Increased apoptosis of bone marrow cells and preserved proliferative capacity of selected progenitors predict for clinical response to anti-inflammatory therapy in myelodysplastic syndromes (original) (raw)
Related papers
Leukemia Research, 1996
Extensive apoptosis or programmed cell death (PCD) of both hematopoietic (erythroid, myeloid, megakaryocytic) and stromal cells in myelodysplastic syndromes (MDS) cancels the high birth-rate resulting in ineffective hematopoiesis and has been demonstrated as the probable basis for peripheral cytopenias in MDS by our group. It is proposed that factors present in the microenvironment are inducing apoptosis in all the cells whether stromal or parenchymal. To investigate this hypothesis further, bone marrow biopsies from 46 MDS patients and eight normal individuals were examined for the presence of three cytokines, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β) and granulocyte macrophage-colony stimulating factor (GM-CSF) and one cellular component, macrophages, by the use of monoclonal antibodies immunohistochemically. Results showed the presence of TNF-α and TGF-β in and cases of MDS respectively, while only 15 cases showed the presence of GM-CSF. Further a significant direct relationship was found between the degree of TNF-α and the incidence of PCD (p = 0.0015). Patients who showed high PCD also had an elevated TNF-α level. Thus, the expression of high amounts of TNF-α and TGF-β and low amounts of the viability factor GM-CSF may be responsible for the high incidence of PCD leading to ineffective hematopoiesis in MDS. Future studies will be directed at attempting to reverse the lesion in MDS by using anti-TNF-α drugs such as pentoxifylline.
Hematology/Oncology Clinics of North America, 2010
Laboratory evidence and clinical evidence suggest that some patients with myelodysplastic syndrome (MDS) have immunologically mediated disease. Autoimmune conditions such as Reynaud syndrome, lupus, rheumatoid arthritis, and polymyalgia are more frequent in MDS patients, and activated cytotoxic T cells and elevated levels of tumor necrosis factor alpha (TNF-) and interferon (IFN) 1-4 are found in MDS. Cytokine dysregulation and excessive apoptosis are most notable in early MDS, 3-6 where up-regulation of Fas-receptor and Fas-ligand expression are hallmarks of the disease. 7-11 The concept of using immunosuppressive treatment (IST) for bone marrow (BM) failure originates severe aplastic anemia (SAA) patients. 12 Gluckman and colleagues 13 were the first to show that hematopoietic recovery could occur in SAA following antithymocyte globulin (ATG) treatment alone. As experience and success in IST for SAA accumulated, small numbers of patients with BM failure secondary tp hypoplastic MDS were treated successfully. The response of such patients led to the establishment a clinical trial of IST at the National Institutes of Health in 1994 to evaluate the ability of ATG to improve BM failure in all forms of MDS. 14 This study showed improvement in 30% of patients with MDS after ATG. Further efforts to identify the profile the characteristics of the IST responder have resulted in better response rates to IST. 15 This article describes the laboratory evidence supporting a role for the immune system in the marrow failure of MDS and clinical trials using IST in these patients.
International Journal of Hematology, 2002
Labeling index (LI), apoptosis, levels of 2 pro-apoptotic cytokines tumor necrosis factor-␣ (TNF-␣) and transforming growth factor- (TGF-), and the number of monocyte/macrophage cells that are the likely source of the cytokines were simultaneously measured in plastic-embedded bone marrow (BM) biopsy sections of 145 patients with myelodysplastic syndromes (MDS). TNF-␣ was correlated with TGF- (P = .001) and with monocyte/macrophage cells (P = .003). Patients with excess blasts in their marrows had a higher TGF- level (P = .01) and monocyte/macrophage number (P = .05). In a linear regression model, TGF- emerged as the most significant biological difference between patients who have excess of blasts and those who do not (P = .01). We conclude that in addition to TNF-␣, TGF- also plays a significant role in the initiation and pathogenesis of MDS, and that a more precise definition of its role will likely identify better preventive and therapeutic strategies.
Blood, 1995
Cell-cycle kinetics were measured in situ after infusions of iododeoxyuridine and/or bormodeoxyuridine in 50 patients with myelodysplastic syndromes (MDS) and the median labeling index in bone marrow (BM) biopsy samples was 28.6%. Unfortunately, 26 of 50 patients showed that > or = 75% of hematopoietic cells of all three lineages were undergoing programmed cell death (PCD) in their biopsy samples as shown by the in situ end labeling (ISEL) technique. Ten patients had 1/3 and eight had 2/3 ISEL+ cells. Stromal cells were frequently ISEL+ and often S-phase cells were also found to be simultaneously ISEL+. Nucleosomal DNA fragments as a ladder in agarose gel were present in BM aspirates of four patients who showed high ISEL and were absent in two who had no ISEL staining in biopsy samples, but only when DNA was extracted after a 4-hour in vitro incubation in complete medium. Therefore, laddering data confirmed the ISEL findings that the majority of hematopoietic cells in MDS are in ...
Leukemia, 1997
By application of morphological and ultrastructural methods nosis. The pathogenesis of MDS is still unclear. It has been for identification of apoptosis, we analyzed the incidence of found that oncogene dysregulation is the basis of the disease. morphologically evident apoptosis in the bone marrow of 30 The paradox of persistent pancytopenia in peripheral blood patients with myelodysplastic syndrome (MDS), and in the with hypercellular bone marrow in most cases of MDS is bone marrow of 12 healthy individuals. According to FAB explained by the term 'ineffective hematopoiesis' but the real classification, out of 30 patients, eight (26.6%) had refractory anemia, three (10%) had refractory anemia with ringed sidero-mechanism responsible has not been explained yet. It has blasts, 14 (46.6%) had refractory anemia with excess of blasts been hypothesized that the mechanism of apoptosis may be and two (6.8%) had refractory anemia with excess of blasts in responsible for the ineffective hematopoiesis in MDS. 4 transformation. Three patients (10%) had chronic myelomono-In this study we analyzed bone marrow samples of 30 cytic leukemia. Cells in apoptosis were examined on semithin patients with MDS in order to evaluate the incidence of slides and expressed as the apoptotic index (AI) (percent counpremature apoptosis, as the morphological equivalent of 'inefted on at least 1000 cells). An overall increase in apoptosis in patients with MDS was found (median AI in patients vs controls, fective hematopoiesis'. 3.13% vs 1.05%, P Ͻ 0.01 by Mann-Whitney U test). Also, negative correlation between AI and white blood cell count was found (linear r = −0.53, or Spearman rank R = −0.52, both Patients and methods P Ͻ 0.01). In patients with evident karyotype changes AI was not higher than in patients with normal karyotype. This sug-Our study included 30 patients with primary MDS stratified gests that discrete alterations in apoptosis are present even in karyotypically 'normal' clones. Our results strongly support the according to criteria of FAB classification. 5 Out of 30 patients, hypothesis that apoptosis has a role in ineffective hematopoeight (26.6%) patients had refractory anemia (RA), three (10%) iesis and may be a mechanism responsible for the paradox of had refractory anemia with ringed sideroblasts (RARS), 14 hypercellular bone marrow and peripheral blood pancytopenia (46.6%) had refractory anemia with excess of blasts (RAEB) in MDS.
Increased apoptosis in bone marrow B lymphocytes but not T lymphocytes in myelodysplastic syndrome
Blood, 2003
The hallmark of myelodysplastic syndrome (MDS) is enhanced apoptosis in myeloid, erythroid, and megakaryocytic cells in the bone marrow leading to ineffective hematopoiesis. Recent studies suggested that immunological and microenvironmental factors play a role in the pathophysiology of this disease. We report a significant increase in apoptosis in bone marrow B lymphocytes in MDS as compared to that found in acute myeloid leukemia and healthy controls. Furthermore, we demonstrate that patients with refractory anemia with excess blasts in transformation (RAEB-T) had apoptosis levels in lymphocytes similar to those seen in other subtypes of MDS. Our findings suggest that the alterations in B lymphocytes in the form of increased apoptosis can be seen in MDS and support the concept that immune modulation plays a role in the pathophysiology of
Biologic characteristics of 164 patients with myelodysplastic syndromes
Leukemia & lymphoma, 1999
Rates of proliferation, apoptosis and cytokine expression were measured in bone marrow (BM) biopsies of 164 myelodysplastic syndrome (MDS) patients. There were 107 males and 57 females. Median age was 69 years and 101 had refractory anemia (RA), 17 RA with ringed sideroblasts (RARS), 38 with RA and excess blasts (RAEB) and 8 with RAEB in transformation (RAEB-t). Apoptosis measured by in-situ end labeling (ISEL) was directly related to the number of macrophages (p = 0.028, n = 83). Mean tumor necrosis factor alpha (TNF-alpha) and ISEL positivity were higher in RAEB + RAEB-t patients (p = 0.0554 and p = 0.06 respectively) while hemoglobin was higher for RA + RARS group (p = 0.0472). Patients with high apoptosis had lower white blood cell counts (p = 0.0009), lower percentage of blasts (p = 0.0009) and higher number of macrophages (p = 0.0086). We conclude that measurements of apoptosis, proliferation and cytokine expression provide important biological information which helps to disti...
Cytometry Part B-clinical Cytometry, 2010
A heterogeneous spectrum of immunophenotypic abnormalities have been reported in myelodysplastic syndromes (MDS). However, most studies are restricted to the analysis of CD34+ cells and/or other major subsets of CD34− cells, frequently not exploring the diagnostic and prognostic impact of immunophenotyping.A heterogeneous spectrum of immunophenotypic abnormalities have been reported in myelodysplastic syndromes (MDS). However, most studies are restricted to the analysis of CD34+ cells and/or other major subsets of CD34− cells, frequently not exploring the diagnostic and prognostic impact of immunophenotyping.Methods:We propose for the first time an immunophenotypic score (IS) based on the altered distribution and immunophenotypic features of maturing/mature compartments of bone marrow (BM) hematopoietic cells in 56 patients with MDS that could contribute to a refined diagnosis and prognostic evaluation of the disease.We propose for the first time an immunophenotypic score (IS) based on the altered distribution and immunophenotypic features of maturing/mature compartments of bone marrow (BM) hematopoietic cells in 56 patients with MDS that could contribute to a refined diagnosis and prognostic evaluation of the disease.Results:Although MDS-associated phenotypes were detected in reactive BM, the overall immunophenotypic profile of BM cells allowed an efficient discrimination between MDS and both normal and reactive BM, once the number and degree of severity of the abnormalities detected per patient were simultaneously considered in the proposed IS. Interestingly, increasingly higher IS were found among patients with MDS showing adverse prognostic factors and in low- versus high-grade cases. The most informative prognostic factors included the number of CD34+ cells, presence of aberrant CD34−/CD117+ precursors, decreased mature neutrophils and CD34− erythroid precursors, and increased numbers of CD36−/lo erythroid precursors; in addition, the IS was an independent prognostic factor for overall survival.Although MDS-associated phenotypes were detected in reactive BM, the overall immunophenotypic profile of BM cells allowed an efficient discrimination between MDS and both normal and reactive BM, once the number and degree of severity of the abnormalities detected per patient were simultaneously considered in the proposed IS. Interestingly, increasingly higher IS were found among patients with MDS showing adverse prognostic factors and in low- versus high-grade cases. The most informative prognostic factors included the number of CD34+ cells, presence of aberrant CD34−/CD117+ precursors, decreased mature neutrophils and CD34− erythroid precursors, and increased numbers of CD36−/lo erythroid precursors; in addition, the IS was an independent prognostic factor for overall survival.Conclusions:Assessment of immunophenotypic abnormalities of maturing/mature BM cells allows an efficient discrimination between MDS and both normal and reactive BM, once the number and degree of severity of the abnormalities detected are simultaneously scored. Interestingly, progressively higher IS were found among patients with MDS with adverse prognostic features and shorter overall survival. © 2010 Clinical Cytometry SocietyAssessment of immunophenotypic abnormalities of maturing/mature BM cells allows an efficient discrimination between MDS and both normal and reactive BM, once the number and degree of severity of the abnormalities detected are simultaneously scored. Interestingly, progressively higher IS were found among patients with MDS with adverse prognostic features and shorter overall survival. © 2010 Clinical Cytometry Society