Marked differences have been found in molecular characteristics between pediatric and adult myelodysplastic syndrome (MDS) patients. The incidence of gene mutations associated with myeloid malignances in pediatric patients is lower than in adults, while the incidence of aberrant methylation is similar between them. It is also worth noting that novel molecular factors such as mitochondrial DNA mutations may play a role in the pathogenesis of childhood MDS. This article summarizes research advances in molecular biology of pediatric MDS.
Child ; DNA Methylation ; DNA, Mitochondrial ; genetics ; Humans ; Mutation ; Myelodysplastic Syndromes ; etiology ; genetics

Myelodysplastic syndrome is a closely related group of acquired bone marrow disorders characterized by ineffective and dysplastic hematopoiesis. These clonal disorders frequently progress to acute leukemia. Acute myelomonocytic leukemia with eosinophilia is characterized by an increase in abnormal eosinophils in the bone marrow, relatively good clinical course and inv (16) chromosomal abnormality. We experienced one case of refractory anemia with excess blasts which progressed to refractory anemia with excess blasts in transformation and finally to acute myelomonocytic leukemia with eosinophilia showing peculiar chromosomal abnormalities of der (1;7).
Adult ; Anemia/pathology ; Anemia/genetics ; Anemia/etiology ; Bone Marrow/pathology ; Case Report ; Chromosomes, Human, Pair 16* ; Disease Progression ; Eosinophilia/pathology ; Eosinophilia/genetics* ; Eosinophilia/etiology ; Human ; Inversion (Genetics)* ; Karyotyping ; Leukemia, Myelocytic, Acute/pathology ; Leukemia, Myelocytic, Acute/genetics* ; Leukemia, Myelocytic, Acute/etiology ; Male ; Myelodysplastic Syndromes/pathology ; Myelodysplastic Syndromes/genetics* ; Myelodysplastic Syndromes/complications

Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell disorders with different mechanisms and diverse prognosis. The excess of ring sideroblasts (RS) is an important presentation MDS, but the mechanisms of RS appearance are obscure and the treatment of MDS-RS is intractable. Splicing factors play a very important role in the maturation process of eucaryon mRNA, recent studies indicate that there is a significant causal relationship between splicing factor 3B subunit 1 (SF3B1) mutation and the presence of ring sideroblasts. Lucubrating the downstream molecular of the mutated SF3B1 can facilitate exploring the mechanisms and new therapeutic strategies of MDS-RS.
Anemia, Sideroblastic ; etiology ; genetics ; Animals ; Humans ; Mutation ; Myelodysplastic Syndromes ; complications ; genetics ; Phosphoproteins ; genetics ; RNA Splicing Factors ; Ribonucleoprotein, U2 Small Nuclear ; genetics

BACKGROUNDMyelodysplastic syndromes (MDSs), also called preleukemias, are a group of myeloid hematopoietic malignant disorders. We studied the transformation of MDS into acute myeloid leukemia (AML).

METHODSLeukemic transformation in 151 patients with MDS was dynamically followed up. The clinical manifestation, peripheral blood and bone marrow condition, karyotypes, immunophenotypes, response to treatment, and prognosis of AML evolution from MDS (MDS-AML) were also observed.

RESULTSDuring the course of this study, over the past eight years and seven months, 21 (13.91%) of 151 MDS patients progressed to overt leukemia, with a median interval of 5 (1 - 23) months. There were no significant differences between rates of leukemic transformation in comparison with the refractory anemia (RA), RA with excess of blasts (RAEB), and RAEB in transformation (RAEB-t) patient groups. Transformation occurred either gradually or rapidly. There were five parameters positively correlated to leukemic transformation: under 40 years of age, pancytopenia of 3 lineages, more than 15% blasts in the bone marrow, at least two abnormal karyotypes, and treatment with combined chemotherapy. All of the 21 patients with leukemia suffered from MDS-AML, and most of them were M2, M4, or M5. Two (9.52%) MDS-AML patients developed extramedullary infiltration. Leukopenia was found in 47.62% of these patients. Two thirds of these patients, whose bone marrows were generally hypercellular, suffered from neutropenia. After developing AML, 8 (47.06%) patients developed abnormal karyotypes. High expression of immature myeloid antigens, including CD33 [(49.83 +/- 24.50)%], CD13 [(36.38 +/- 33.84)%], monocytic antigen CD14 [(38.50 +/- 24.60)%], and stem cell marker CD34 [(34.67 +/- 30.59)%], were found on bone marrow mononuclear cells from MDS-AML patients after leukemic transformation. In some cases, lymphoid antigens, such as CD5, CD7, CD9, and CD19, coexisted with myeloid antigens. A low complete remission rate (31.25%) and a short survival time, with median survival of 6 (1 - 28) months, were found in patients with MDS-AML treated by induction chemotherapy.

CONCLUSIONSMDS has a high risk of developing into AML, either gradually or rapidly. Patients with MDS-AML have specific biological characteristics and a worse prognosis.

Adolescent ; Adult ; Aged ; Chromosome Aberrations ; Female ; Humans ; Immunophenotyping ; Leukemia, Myeloid, Acute ; etiology ; genetics ; immunology ; Male ; Middle Aged ; Myelodysplastic Syndromes ; complications ; genetics ; immunology ; Prognosis

Among tumor suppressor genes, p15(INK4b) gene is gaining more attention for its important role in the progression of myelodyplastic syndrome (MDS). Serial studies demonstrated that highly frequent hypermethylation of p15(INK4b) gene, which is located at the 5'CpG island in the promoter region of exon 1 and is the main reason of inactivation of p15(INK4b) gene, occurs during the development of MDS towards AML. The assay of methylation-specific PCR (MSP) is sensitive to this pattern of methylation which is restricted to the MDS clone. Apoptosis mediated by cytokines such as Fas antigen and TGF-beta, and bHLH proteins is inhibited by the inactivation of p15(INK4b) gene. This may result in the evolution of MDS clone to AML. In as much as the close relationship between p15(INK4b) gene methylation and MDS, modulation of the methylation status of p15(INK4b) gene may be considered as a noval treatment modality for MDS.
Cell Cycle Proteins ; genetics ; Cyclin-Dependent Kinase Inhibitor p15 ; Cyclin-Dependent Kinase Inhibitor p16 ; genetics ; DNA Methylation ; Gene Deletion ; Genes, Tumor Suppressor ; Humans ; Mutation ; Myelodysplastic Syndromes ; etiology ; genetics ; therapy ; Tumor Suppressor Proteins

The myelodysplastic syndrome (MDS) is a group of heterogeneous clonal disorders. So far, the etiology and pathogenesis of MDS is poorly understood. Recently, more and more epigenetic regulator gene such as TET2, ASXL1, EZH2, DNMT3A and UTX mutations were detected in patients with MDS: TET2 may convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (hmC). TET2 is the most frequently mutated gene in MDS known so far and it may act as tumor-suppressor gene. ASXL1 belongs to the enhancer of trithorax and Polycomb (ETP) gene group. MDS phenotypes may be caused not only by loss-of-function of ASXL1 but also by gain-of-function mutations, overexpression of this gene and so on. EZH2 is a kind of histone methyltransferase. EZH2 is frequently over-expressed in a wide variety of cancerous tissue types, which reveals it has oncogenic activity. While, defined mutations resulted in dysfunction of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies. DNMT3A belongs to the DNA methyltransferases (DNMT) gene family. It may be correlated with abnormal methylation status in patients with MDS. UTX coding protein is a histone demethylase, and UTX can affect cell proliferation as well as cell fate decision. Inactivating UTX mutations are found in multiple cancer types recently. These gene mutations may play key roles in the pathogenesis of MDS, which are summarized in this review.
DNA (Cytosine-5-)-Methyltransferases ; genetics ; DNA-Binding Proteins ; genetics ; Enhancer of Zeste Homolog 2 Protein ; Genes, Regulator ; Genes, Tumor Suppressor ; Histone Demethylases ; genetics ; Humans ; Mutation ; Myelodysplastic Syndromes ; etiology ; genetics ; physiopathology ; Nuclear Proteins ; genetics ; Polycomb Repressive Complex 2 ; genetics ; Proto-Oncogene Proteins ; genetics ; Repressor Proteins ; genetics

OBJECTIVETo detect the incidence of the HFE gene C282Y and H63D mutations in patients with myelodysplastic syndromes (MDS) and aplastic anemia (AA), and analyze the relationship of these mutations with iron metabolism, and organs impairment from iron overload.

METHODSThe incidence of the C282Y and H63D mutations in 271 MDS, 402 AA patients and 1615 normal subjects was measured by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) combining with DNA sequencing. Iron metabolism parameters and iron overload indices were retrospectively compared between HFE gene mutation and unmutation groups in MDS and AA patients with no transfusion history.

RESULTSNo C282Y and C282Y/H63D compound mutation was detected in all the three groups. The incidence of H63D heterozygous and homozygous genotype did not significantly differ between AA cases and controls (9.7% vs 10.2%, 0.25% vs 0.24% respectively, both P > 0.05). The frequency of H63D heterozygous genotype in MDS patients was significantly lower than that in controls (4.1% vs 10.2%, P = 0.002). H63D homozygous was not found in MDS patients. In both MDS and AA patients with no RBC transfusion history, serum ferritin (SF), transferrin saturation value (TS), serum iron concentration (SI) were close to or higher than normal; and unsaturated iron-binding capacity (UIBC) value was significantly lower. There was no significant difference in SF, SI, TS values between HFE-mutation and -unmutation MDS patients. For AA patients, only the level of SI was significantly higher in HFE-mutant group than in -unmutation group [42.6 (24.6-60.4) micromol/L vs 32.0 (8.4-63.3) micromol/L, P = 0.011]. There was no significant difference in the values of liver enzyme, fasting blood sugar (FBS), abnormal electrocardiogram (ECG), peripheral blood indices between HFE-mutation and -unmutation MDS and AA groups (all P > 0.05).

CONCLUSIONThe distribution of C282Y and H63D mutations has ethnic and genetic disparity, the frequency in Chinese population is lower than that in Caucasian. It seems that MDS and AA patients are susceptible to iron overload, in the diseases itself and the mutations of HFE gene are not the major factor for iron overload in the patients.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anemia, Aplastic ; complications ; genetics ; Case-Control Studies ; Child ; Child, Preschool ; China ; Female ; Genotype ; Hemochromatosis Protein ; Histocompatibility Antigens Class I ; genetics ; Humans ; Iron ; blood ; Iron Overload ; etiology ; genetics ; Male ; Membrane Proteins ; genetics ; Middle Aged ; Mutation ; Myelodysplastic Syndromes ; complications ; genetics ; Young Adult

Ionizing radiation including I131 might produce chromosomal translocation, causing hematologic malignancy. The incidence of leukemia following radioactive iodine treatment for thyroid cancer has been reported to be approximately 0.1 to 2.0% in Western countries, whereas fewer cases have been reported in Korea. We hereby report four cases of secondary hematologic malignancy, who received iodine therapy for thyroid cancer after thyroidectomy: two cases of acute lymphoblastic leukemia with t(9;22)(q34;q11.2), a case of MDS with 5q deletion, and a case of MDS with normal karyotype. Three cases of hematologic malignancy have developed after cumulative dosage of less than 800 mCi. The treatment intervals in two cases were less than 12 months, and the other two cases had I131 therapy only once. Assessment of causality using the Naranjo probability scale for adverse drug reactions showed that a 'possible' relationship existed between the use of I131 and secondary hematologic malignancy in all of the four cases in this report.
Adult ; Chromosomes, Human, Pair 22 ; Chromosomes, Human, Pair 5 ; Chromosomes, Human, Pair 9 ; Female ; Gene Deletion ; Hematologic Neoplasms/*diagnosis/genetics ; Humans ; Iodine Radioisotopes/*adverse effects/therapeutic use ; Leukemia, Radiation-Induced/*diagnosis/etiology ; Middle Aged ; Myelodysplastic Syndromes/diagnosis/genetics ; Neoplasms, Second Primary/*diagnosis/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/genetics ; Thyroid Neoplasms/*radiotherapy ; Thyroidectomy ; Translocation, Genetic

BACKGROUND: Therapy-related myeloid neoplasms (t-MN) occur as late complications of cytotoxic therapy. This study reviewed clinical and cytogenetic characteristics of patients with t-MN at a single institution in Korea. METHODS: The study subjects included 39 consecutive patients diagnosed with t-MN. Each subject's clinical history of previous diseases, treatments, and laboratory data was reviewed, including cytogenetics. The primary diagnosis was hematologic malignancy in 14 patients and solid tumor in 25 patients. RESULTS: Therapy-related acute myeloid leukemia (t-AML, 66.7%) was found to be more common than therapy-related myelodysplastic syndrome (t-MDS). Primary hematologic malignancies that were commonly implicated included mature B-cell neoplasm and acute leukemia. Breast cancer was the most common primary solid tumor. The mean time interval from cytotoxic therapy initiation to t-MN detection was 49 months. Chromosomal aberrations were observed in 35 patients, and loss of chromosome 5, 7, or both accounted for 41% of all cases. Balanced rearrangements occurred in 13 patients; these patients showed shorter latency intervals (mean, 38 months) than patients with loss of chromosome 5 or 7 (mean, 61 months). CONCLUSIONS: In this study, we determined the clinical and cytogenetic characteristics of Korean patients with t-MN. Although our results were generally consistent with those of previous reports, we found that t-MN resulting from de novo leukemia was common and that t-AML was more common than t-MDS at presentation. Multi-institutional studies involving a larger number of patients and additional parameters are required to investigate the epidemiology, genetic predisposition, and survival rate of t-MN in Korea.
Adolescent ; Adult ; Aged ; Antineoplastic Agents/*adverse effects/therapeutic use ; Asian Continental Ancestry Group ; Bone Marrow/pathology ; Breast Neoplasms/drug therapy/pathology/radiotherapy ; Child ; Child, Preschool ; Chromosome Aberrations ; Chromosomes, Human, Pair 5 ; Chromosomes, Human, Pair 7 ; Female ; Hematologic Neoplasms/drug therapy/pathology/radiotherapy ; Humans ; Karyotyping ; Leukemia, Myeloid, Acute/*diagnosis/etiology/genetics ; Male ; Middle Aged ; Myelodysplastic Syndromes/*diagnosis/etiology/genetics ; Neoplasms, Second Primary/*diagnosis/etiology/genetics ; Republic of Korea ; Young Adult

Treatment-related myelodysplastic syndrome (t-MDS) and acute myelogenous leukemia (t-AML) are now well established as complications of cytotoxic chemotherapy. We experienced a 28-yr-old female patient who developed t-MDS/t-AML with characteristic chromosomal abnormalities including 11q23 chromosomal rearrangement following high-dose chemotherapy with autologous stem cell transplantation (ASCT) for non-Hodgkin's lymphoma. The patient was admitted with bulky abdominal masses of B cell lineage non-Hodgkin's lymphoma. After 2 cycles of systemic chemotherapy of the Vanderbilt regimen, the patient underwent ASCT with high dose chemotherapy of the BEAC regimen. She also received radiation of 48 Gy for the residual periportal lymphadenopathy. The initial cytogenetic analysis of the infused mononuclear cells revealed a normal karyotype. Twenty two months after the ASCT, pancytopenia was noted and her bone marrow aspirate showed dysplastic hemopoiesis with myeloblasts up to 12% of nonerythroid nucleated cells. The patient was diagnosed as t-MDS (refractory anemia with an excess of blasts). Cytogenetic analysis showed complex chromosomal abnormalities including 11q23 rearrangement, which is frequently found in topoisomerase II inhibitor-related hematologic malignancies. Four months later, it was noted that the t-MDS had evolved into an overt t-AML. Cytogenetic analysis showed an evolving pattern with more complex abnormalities. The patient was treated with combination che-motherapy, but her leukemic cells were resistant to the therapy.
Adult ; Antineoplastic Agents, Phytogenic/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/*adverse effects ; B-Lymphocytes/cytology ; Bone Marrow Cells/pathology ; Carmustine/*adverse effects ; Chromosome Aberrations ; Chromosomes, Human, Pair 11 ; Combined Modality Therapy/adverse effects ; Cyclophosphamide/*adverse effects ; Cytarabine/*adverse effects ; Etoposide/*adverse effects ; Female ; Gene Rearrangement ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Leukemia, Myeloid, Acute/*etiology/genetics ; Lymphoma, Non-Hodgkin/*therapy ; Myelodysplastic Syndromes/*etiology/genetics ; Neoplasms, Second Primary/*etiology ; Pelvis ; Pregnancy ; Pregnancy Complications, Neoplastic/*therapy ; Transplantation, Autologous