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1.  Cytogenetic profile of Indian patients with de novo myelodysplastic syndromes 
Background & objectives:
Myelodysplastic syndrome (MDS) is a clonal haematopoietic stem cell disorder characterized by ineffective haematopoiesis and leukaemia progression. Cytogenetic analysis has proven to be a mandatory part of the diagnosis of MDS as well as a major indicator for predicting clinical course and outcome. Studies on cytogenetics of MDS are reported mostly from the West and only a few are available from Asian countries. We report herein cytogenetic studies on 40 Indian patients with primary MDS to find out the occurrence and type of chromosome abnormalities and recurring defects.
Cytogenetic analysis was done using GTG banding and karyotyped according to the International System for Human Cytogenetic Nomenclature (ISCN).
Of the 40 patients, 19 patients (47.5%) showed clonal karyotypic abnormalities with distribution as follows: 3 of 15 (20%) of refractory anaemia (RA), 4 of 7 (57%) of refractory anaemia with excess blasts-1 (RAEB-1), 4 of 6 (67%) of refractory anaemia with excess blasts 2 (RAEB-2), 2 of 3 (67%) of refractory anaemia with ring sideroblasts (RARS), 2 of 4 (50%) of refractory cytopenia with multilineage dysplasia (RCMD), none (0%) RCMD-ringed sideroblasts (RCMD-RS) and 4 patients with 5q syndrome. The frequent abnormalities observed in our study were -7, 5q-and trisomy 8.
Interpretation & conclusions:
Two rare chromosomal abnormalities (6q-, 3q-) were found with unknown prognostic significance. Hence, cytogenetic analysis may be incorporated in the routine diagnosis of MDS since there are racial differences in clinical pictures and the molecular events.
PMCID: PMC3237242  PMID: 22089606
AML; chromosomal abnormalities; cytogenetics; myelodysplastic syndromes
2.  Plasma Protein Biomarker Candidates for Myelodysplastic Syndrome Subgroups 
BioMed Research International  2015;2015:209745.
In recent years the plasma proteomes of several different myelodysplastic syndrome (MDS) subgroups have been investigated and compared with those of healthy donors. However, the resulting data do not facilitate a direct and statistical comparison of the changes among the different MDS subgroups that would be useful for the selection and proposal of diagnostic biomarker candidates. The aim of this work was to identify plasma protein biomarker candidates for different MDS subgroups by reanalyzing the proteomic data of four MDS subgroups: refractory cytopenia with multilineage dysplasia (RCMD), refractory anemia or refractory anemia with ringed sideroblasts (RA-RARS), refractory anemia with excess blasts subtype 1 (RAEB-1), and refractory anemia with excess blasts subtype 2 (RAEB-2). Reanalysis of a total of 47 MDS patients revealed biomarker candidates, with alpha-2-HS-glycoprotein and leucine-rich alpha-2-glycoprotein as the most promising candidates.
PMCID: PMC4584066  PMID: 26448929
3.  Plasma protein alterations in the refractory anemia with excess blasts subtype 1 subgroup of myelodysplastic syndrome 
Proteome Science  2012;10:31.
Refractory anemia with excess blasts subtype 1 (RAEB-1) is a subgroup of myelodysplastic syndrome. It represents a heterogeneous group of oncohematological bone marrow diseases, which occur particularly in elderly patients. The aim of this proteomic study was to search for plasma protein alterations in RAEB-1 patients.
A total of 24 plasma samples were depleted of fourteen high-abundant plasma proteins, analyzed with 2D SDS-PAGE, compared, and statistically processed with Progenesis SameSpots software. Proteins were identified by nanoLC-MS/MS. Retinol-binding protein 4 and leucine-rich alpha-2-glycoprotein were relatively quantified using mass spectrometry. 56 significantly differing spots were found; and in 52 spots 50 different proteins were successfully identified. Several plasma proteins that changed either in their level or modification have been described herein. The plasma level of retinol-binding protein 4 was decreased, while leucine-rich alpha-2-glycoprotein was modified in RAEB-1 patients. Changes in the inter-alpha-trypsin inhibitor heavy chain H4, altered protein fragmentation, or fragments modifications were observed.
This study describes proteins, which change quantitatively or qualitatively in the plasma of RAEB-1 patients. It is the first report on qualitative changes in the leucine-rich alpha-2-glycoprotein in the RAEB-1 subgroup of myelodysplastic syndrome. Described changes in the composition or modification of inter-alpha-trypsin inhibitor heavy chain H4 fragments in RAEB-1 are in agreement with those changes observed in previous study of refractory cytopenia with multilineage dysplasia, and thus H4 fragments could be a marker specific for myelodysplastic syndrome.
PMCID: PMC3470985  PMID: 22568928
Myelodysplastic syndrome; RAEB-1; Plasma proteome; Refractory anemia
We describe long-term disease-free survival after unrelated donor bone marrow transplantation (BMT) for myelodysplastic syndrome (MDS) in 118 patients aged ≤18 years. Forty-six patients had refractory cytopenia (RC), 55, refractory anemia with excess blasts (RAEB) and 17, refractory anemia with excess blasts in transformation (RAEB-t). Transplant-related mortality was higher after mismatched BMT (relative risk [RR] 3.29, p=0.002). Disease recurrence was more likely with advanced stages of MDS at the time of BMT: RAEB (RR 6.50, p=0.01) or RAEB-t (RR 11.00, p=0.004). Treatment failure (recurrent disease or death from any cause; inverse of disease-free survival [DFS]) occurred in 68 patients. Treatment failure was higher after mismatched BMT (RR 2.79, p=0.001) and in those with RAEB-t (RR 2.38, p=0.02). Secondary MDS or chemotherapy prior to BMT was not associated with recurrence or treatment failure. Similarly, cytogenetic abnormalities were not associated with transplant outcomes. Eight-year DFS for patients with RC after matched and mismatched unrelated donor BMT was 65% and 40%, respectively. Corresponding DFS for patients with RAEB and RAEB-t was 48% and 28%, respectively. When a matched adult unrelated donor is available, BMT should be offered as first-line therapy and children with RC can be expected to have the best outcome.
PMCID: PMC3033968  PMID: 20813197
pediatric myelodysplastic syndrome; unrelated donor; bone marrow transplantation
5.  Increased Expression of Interferon Signaling Genes in the Bone Marrow Microenvironment of Myelodysplastic Syndromes 
PLoS ONE  2015;10(3):e0120602.
The bone marrow (BM) microenvironment plays an important role in the pathogenesis of myelodysplastic syndromes (MDS) through a reciprocal interaction with resident BM hematopoietic cells. We investigated the differences between BM mesenchymal stromal cells (MSCs) in MDS and normal individuals and identified genes involved in such differences.
Materials and Methods
BM-derived MSCs from 7 MDS patients (3 RCMD, 3 RAEB-1, and 1 RAEB-2) and 7 controls were cultured. Global gene expression was analyzed using a microarray.
We found 314 differentially expressed genes (DEGs) in RCMD vs. control, 68 in RAEB vs. control, and 51 in RAEB vs. RCMD. All comparisons were clearly separated from one another by hierarchical clustering. The overall similarity between differential expression signatures from the RCMD vs. control comparison and the RAEB vs. control comparison was highly significant (p = 0), which indicates a common transcriptomic response in these two MDS subtypes. RCMD and RAEB simultaneously showed an up-regulation of interferon alpha/beta signaling and the ISG15 antiviral mechanism, and a significant fraction of the RAEB vs. control DEGs were also putative targets of transcription factors IRF and ICSBP. Pathways that involved RNA polymerases I and III and mitochondrial transcription were down-regulated in RAEB compared to RCMD.
Gene expression in the MDS BM microenvironment was different from that in normal BM and exhibited altered expression according to disease progression. The present study provides genetic evidence that inflammation and immune dysregulation responses that involve the interferon signaling pathway in the BM microenvironment are associated with MDS pathogenesis, which suggests BM MSCs as a possible therapeutic target in MDS.
PMCID: PMC4372597  PMID: 25803272
6.  Proteome Changes in the Plasma of Myelodysplastic Syndrome Patients with Refractory Anemia with Excess Blasts Subtype 2 
Disease Markers  2014;2014:178709.
The goal of this study was to explore the plasma proteome of myelodysplastic syndrome (MDS) patients with refractory anemia with excess blasts subtype 2 (RAEB-2) in comparison to healthy controls. 20 plasma samples were separated with 2D electrophoresis and statistically processed with Progenesis SameSpots software. 47 significantly differing (P < 0.05) spots were observed, and 27 different proteins were identified by nano-LC-MS/MS. Mass spectrometry-based relative label-free quantification showed a 2-fold increase of the leucine-rich alpha-2-glycoprotein (LRAG) peptide levels in the RAEB-2 group. Changes in the fragments of the inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) protein were observed. Western blot analysis showed no differences in albumin and ITIH4 levels, while increased expression was observed for LRAG in the RAEB-2 group. Quantification using ELISA showed decreased plasma level of alpha-2-HS glycoprotein in the RAEB-2 group. In conclusion, this is the first time that alpha-2-HS glycoprotein and LRAG were proposed as new biomarkers of RAEB-2 and advanced MDS, respectively. Alpha-2-HS glycoprotein, a protein involved in the bone marrow development and previously proposed as a MDS biomarker candidate, was significantly decreased in RAEB-2. Increased expression and changes in modification(s) were observed for LRAG, a protein involved in granulocytic and neutrophil differentiation, and angiogenesis.
PMCID: PMC4055597  PMID: 24958999
7.  Alteration in Endoglin-Related Angiogenesis in Refractory Cytopenia with Multilineage Dysplasia 
PLoS ONE  2013;8(1):e53624.
The functional mechanisms involved in angiogenesis and the potential role of endoglin (ENG), recently described as a new marker for this process, have not been explored in Myelodysplastic Syndromes (MDS). In order to gain insight in MDS angiogenesis a combined analysis in bone marrow (BM) of gene expression levels, angiogenesis-related soluble factors and functional angiogenesis-related studies was carried out. Ninety-seven MDS patients and forty-two normal BM samples were studied. The morphology of the capillary-like structures originated by two endothelial cells lines in the BM environment of patients with refractory cytopenia with multilineage dysplasia (RCMD) was different from those of the remaining MDS. In addition, the BM mononuclear cells from RCMD patients displayed over-expression of VEGF, HIF and FN1 while they showed reduced expression of ENG in contrast to the normal ENG expression of the remaining low-risk MDS and the high expression of ENG in high-risk MDS subtype. Moreover, higher soluble ENG and soluble FLT-1 levels in BM microenvironment were observed in RCMD cases, which distinguished them from other individuals. Therefore, the present study suggests that the patterns of angiogenesis are different between the MDS subtypes. The differences in angiogenesis observed in RCMD patients could be related to ENG abnormalities.
PMCID: PMC3547003  PMID: 23341958
8.  Plasma proteome changes associated with refractory cytopenia with multilineage dysplasia 
Proteome Science  2011;9:64.
Refractory cytopenia with multilineage dysplasia (RCMD) is a subgroup of myelodysplastic syndrome (MDS), which belongs to oncohematological diseases, occurring particularly in elderly patients, and represents a heterogeneous group of bone marrow diseases. The goal of this study was to look for plasma proteins that changed quantitatively or qualitatively in RCMD patients.
A total of 46 plasma samples were depleted, proteins were separated by 2D SDS-PAGE (pI 4-7), and proteomes were compared using Progenesis SameSpots statistical software. Proteins were identified by nanoLC-MS/MS. Sixty-one unique, significantly (p < 0.05, ANOVA) different spots were found; proteins in 59 spots were successfully identified and corresponded to 57 different proteins. Protein fragmentation was observed in several proteins: complement C4-A, complement C4-B, inter-alpha-trypsin inhibitor heavy chain H4, and endorepellin.
This study describes proteins, which change quantitatively or qualitatively in RCMD patients, and represents the first report on significant alterations in C4-A and C4-B complement proteins and ITIH4 fragments in patients with MDS-RCMD.
PMCID: PMC3192726  PMID: 21975265
myelodysplastic syndrome; refractory cytopenia; dysplasia; proteome
9.  Effects of 5-azacytidine on natural killer cell activating receptor expression in patients with refractory anemia with excess of blasts 
Leukemia Research Reports  2015;4(1):15-17.
Epigenetic drugs modify DNA methylation and are used in refractory anemia with excess of blasts (RAEB). These drugs may reactivate anti-oncogene expression and restore a normal phenotype instead of inducing antitumor toxicity, although they also have immunosuppressive effects on T-lymphocytes [1] In RAEB and acute myeloid leukemia, a defect in natural killer (NK) cell cytotoxicity has been shown, which relies on abnormal expression of activating receptors. Previous study has shown that 5-azacytidine impaired mRNA synthesis and induced apoptosis in NK cells [2]. In this study we investigated the effect of the demethylating drug 5-azacytidine (Vidaza®) on NK receptors with the hypothesis that demethylation of the promoters of activating NK receptor genes induces gene reactivation and thus may increase their expression.
•We analyze the effects of the demethylating agent azacytidine on NK cells in RAEB.•The expression of NCRs and NKG2D activating molecules are not modified.•The expression of the co-stimulating molecule 2B4/CD244 is drastically decreased.•The expression of inhibitory NK cell molecules is not modified (data not shown).•These data argue for the association of demethylating agents with IMIDs in RAEB.
PMCID: PMC4327760  PMID: 25709892
Natural killer cells; Refractory anemia with excess of blasts; Natural cytotoxicity receptors; Demethylation; 5-azacytidine
10.  Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS) 
Annals of Hematology  2012;92(1):1-9.
Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. There are two forms of sideroblastic anemia, i.e., congenital sideroblastic anemia (CSA) and acquired sideroblastic anemia. In order to clarify the pathophysiology of sideroblastic anemia, a nationwide survey consisting of clinical and molecular genetic analysis was performed in Japan. As of January 31, 2012, data of 137 cases of sideroblastic anemia, including 72 cases of myelodysplastic syndrome (MDS)–refractory cytopenia with multilineage dysplasia (RCMD), 47 cases of MDS–refractory anemia with ring sideroblasts (RARS), and 18 cases of CSA, have been collected. Hemoglobin and MCV level in CSA are significantly lower than those of MDS, whereas serum iron level in CSA is significantly higher than those of MDS. Of 14 CSA for which DNA was available for genetic analysis, 10 cases were diagnosed as X-linked sideroblastic anemia due to ALAS2 gene mutation. The mutation of SF3B1 gene, which was frequently mutated in MDS-RS, was not detected in CSA patients. Together with the difference of clinical data, it is suggested that genetic background, which is responsible for the development of CSA, is different from that of MDS-RS.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-012-1564-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3536986  PMID: 22983749
Congenital sideroblastic anemia; Myelodysplastic syndrome; ALAS2
11.  The Role of the Iron Transporter ABCB7 in Refractory Anemia with Ring Sideroblasts 
PLoS ONE  2008;3(4):e1970.
Refractory Anemia with Ring Sideroblasts (RARS) is an acquired myelodysplastic syndrome (MDS) characterized by an excess iron accumulation in the mitochondria of erythroblasts. The pathogenesis of RARS and the cause of this unusual pattern of iron deposition remain unknown. We considered that the inherited X-linked sideroblastic anemia with ataxia (XLSA/A) might be informative for the acquired disorder, RARS. XLSA/A is caused by partial inactivating mutations of the ABCB7 ATP-binding cassette transporter gene, which functions to enable transport of iron from the mitochondria to the cytoplasm. Furthermore, ABCB7 gene silencing in HeLa cells causes an accumulation of iron in the mitochondria. We have studied the role of ABCB7 in RARS by DNA sequencing, methylation studies, and gene expression studies in primary CD34+ cells and in cultured erythroblasts. The DNA sequence of the ABCB7 gene is normal in patients with RARS. We have investigated ABCB7 gene expression levels in the CD34+ cells of 122 MDS cases, comprising 35 patients with refractory anemia (RA), 33 patients with RARS and 54 patients with RA with excess blasts (RAEB), and in the CD34+ cells of 16 healthy controls. We found that the expression levels of ABCB7 are significantly lower in the RARS group. RARS is thus characterized by lower levels of ABCB7 gene expression in comparison to other MDS subtypes. Moreover, we find a strong relationship between increasing percentage of bone marrow ring sideroblasts and decreasing ABCB7 gene expression levels. Erythroblast cell cultures confirm the low levels of ABCB7 gene expression levels in RARS. These data provide an important link between inherited and acquired forms of sideroblastic anemia and indicate that ABCB7 is a strong candidate gene for RARS.
PMCID: PMC2276313  PMID: 18398482
12.  Interphase ribosomal RNA cistron silver staining in refractory anaemias with and without excess blasts. 
Molecular Pathology  1997;50(2):92-95.
AIM: To evaluate the haemopoietic function of bone marrow blood forming cells in human myelodysplastic syndromes (MDS) by silver staining of nucleolar organiser regions (AgNORs). METHODS: Nucleoli were investigated in bone marrow blast cells and in erythroid, granulocytic, and megakaryocytic cells from 12 haematologically healthy subjects, and from 26 patients with MDS, including 14 with refractory anaemia (RA), nine with RA with excess blasts (RAEB), and three with RAEB in transformation (RAEB-t). The investigation was performed before treatment using a one step silver staining method. In each case 50 to 100 blasts, promyelocytes, myelocytes, immature (pronormoblastic and basophilic normoblastic) and mature (polychromatic normoblastic) erythroid elements, and megakaryocytes were evaluated for the mean numbers of nucleoli and AgNORs per nucleus. Student's t test was used to compare the patient and control groups. Other statistical analyses were carried out by the computer assisted "HEMA" system. RESULTS: Compared with controls, the number of AgNORs in blasts, promyelocytes, immature erythroid elements, and megakaryocytes was decreased, whereas in myelocytes and polychromatic normoblasts it was similar. There was also a difference in the AgNOR scores in blood forming cells from patients with RAEB/ RAEB-t v RA. CONCLUSIONS: The loss of AgNOR sites in cellular series in MDS may result from the decrease of their proliferative potential with disease progression, intrinsic defects in maturation, and extensive apoptosis.
PMCID: PMC379590  PMID: 9231157
13.  Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine* 
European journal of haematology  2010;85(2):130-138.
Myelodysplastic syndrome (MDS) treatment can initially worsen patients’ clinical condition and they may discontinue therapy before achieving benefit. We present previously unpublished data from two large phase III trials describing common adverse events (AEs) associated with azacitidine and methods to manage them.
In the Cancer and Leukemia Group B (CALGB) 9221 study, patients with any French-American-British (FAB) subtype of MDS were randomized to azacitidine or best supportive care (BSC). After 56 d, patients randomized to BSC with disease progression could cross over to receive azacitidine. In the AZA-001 study, patients with higher-risk MDS (FAB-defined refractory anemia with excess blasts (RAEB), RAEB in transformation, or chronic myelomonocitic leukaemia and IPSS int-2 or high) were randomized to azacitidine or to conventional care regimens (CCR), which included low-dose ara-C, BSC, or intensive chemotherapy. In both studies, azacitidine dose was 75 mg/m2/d SC for 7 d every 28 d. AEs were graded per National Cancer Institute’s Common Toxicity Criteria version 2.0 (AZA-001) or CALGB Expanded CTC (CALGB 9221).
In safety-evaluable patients in AZA-001 (N = 175) or CALGB 9221 (N = 150), the most common AEs with azacitidine included hematologic (eg, cytopenias) and non-hematologic administration-related events (eg, injection-site reactions and gastrointestinal disorders). Most AEs were transient and resolved during ongoing therapy (> 83%). Hematologic AEs, most frequently observed during early treatment cycles, decreased during subsequent cycles and were usually managed with dosing delays (23–29%). Gastrointestinal symptoms were primarily managed with anti-emetics and laxatives.
Hematologic and non-hematologic AEs with azacitidine decreased in frequency as treatment continued. Awareness of the onset, duration and management of AEs can facilitate treatment, permitting patients to continue therapy for maximum benefit.
PMCID: PMC4000014  PMID: 20394651
azacitidine; safety; disease management; myelodysplastic syndromes; adverse drug event
14.  Plasma proteome changes associated with refractory anemia and refractory anemia with ringed sideroblasts in patients with myelodysplastic syndrome 
Proteome Science  2013;11:14.
Refractory anemia and refractory anemia with ringed sideroblasts are two myelodysplastic syndrome (MDS) subgroups linked with anemia. MDS is a group of heterogeneous oncohematological bone marrow disorders characterized by ineffective hematopoiesis, blood cytopenias, and progression of the disease toward acute myeloid leukemia. The aim of this study was to search for plasma proteome changes in MDS patients with refractory anemia and refractory anemia with ringed sideroblasts.
A total of 26 patient and healthy donor plasma samples were depleted of fourteen high-abundant plasma proteins, separated with 2D electrophoresis, and statistically processed with Progenesis SameSpots software. 55 significantly differing spots were observed and corresponded to 39 different proteins identified by nanoLC-MS/MS. Changes in the fragments of the inter-alpha-trypsin inhibitor heavy chain H4 protein were observed. Using mass spectrometry-based relative label-free quantification of tryptic peptides, there were differences in alpha-2-HS-glycoprotein peptides, while no differences were observed between the control and patient sample groups for retinol-binding protein 4 peptides.
This study describes plasma proteome changes associated with MDS patients with refractory anemia and refractory anemia with ringed sideroblasts. Changes observed in the inter-alpha-trypsin inhibitor heavy chain H4 fragments were in agreement with our previous studies of other MDS subgroups: refractory cytopenia with multilineage dysplasia and refractory anemia with excess blasts subtype 1. Mass spectrometry-based relative quantification of retinol-binding protein 4 peptides has shown that there are differences in the modification of this protein between refractory anemia with excess blasts subtype 1 patients and MDS patients with refractory anemia and refractory anemia with ringed sideroblasts. Alpha-2-HS-glycoprotein seems to be a new potential MDS biomarker candidate.
PMCID: PMC3635902  PMID: 23566303
Myelodysplastic syndrome; Refractory anemia; Refractory anemia with ringed sideroblasts; Proteome changes; Alpha-2-HS-glycoprotein
15.  Membranous glomerulonephritis in a patient with myelodysplastic syndrome-refractory cytopenia with multilineage dysplasia 
A 74-year-old woman presented with edema in the lower extremities. Laboratory tests revealed anemia, thrombocytopenia, hypoalbuminemia, hypercholesterolemia, and nephrotic-range proteinuria. Myelodysplastic syndrome-refractory cytopenia with multilineage dysplasia (MDS-RCMD) was confirmed by bone marrow biopsy. Renal biopsy demonstrated membranous glomerulonephritis (MGN), stage I. Based on these clinicopathologic results, she was diagnosed as having MGN with MDS-RCMD. This is a rare case report of MGN in a parient with MDS-RCMD featuring nephrotic syndrome.
PMCID: PMC4714092  PMID: 26877929
Membranous glomerulonephritis; Myelodysplastic syndrome; Nephrotic syndrome; Refractory cytopenia with multilineage dysplasia
16.  Haematological features of primary myelodysplastic syndromes (PMDS) at initial presentation: a study of 118 cases. 
Journal of Clinical Pathology  1983;36(10):1129-1135.
The haematological features of 118 cases of primary myelodysplastic syndromes (PMDS) were reviewed to see how these could be related and classified according to the recent FAB proposals. A majority of the cases were elderly who presented with a macrocytic or normocytic anaemia and reticulocytopenia. Cases of acquired idiopathic sideroblastic anaemia (AISA) usually had normal leucocyte and platelet counts, erythroid hyperplasia, marked dyserythropoiesis and more than 20% ringed sideroblasts. Cases of refractory anaemia with excess of blasts (RAEB) had frequent neutropenia and thrombopenia usually with prominent dysgranulopoiesis and dysthrombopoiesis. Refractory anaemia or refractory cytopenia appeared morphologically to be a heterogeneous group. Leukaemic transformation did not occur in any of these 16 cases of AISA whereas six of the 34 cases of RAEB transformed into acute leukaemia. It appears that the cases of PMDS present with well defined haematological features which permit recognition of different groups; these latter groups appear to be morphologically and prognostically distinct.
PMCID: PMC498488  PMID: 6619310
17.  Progressive chromatin repression and promoter methylation of CTNNA1 associated with advanced myeloid malignancies 
Cancer research  2009;69(21):8482-8490.
Complete loss or deletion of the long arm of chromosome 5 is frequent in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). The putative gene(s) deleted and responsible for the pathogenesis of these poor prognosis hematological disorders remain controversial. This study is a comprehensive analysis of previously implicated and novel genes for epigenetic inactivation in AML and MDS. In 146 AML cases, methylation of CTNNA1 was frequent, and more common in AML patients with 5q deletion (31%) than those without 5q deletion (14%), while no methylation of other 5q genes was observed. In 31 MDS cases, CTNNA1 methylation was only found in high risk MDS (≥RAEB2), but not in low risk MDS (
PMCID: PMC3081599  PMID: 19826047
del(5q); monosomy 5; CTNNA1; methylation; myelodysplastic syndrome; acute myelogenous leukemia; methylation; Progressive silencing; AML transformation
British journal of haematology  2010;149(2):244-249.
In the phase III AZA-001 trial, low-dose cytarabine (LDara-C), the most widely used low-dose chemotherapy in patients with higher-risk myelodysplastic syndrome (MDS) who are ineligible for intensive treatment, was found to be associated with poorer survival compared with azacitidine. This analysis further compared the efficacy and the toxicity of these two drug regimens. Before randomization, investigators preselected patients to receive a conventional care regimen, one of which was LDara-C. Of 94 patients preselected to LDara-C, 45 were randomized to azacitidine and 49 to LDara-C. Azacitidine patients had significantly more and longer haematologicalal responses and increased red blood cell transfusion independence. Azacitidine prolonged overall survival versus LDara-C in patients with poor cytogenetic risk, presence of −7/del(7q), and French-American-British subtypes refractory anaemia with excess blasts (RAEB) and RAEB in transformation. When analyzed per patient year of drug exposure, azacitidine treatment was associated with fewer grade 3–4 cytopenias and shorter hospitalisation time than LDara-C in these higher-risk MDS patients.
PMCID: PMC4000023  PMID: 20136825
azacitidine; higher-risk myelodysplastic syndromes; low-dose cytarabine (ara-C); myelodysplastic syndromes; survival
Neoplasia (New York, N.Y.)  2011;13(11):1035-1042.
The molecular pathogenesis of myelodysplastic syndrome (MDS) and its progression to secondary acute myeloid leukemia (sAML) remain to be explored. Somatic C-CBL mutations were recently described in MDS. Our study aimed to determine the role of C-CBL mutations in the progression of MDS to sAML and sought to correlate with clinicohematological features and outcome. Bone marrow samples from 51 patients with high-risk MDS (13 with refractory cytopenia with multilineage dysplasia, 19 with refractory anemia with excess blast 1, and 19 with refractory anemia with excess blast 2) were analyzed for C-CBL mutations at both diagnosis and sAML in the same individuals. Mutational analysis was performed for exons 7 to 9 of C-CBL gene. Of the 51 paired samples, C-CBL mutations were identified in 6 patients at the sAML phase. One patient retained the identical C-CBL mutation (G415S) at sAML evolution and exhibited clonal expansion. The other five patients acquired C-CBL mutations (Y371S, F418S, L370_Y371 ins L, L399V, and C416W) during sAML evolution. Three of the six patients harboring C-CBL mutations at sAML had additional gene mutations including JAK2V617F, PTPN11, or N-RAS. There was no significant difference in clinicohematological features and overall survival with respect to C-CBL mutation status. Our results show that C-CBL mutation is very rare (0.6%) in MDS, but acquisition and/or expansion of C-CBL mutant clones occur in 11.8% of patients during sAML transformation. The findings suggest that C-CBL mutations play a role at least in part in a subset of MDS patients during sAML transformation.
PMCID: PMC3226941  PMID: 22131879
Oncology Letters  2016;11(4):2347-2352.
Thrombocytopenia is a common, often fatal complication experienced by patients with myelodysplastic syndromes (MDS). 5-aza-2′-deoxycytidine (decitabine) has been used to treat MDS patients with thrombocytopenia with a response rate of 45–50%. However, the mechanism of its effects on megakaryocytes remains unclear. In the present study, the effect of decitabine on megakaryocyte maturation was investigated. A total of 20 MDS patients diagnosed with thrombocytopenia were enrolled, including 16 refractory anemia with excess blasts (RAEB)-1 patients and 4 RAEB-2 patients], in addition to 20 leukemia patients that had achieved complete remission and 20 healthy donors. Overall, 65% of MDS patients exhibited a response to decitabine, with an increase in platelet count identified in 80% of patients. In the MDS group, the mean platelet count was significantly increased following one cycle of decitabine chemotherapy (36.85±24.54 vs. 84.90±61; P=0.001); however, no significant difference in megakaryocyte number was identified prior to and following treatment. Additionally, bone marrow mononuclear cells of the MDS patients were cultured in vitro with various concentrations of decitabine (0.0, 2.0, 2.5, 3.0 µM), and cluster of differentiation (CD)41 levels were examined via flow cytometry. The MDS and normal control groups exhibited the highest levels of CD41 expression following treatment with 2.0 µM decitabine (mean fluorescence intensity, 294.07±47.34 and 258.95±28.05, respectively). In conclusion, these results indicate that the DNA-hypomethylating agent, decitabine, may induce the differentiation and maturation of myelodysplastic megakaryocytes in MDS patients, even at low concentrations. Thus, the repeated administration of decitabine at lower doses in MDS patients may be useful in clinical practice, and may lead to the development of alternative treatments for other diseases of abnormal megakaryocyte differentiation, such as idiopathic thrombocytopenic purpura, however, future studies are required to investigate this.
PMCID: PMC4812569  PMID: 27073478
myelodysplastic syndromes; decitabine; thrombocytopenia
PLoS ONE  2013;8(6):e67537.
In recent years, epidemiologic studies have reported controversial results relating cigarette smoking to myelodysplastic syndromes (MDS) risk. A meta-analysis was performed to assess such potential relationship between cigarette smoking and incidence of MDS.
A search of literature published before October 2012 for observational studies evaluating the association between cigarette smoking and MDS, returned 123 articles and of these, 14 were selected for this study. The outcomes from these studies were calculated and reported as odds ratios (OR). Quality assessments were performed with the Newcastle-Ottawa Scale. Heterogeneity was evaluated by the I2 index and source of heterogeneity was detected by sensitivity analyses. Finally, publication bias was assessed through visual inspection of funnel plots and Egger’s test.
The pooled OR of developing MDS in ever-smokers was 1.45 (95% CI, 1.25 to 1.68) versus non-smokers. Current and former smokers had increased risks of MDS, with ORs of 1.81 (95% CI, 1.24 to 2.66) and 1.67 (95% CI, 1.42 to 1.96), respectively. In subset analyses, ever-smokers had increased risks of developing MDS if they were living in the United States, or in Europe, female in gender, had refractory anemia (RA)/RA with ringed sideroblasts (RARS) or RA with excess blasts (RAEB)/RAEB in transformation (RAEBt), respectively. Our results demonstrated that the association was stronger in individuals who smoked ≥20 cigarettes/day (OR, 1.62; 95% CI, 1.03 to 2.55) versus those who smoked <20 cigarettes/day (OR, 1.36; 95% CI, 1.13 to 1.64). Moreover, individuals who smoked more than 20 pack-years had increased MDS risk (OR, 1.94; 95% CI, 1.29 to 2.92).
Our outcomes show that smoking increases the risk of developing MDS in ever-smokers who are current or former smokers. We also demonstrate here that positive association between cigarette smoking and risk of MDS exists, and occurs in a dose-dependent manner.
PMCID: PMC3689714  PMID: 23805315
Granulocytic sarcoma (GS) is an uncommon and localized extramedullary tumor composed of immature granulocytic cells. Most GS reported in large series were not associated with overt acute myelogenous leukemia. Gastric perforation occurred during prednisolone therapy in a 72-year-old Japanese male with a four-month history of a myelofibrosis-like state. Subtotal gastrectomy was performed for a suspected gastric ulcer perforation. Gastric histologic, immunohistochemical and cytochemical examination revealed diffuse infiltration by sheets of myeloblasts and promyelocytes with scant or moderately abundant cytoplasm including a few eosinophilic myelocytes. Bone marrow study done in one month after the operation disclosed refractory anemia with excess of blasts (RAEB). Leukemic transformation occurred two months later, and a subcutaneous tumor appeared on the forehead. The forehead tumor predominantly consisted of myeloblasts without evidence of maturation. Both the stomach and forehead tumors were examined immunohistochemically with a panel of monoclonal antibodies (LCA, L26, MT1, UCHL1, OPD4, LN-1, LN-2, LN-3, MB1, Leu-M1, PM) and polyclonal antibodies (lysozyme, alpha 1-antitrypsin, alpha 1-antichymotrypsin, S-100 protein, lactoferrin), as well as naphthol-ASD-chloroacetate esterase staining to investigate and characterize the reliable marks for GS, and the patient was diagnosed as GS. We found that gastric GS may occur in a myelofibrosis-like state followed by RAEB of myelodysplastic syndrome and that naphthol-ASD-chloroacetate esterase staining and immunohistochemical detection of MT1, lysozyme, and alpha 1-antitrypsin were the most reliable markers for confirming the diagnosis of GS.
PMCID: PMC3053922  PMID: 8703373
Oncology Letters  2015;11(1):355-359.
The aim of the present study was to evaluate the treatment outcome of homoharringtonine, cytarabine (AraC) and aclarubicin combination therapy as induction treatment for myelodysplastic syndromes-refractory anemia with excess blasts (MDS-RAEB). A total of 24 patients with MDS-RAEB who were aged between 18 and 66 years were treated with homoharringtonine, AraC and aclarubicin (HAA regimen). The HAA regimen consisted of homoharringtonine (2 mg/m2 intramuscularly twice daily, days 1–3), AraC (75 mg/m2 injected subcutaneously twice daily, days 1–7) and aclarubicin (12 mg/m2, days 1–7). The overall response rate was 79% with a complete remission rate of 58.3% and partial remission rate of 20.7%. There was no evidence of early mortality in this group of patients. The median overall survival (OS) was 36.2 months (95% confidence interval, 24.6–47.4 months), and the estimated three year overall survival rate was 45.8%. In conclusion, HAA combination therapy is a suitable induction regimen for patients with MDS-RAEB, which may improve the outcome for de novo higher-risk MDS patients, particularly of those with favorable and intermediate cytogenetics.
PMCID: PMC4727161  PMID: 26870217
myelodysplastic syndromes; high-intensity chemotherapy; homoharringtonine; aclarubicin; cytarabine
Leukemia Research Reports  2014;4(1):1-3.
Refractoriness to growth factor therapy is commonly associated with inferior outcome in patients with low-risk myelodysplastic syndrome (LR-MDS) who require treatment for cytopenias. However, the mechanisms leading to refractoriness are unknown. Here we describe a clinically depressed 74-year-old male with refractory cytopenia with multilineage dysplasia (RCMD) and documented growth factor refractory anemia after erythropoeisis stimulating agent (ESA) therapy, who attained transfusion and growth factor independence after the addition of sertraline to his medication regimen. Our case demonstrates hematological improvement-erythroid (HI-E) in growth factor refractory, low risk MDS and highlights a potential mechanistic link between common inflammatory diseases and LR-MDS.
•Our case shows HI-E with sertraline in growth factor refractory, low risk MDS.•We highlight a potential mechanism between common inflammatory diseases and LR-MDS.•This is the first report of potential therapeutic role for SSRIs in myelodysplasia.
PMCID: PMC4327762  PMID: 25709889
Myelodysplasia; Transfusion dependence; Erythropoietin; Sertraline
Journal of Clinical Pathology  1988;41(7):763-767.
Thirty three patients with refractory myelodysplastic anaemias (RMDA) with marrow hypocellularity were reviewed to see whether they differed from those with normocellular or hypercellular marrows. The median age was 65 years with a male:female ratio of 26:7. There were 11 cases of refractory anaemia (RA), four of refractory anaemia with ringed sideroblasts (RARS), and 18 of refractory anaemia with excess of blasts (RAEB). All presented with peripheral cytopenias, mostly pancytopenia or bicytopenia dysplasia in one or more cell lineages, and a marrow biopsy specimen with less than normal numbers of nucleated cells for the age. Twenty four patients died, including 14 of the 16 who developed acute non-lymphocytic leukaemia (ANLL). The results suggest that patients with hypocellular RMDA have a similar prognosis to those with normocellular or hypercellular marrows at presentation.
PMCID: PMC1141585  PMID: 3410972

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