Growth advantage of CD34+ cells in trisomy 8 highrisk myelodysplastic syndrome despite enhanced apoptotic signals

Abstract CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) are distinguished from other MDS cells and from normal hematopoietic cells by their pronounced expression of apoptotic markers. Paradoxically, trisomy 8 clones can persist in patients with bone marrow failure and expand following immunosuppression. We previously demonstrated up-regulation of c-myc and CD1 by microarray analysis. Here, we confirmed these findings by real-time polymerase chain reaction (PCR), demonstrated up-regulation of survivin, c-myc, and CD1 protein expression, and documented comparable colony formation by annexin+ trisomy 8− CD34+ and annexin− CD34 cells. There were low levels of DNA degradation in annexin+ trisomy 8 CD34 cells, which were comparable with annexin− CD34 cells. Trisomy 8 cells were resistant to apoptosis induced by gamma irradiation. Knock-down of survivin by siRNA resulted in preferential loss of trisomy 8 cells. These results suggest that trisomy 8 cells undergo incomplete apoptosis and are nonetheless capable of colony formation and growth.

Download Full-text

Successful treatment by thalidomide therapy of intestinal Behçet’s disease associated with trisomy 8 myelodysplastic syndrome

Rheumatology ◽

10.1093/rheumatology/keaa848 ◽

2020 ◽

Author(s):

Qinglin Wei ◽

Xingyue Zhang ◽

Ying Peng ◽

Kun Chen ◽

Shuangnian Xu ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Behçet’S Disease ◽

Successful Treatment ◽

Behcet’S Disease ◽

Behçet's Disease ◽

Trisomy 8 ◽

Intestinal Behçet’S Disease ◽

Behcet's Disease ◽

Intestinal Behcet’S Disease ◽

Intestinal Behçet's Disease

Download Full-text

Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities

Blood ◽

10.1182/blood-2004-01-0103 ◽

2004 ◽

Vol 104 (13) ◽

pp. 4210-4218 ◽

Cited By ~ 104

Author(s):

Guibin Chen ◽

Weihua Zeng ◽

Akira Miyazato ◽

Eric Billings ◽

Jaroslaw P. Maciejewski ◽

...

Keyword(s):

Gene Expression ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Small Sample ◽

Hematopoietic Progenitor Cell ◽

Molecular Characteristics ◽

Hematopoietic Progenitor ◽

Trisomy 8 ◽

Monosomy 7 ◽

Cd34 Cells

Abstract Aneuploidy, especially monosomy 7 and trisomy 8, is a frequent cytogenetic abnormality in the myelodysplastic syndromes (MDSs). Patients with monosomy 7 and trisomy 8 have distinctly different clinical courses, responses to therapy, and survival probabilities. To determine disease-specific molecular characteristics, we analyzed the gene expression pattern in purified CD34 hematopoietic progenitor cells obtained from MDS patients with monosomy 7 and trisomy 8 using Affymetrix GeneChips. Two methods were employed: standard hybridization and a small-sample RNA amplification protocol for the limited amounts of RNA available from individual cases; results were comparable between these 2 techniques. Microarray data were confirmed by gene amplification and flow cytometry using individual patient samples. Genes related to hematopoietic progenitor cell proliferation and blood cell function were dysregulated in CD34 cells of both monosomy 7 and trisomy 8 MDS. In trisomy 8, up-regulated genes were primarily involved in immune and inflammatory responses, and down-regulated genes have been implicated in apoptosis inhibition. CD34 cells in monosomy 7 showed up-regulation of genes inducing leukemia transformation and tumorigenesis and apoptosis and down-regulation of genes controlling cell growth and differentiation. These results imply distinct molecular mechanisms for monosomy 7 and trisomy 8 MDS and implicate specific pathogenic pathways.

Download Full-text

Routes of Clonal Evolution into Complex Karyotypes in Myelodysplastic Syndrome Patients with 5q Deletion

International Journal of Molecular Sciences ◽

10.3390/ijms19103269 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3269 ◽

Cited By ~ 1

Author(s):

Simone Feurstein ◽

Kathrin Thomay ◽

Winfried Hofmann ◽

Guntram Buesche ◽

Hans Kreipe ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Clonal Evolution ◽

Suppressor Gene ◽

Trisomy 8 ◽

Multicolor Fish ◽

Catastrophic Event ◽

Evolution And Development ◽

Gene Tp53

Myelodysplastic syndrome (MDS) can easily transform into acute myeloid leukemia (AML), a process which is often associated with clonal evolution and development of complex karyotypes. Deletion of 5q (del(5q)) is the most frequent aberration in complex karyotypes. This prompted us to analyze clonal evolution in MDS patients with del(5q). There were 1684 patients with low and intermediate-risk MDS and del(5q) with or without one additional cytogenetic abnormality, who were investigated cytogenetically in our department, involving standard karyotyping, fluorescence in situ hybridization (FISH) and multicolor FISH. We identified 134 patients (8%) with aspects of clonal evolution. There are two main routes of cytogenetic clonal evolution: a stepwise accumulation of cytogenetic events over time and a catastrophic event, which we defined as the occurrence of two or more aberrations present at the same time, leading to a sudden development of highly complex clones. Of the 134 patients, 61% underwent a stepwise accumulation of events whereas 39% displayed a catastrophic event. Patients with isolated del(5q) showed significantly more often a stepwise accumulation of events rather than a catastrophic event. The most frequent aberrations in the group of stepwise accumulation were trisomy 8 and trisomy 21 which were significantly more frequent in this group compared to the catastrophic event group. In the group with catastrophic events, del(7q)/-7 and del(17p)/-17 were the most common aberrations. A loss of 17p, containing the tumor suppressor gene TP53, was found significantly more frequent in this group compared to the group of stepwise accumulation. This leads to the assumption that the loss of TP53 is the driving force in patients with del(5q) who undergo a sudden catastrophic event and evolve into complex karyotypes.

Download Full-text

EBF1 gene promotes the proliferation and inhibits the apoptosis of bone marrow CD34+ cells in patients with myelodysplastic syndrome through negative regulation of mitogen‐activated protein kinase axis

Journal of Cellular Biochemistry ◽

10.1002/jcb.27177 ◽

2018 ◽

Vol 120 (2) ◽

pp. 1407-1419 ◽

Cited By ~ 1

Author(s):

Shuang Hou ◽

Jie Hao ◽

Yan‐Yu Wang ◽

Bing‐Bing Zhao ◽

Gong‐Wei Xiao ◽

...

Keyword(s):

Bone Marrow ◽

Protein Kinase ◽

Myelodysplastic Syndrome ◽

Negative Regulation ◽

Mitogen Activated Protein Kinase ◽

Cd34 Cells ◽

Mitogen Activated Protein

Download Full-text

Apoptosis Resistance of Blood Cells From Patients With Paroxysmal Nocturnal Hemoglobinuria, Aplastic Anemia, and Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v90.7.2716.2716_2716_2722 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2716-2722 ◽

Cited By ~ 2

Author(s):

Kentaro Horikawa ◽

Hideki Nakakuma ◽

Tatsuya Kawaguchi ◽

Norihiro Iwamoto ◽

Shoichi Nagakura ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Clinical Manifestations ◽

Interferon Γ ◽

Apoptosis Resistance ◽

Molecular Events ◽

Cd34 Cells ◽

Factor Α

Bone marrow (BM) hypoplasia is a major cause of death in paroxysmal nocturnal hemoglobinuria (PNH). However, little is known about the molecular events leading to the hypoplasia. Considering the close pathologic association between PNH and aplastic anemia (AA), it is suggested that a similar mechanism operates in the development of their BM failure. Recent reports have indicated apoptosis-mediated BM suppression in AA. It is thus conceivable that apoptosis also operates to cause BM hypoplasia in PNH. If this is the case, PNH clones need to survive apoptosis and show considerable expansion leading to clinical manifestations. We report here that granulocytes obtained from 11 patients with PNH were apparently less susceptible than those from 20 healthy individuals to both spontaneous apoptosis without any ligands and that induced by anti-FAS (CD95) antibody in vitro. The patients' BM CD34+ cells were also resistant to apoptosis induced by treatment with tumor necrosis factor-α, interferon-γ, and subsequently with anti-FAS antibody. In lymphocytes, the pathologic resistance was not discriminated from inherent resistance to apoptosis. Granulocytes from 13 patients with AA and 12 patients with myelodysplastic syndrome (MDS) exhibited similar resistance to apoptosis. CD34+ cells from MDS-BM also showed similar tendency. Thus, the comparative resistance to apoptosis supports the pathogenic implication of apoptosis in marrow injury of PNH and related stem cell disorders.

Download Full-text

Clinico-Hematological and cytogenetic spectrum of adult myelodysplastic syndrome The first retrospective cross-sectional study in Iranian patients

10.21203/rs.3.rs-249637/v1 ◽

2021 ◽

Author(s):

Mostafa Paridar ◽

Kazem Zibara ◽

Seyed Esmaeil Ahmadi ◽

Abbas Khosravi ◽

Maral Soleymani ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Cross Sectional Study ◽

Cytogenetic Abnormality ◽

Sectional Study ◽

Trisomy 8 ◽

Cross Sectional ◽

Iron Storage ◽

Monosomy 7 ◽

Female Ratio ◽

Cytogenetic Abnormalities

Abstract Background Myelodysplastic syndrome (MDS), a heterogeneous group of hematopoietic malignancy, has been shown to present different cytogenetic abnormalities, risk factors, and clinico-hematological features in different populations and geographic areas. Herein, we determined the cytogenetic spectrum and clinico-hematological features of Iranian MDS patients for the first time. Methods This prospective cross-sectional study was conducted on 103 patients with MDS in Ahvaz, southwest of Iran, from 2014 to 2018. Clinical presentations, complete blood counts (CBC), and bone marrow (BM) biopsy samples were assessed. Perls' staining was used to evaluate BM iron storage. The cytogenetic evaluation was performed using the conventional G banding method on the BM. Results Patients’ median age was 62.3 (ranged from 50–76), and the majority were male (72.8%). The most common clinical symptom at the time of admission was fatigue (n = 33) followed by pallor (n = 27). The most common subgroup was MDS-Multi Lineage Dysplasia (MDS-MLD) (n = 38, 36.8%), followed by MDS-Single Lineage Dysplasia (MDS-SLD) (n = 28, 18.4%). A normal karyotype was observed in 59 patients (57.3%), while 44 patients (42.7%) had cytogenetic abnormalities. Trisomy 8 (+ 8) was the most common cytogenetic abnormality (n = 14) followed by dell 17p (n = 9) and monosomy 7 (-7) (n = 7). Twelve patients (11.65 %) were transformed to AML. Conclusion Our data betokened that among our MDS patients, Trisomy 8 is the predominant cytogenetic abnormality, and MDS-MLD and MDS-SLD are the most common of subtypes. Noteworthy, the male: female ratio was slightly higher in Iran than in previous reports from other parts of the world. Our study is the first report of the clinical, hematological, and cytogenetic spectrum of MDS patients in Iran

Download Full-text

A case of Behcet's disease associated with myelodysplastic syndrome involving trisomy 8 and a gain-of-function mutation in SHP-2

Rheumatology ◽

10.1093/rheumatology/ker137 ◽

2011 ◽

Vol 50 (7) ◽

pp. 1342-1344 ◽

Cited By ~ 6

Author(s):

T. Shigemura ◽

K. Agematsu ◽

T. Yamazaki ◽

K. Sakashita ◽

Y. Nakayama ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Behçet’S Disease ◽

Behcet’S Disease ◽

Behçet's Disease ◽

Trisomy 8 ◽

Gain Of Function ◽

Behcet's Disease

Download Full-text

Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells

Blood ◽

10.1182/blood.v88.11.4275.4275 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4275-4287 ◽

Cited By ~ 140

Author(s):

R Rajapaksa ◽

N Ginzton ◽

LS Rott ◽

PL Greenberg

Keyword(s):

Myelodysplastic Syndrome ◽

Cell Survival ◽

Marrow Cell ◽

Leukemic Cell ◽

Refractory Anemia ◽

Maturation Stage ◽

Mean Values ◽

Cd34 Cells ◽

Marrow Cells

Abstract Ineffective hematopoiesis with associated cytopenias and potential evolution to acute myeloid leukemia (AML) characterize patients with myelodysplastic syndrome (MDS). We evaluated levels of apoptosis and of apoptosis-related oncoproteins (c-Myc, which enhances, and Bcl-2, which diminishes apoptosis) expressed within CD34+ and CD34- marrow cell populations of MDS patients (n = 24) to determine their potential roles in the abnormal hematopoiesis of this disorder. Marrow cells were permeabilized and CD34+ and CD34- cells were separately analyzed by FACS to detect: (1) a subdiploid (sub-G1) DNA population, and (2) expression of Bcl-2 and c-Myc oncoproteins. Within the CD34+ subset, a significantly increased percentage of cells demonstrated apoptotic/sub- G1 DNA content in early (ie. refractory anemia) MDS patients compared with normal individuals and AML patients (mean values: 9.1% > 2.1% > 1.2%). Correlated with these findings, the ratio of expression of c-Myc to Bcl-2 oncoproteins among CD34+ cells was significantly increased for MDS patients compared to those from normal and AML individuals (mean values: 1.6 > 1.2 > 0.9). Bcl-2 and c-Myc oncoprotein levels were maturation stage-dependent, with high levels expressed within CD34+ marrow cells, decreasing markedly with myeloid maturation. Treatment of seven MDS patients with the cytokines granulocyte colony-stimulating factor plus erythropoietin was associated with decreased levels of apoptosis within CD34+ marrow cells and may contribute to the enhanced hematopoiesis in vivo that was shown. These findings are consistent with the hypothesis that altered balance between cell-death (eg, c-Myc) and cell-survival (eg, Bcl-2) programs were associated with the increased degrees of apoptosis present in MDS hematopoietic precursors and may contribute to the ineffective hematopoiesis in this disorder, in contrast to decreased apoptosis and enhanced leukemic cell survival in AML.

Download Full-text