelet-derived growth factor, hepatocyte growth factor, EGF, TNF-α, TGF-a, TNF-β, IL-I, IL-6, IL-8, and granulocyte-macrophage CSF.89,93 Increased angiogenesis has been observed in MDSs88,94-95 in association with elevated levels of VEGF, basic fibroblast growth factor, and hepatocyte growth factor.96 Furthermore, the extent of angiogenesis has been correlated with disease progression with increasing bone marrow vascularity associated with more advanced disease (progressive subtypes per FAB classification).88,94 Overexpression of specific angiogenic mediators in hematopoietic cells supports the influence of tumor microenvironment and suggests an autocrine role for these cytokine factors in promoting neoplastic growth and proliferation in MDSs.95,97

Receptor Tyrosine Kinase Genes

FIT3, a frequently mutated gene in AML, encodes for a class III receptor tyrosine kinase preferentially expressed on hematopoietic progenitor cells. When engaged by its ligand, phosphorylated FLT3 activates signal transduction pathways involved in the proliferation of pluripotent and progenitor cells, including RAS/MAPK, STATS, PLCγ, and SHIP.98-100 An internal tandem duplication of this gene (FLT-ITD) has been reported in approximately 20% of AML patients and 3% of MDS patients, and this mutation has been associated with poor prognosis or increased incidence of leukemic transformation in MDSs.101-102 Another mutation in the second tyrosine kinase domain (TDK) within the activation loop of FLT3 has also been identified in hematologic malignancies. One recent study reported this D835 mutation of the FLT3 gene in 30 (7%) of 429 AML cases, 1 (3.4%) of 29 MDS cases, and 1 (2.8%) of 36 acute lymphocytic leukemia cases.103 These mutations disrupt normal tyrosine kinase activity and likely contribute to the dysregulated cellular signaling associated with leukemic progression. The frequency of FLT3 mutations among hematologic malignancies suggests their significance in the pathophysiology of hematopoietic progenitor cells.

Genes Regulating DNA Methylation and Histone Deacetylation

Important mechanisms for epigenetic alteration of gene expression include DNA methylation and histone acetylation. Dysregulation of these genes that encode enzyme and protein products responsible for modifying chromatin structure and DNA methylation patterns contributes to carcinogenesis by transcriptional inactivation of critical genes; these genes may include tumor suppressor genes, DNA repair genes, or other genes involved in cellular proliferation and differentiation. Aberration of DNA methylation has been linked to various solid neoplasms and hematologic malignancies.104-105 Although genomic hypomethylation with chromosomal instability was initially observed in tumorigenesis,106-110 recent studies suggest that hypermethylation of CpG islands on promoter regions may represent a common mechanism for inactivation of tumor suppressor genes in many human cancers, including hematopoietic neoplasms.62-64,111-115 Hypermethylation of various genes, including E-cadherin,15,116,117 calcitonin,15,1180-120 estrogen receptor,15,121 HICl,122-125 and cyclin-dependent kinase inhibitor genes p15, p16, p21, and p57,62-64,111-115 have been implicated in hematologic malignancies.

Gene expression inactivation associated with DNA methylation may occur through multiple synergistic mechanisms. CpG methylation of gene promoter regions imposing steric obstruction to transcription factors may be accompanied by subsequent recruitment of methyl CpG binding domain proteins, histone deacetylase, and other transcriptional corepressors126"130; these interrelated mechanisms act in concert to repress transcription collaboratively. Chromatin modification through histone deacetylation is a related mechanism coupled to DNA methylation that stabilizes reduced chromatin conformations protected from transcriptional activity. When assembled to methylated promoters, histone deacetylases and other recruited binding proteins function as corepressors of transcription.

In MDSs, aberrant DNA methylation of calcitonin and p15^sup INK4B^ has been reported with increased frequency.62-64,119,120 Particularly, hypermethylation of p15^sup INK4B^ tumor suppressor gene has been described in association with MDS progression and leukemic transformation.62-64,131-133 p15 encodes an inhibitor of cyclin-dependent kinases 4 and 6, which mediate Gl/S progression within the cell cycle with TGF-β induction.134'137 Correlating with absent p!5 expression, hypermethylation of CpG promoter regions of p15^sup INK4B^ has been observed in advanced MDS subtypes (FAB), including RAEB and RAEB-t.62,64,138 Furthermore, pl5 gene methylation is reported at higher incidence in acute leukemia transformed from MDSs.64,131,132,138 These observations suggest that aberrant p!5 methylation may represent a potential marker for detection of MDS progression and leukemic evolution.

lmmunomodulatory Cytokine Genes

Immune dysregulation that involves the elaboration of proinflammatory or immunoregulatory molecules has been suggested as a pathophysiologic phenomenon underlying the marrow failure and hematopoietic insufficiency characteristic of MDSs. Dysregulation of genes that encode immunomodulatory cytokines in bone marrow stromal cells is believed to play an important role in the pathogenesis of MDS.

One of the most well-characterized immunomodulatory cytokines, TNF-α has been shown to express strong inhibitory activity in hematopoiesis.139-141 It has also been implicated in effecting the function or expression of related negative regulatory cytokines such as IFN-γ, IFN-γ receptor, and Fas in hematopoietic cells.142 Both TNF-α and IFN-γ have been shown to promote up-regulation of Fas and Fas-ligand in hematopoietic precursors.142,143 Furthermore, data suggest that TNF-α is involved in the signaling pathways of apoptosis,26,78,144-146 and elevated levels of TNF-α have been correlated with excessive apoptotic death in MDSs.26-142-147-149 Several studies report up-regulation of TNF-α in bone marrow cells (macrophages and fibroblasts) and stroma of MDS patients.78,145,147-150-152 Highest TNFα positivity has been associated with RA subtype145 and advanced MDS subtypes RAEB and RAEB-t.153 Despite the unclear relationship between TNF-α expression and MDS disease stage, growing evidence supports the central role of TNF-α in cytokine-mediated hematopoietic suppression and apoptotic cell death in MDS pathogenesis.

Other cytokines reportedly involved in the processes leading to ineffective hematopoiesis in MDSs include TGF β, IL-Iβ, and TNFrelated signaling molecules TRADD/ FADD, RIP, and TRAIL (TNF-related apoptosis inducing ligand).144,152,154-157

Other Novel Genes Recently Identified by cDNA Microarray Technology

The completion of the human genome project has enabled us to exploit high-throughput genomic approaches in studying the pathogenesis of MDSs and the molecular pathways important in disease initiation and evolution. Within the past 4 years, application of cDNA microarray technology to evaluate RNA expression profiles has facilitated the identification of numerous previously unidentified genes associated with MDSs (Table 5).I58-162 However, the results from various studies have been inconsistent and occasionally conflicting. In the work of Miyazato et al,160 comparing 5 MDS patients with 5 patients with de novo AML, only a few genes were identified as putatively "MDS specific"; these genes included those encoding for DIk (also known as fetal antigen 1 and stromal cell protein 1), Tec, and inositol 1,4,5-triphosphate receptor type 1. In contrast, Hofmann et al158 described numerous genes identified as differentially regulated in MDS patient populations at the time of diagnosis; these genes further discriminated low-risk from high-risk MDS patients. Ueda et al162 identified 11 poor prognosis genes and 6 good prognosis genes from the blast cells of 30 MDS patients that correlated with MDS progression. However, none of the prognostic genes in studies by Hofmann et al or Ueda et al was cited in common.158-162 Among the several genes implicated in MDS progression by Ueda et al, only one gene (JLl-R) was up-regulated in the group of high-risk MDS patients evaluated by Chen et al.159 Although these studies yield interesting data, they are limited by the small number of cases evaluated, the retrospective nature of their study design, and the lack of longitudinal comparison of the studied populations. Nonetheless, these studies demonstrate the potential for the application of genome-wide approaches in investigating the molecular pathogenesis of MDSs. Continuing refinement of this technology with accompanying improvements in research design and application may potentially enable us to (1) define the precise mechanisms involved in the initiation and progression of MDSs, (2) identify biomarkers for accurately diagnosing and predicting progression of MDSs, and (3) develop novel targeted therapies for preventing the onset or progression of MDSs.

CONCLUSION

The MDSs remain inadequately characterized disorders; however, novel strategies for studying disease pathogenesis and progression continue to shape our understanding of and approach to diagnosing and treating MDSs. The heterogeneity of the clinical, morphologic, biologic, and genetic characteristics of MDSs has led to evolving classification systems and active research proposed to elucidate its pathobiology and disease processes. Mechanisms of this complex disease include pluripotent stem cell injury with multistep pathogenesis and deranged hematopoietic proliferation, differentiation, and apoptosis. Furthermore, development and progression of MDSs are likely mediated by genetic abnormalities at the molecular level. Underlying the marrow failure and evolutionary potential in MDSs is dysregulation of multiple genes, including those involving oncogenesis, cell cycle regulation, apoptosis, angiogenesis, immunomodulation, and epigenetic modulation.

Improvements in our approaches to cytogenetic and molecular studies of MDSs have started to clarify the molecular pathogenesis of this disease. Evolving characterization of MDSs will continue to enhance our understanding of the pathogenetic mechanisms and improve current strategies for managing these diseases.

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Ha Thanh Nishino, MD; Chung-Che Chang, MD, PhD

Accepted for publication June 15, 2005.

From the Department of Pathology, The Methodist Hospital, Houston, Tex.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Chung-Che Chang, MD, PhD, Department of Pathology, The Methodist Hospital, 6565 Fannin, MS205, Houston, TX 77030 (e-mail: jeffchang@tmh.tmc.edu).

Copyright College of American Pathologists Oct 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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