Apoptotic rate in patients with myelodisplastic syndrome treated with modulatory compounds of pro‐apoptotic cytokines

Abstract

Excessive apoptosis has a central role in ineffective hematopoiesis in myelodysplastic syndrome (MDS). The aim of the study was to quantify apoptosis and Bcl‐2 expression in patients with MDS and to use these parameters in the evaluation of treatment efficacy with compounds modulating proapoptotic cytokines. Bone marrow (BM) samples from eight MDS patients were studied: four with refractory anemia and four with refractory anemia with ringed sideroblasts. Two patients with Hodgkin disease without BM determination were studied for control. Therapy consisted in administration of pentoxyphylline, dexamethasone and ciprofloxacin. Biochemical assay of apoptosis and Bcl‐2 was performed using annexin V‐biotin conjugate antibody and anti‐human Bcl‐2 antibody respectively, followed by streptavidine‐peroxidase conjugate, and peroxidase substrate. Ultrastructural investigation of BM samples was performed with standard electron microscopy techniques. Most of BM hematopoietic cells in the MDS patients had ultrastructural features of various stages of apoptosis including chromatin condensation and margination, cytoplasm condensation and budding of nuclear and plasma membranes to produce apoptotic bodies. Bcl‐2 expression showed an inverse correlation with the rate of the apoptotic process. Periodic evaluation of these two parameters has shown an increase of Bcl‐2 expression and a decrease of apoptotic rate in patients who had responded to the treatment. Response to the treatment was appreciated in accordance with their transfusion needs. Treatment efficiency diminished in time. The rate of apoptosis was inversely correlated with the level of Bcl‐2 expression. These results confirm the importance of the apoptotic process evaluation in monitoring MDS treatment.

Clinical Importance of Transforming Growth Factor-β but Not of Tumor Necrosis Factor-α Gene Polymorphisms in Patients with the Myelodysplastic Syndrome Belonging to the Refractory Anemia Subtype

“…One of the genetic factors may be an aberration of cytokine regulation and cytokine production, which can lead to an increased apoptosis of hematopoietic progenitor cells, and aberrant hematopoiesis. The excessive production of growth-inhibitory cytokines such as TNF-␣ in patients with MDS has been described [3,4,29] . Recent data indicate that TGF-␤ inhibits myeloid, erythroid, megakaryocytic and multilineage colony formation [5][6][7] .…”

“…A number of investigators have demonstrated an excessive production of proapoptotic cytokines in the bone marrow of MDS patients. Several studies have stressed the im portance of increased levels of tumor necrosis factor-␣ (TNF-␣ ) in the serum and bone marrow in promoting apoptosis [3,4] . Transforming growth factor-␤ (TGF-␤ ) is another cytokine which is generally considered to be a negative key regulator of hematopoietic stem and progenitor cells [5][6][7] .…”

Bone marrow malignancies as paradigms of dysfunctional cell adhesion mechanisms

“…While pro-apoptotic mechanisms are activated in HSPCs in MDS, the evolution to an aggressive AML includes a suppression of apoptosis due to changes in intracellular levels of Bcl-2-family proteins [156,143] . Nevertheless, important interactions between leukemic cells and BM microenvironment also contribute to AML progression: When natural killer cells and cytotoxic lymphocytes adhere to BM stroma, they inhibit AML blasts clonogenic growth; however, AML cells compete with them for stromal binding sites via β1 (principally VLA-4) and β2 integrins, escaping from apoptosis [70,72,157] .…”

“…Other adhesion molecule patterns are modified in HSPCs from MDS and secondary AML, like ICAM-1 (overexpressed) and L-selectin (underexpressed), having prognosis importance [154] . Also, plasma levels of soluble CD44 are significantly elevated in MDS patients as compared to those of healthy donors and are increased in high-risk MDS subtypes [155] .While pro-apoptotic mechanisms are activated in HSPCs in MDS, the evolution to an aggressive AML includes a suppression of apoptosis due to changes in intracellular levels of Bcl-2-family proteins [156,143] . Nevertheless, important interactions between leukemic cells and BM microenvironment also contribute to AML progression: When natural killer cells and cytotoxic lymphocytes adhere to BM stroma, they inhibit AML blasts clonogenic growth; however, AML cells compete with them for stromal binding sites via β1 (principally VLA-4) and β2 integrins, escaping from [70,72,157] .…”

Evaluación de los índices y la morfología plaquetaria como posibles biomarcadores de valor pronóstico en síndrome mielodisplásico

“…Los síndromes mielodisplásicos (SMD) corresponden a un grupo heterogéneo de trastornos clonales de células madre hematopoyéticas que conducen al desarrollo de citopenias progresivas las cuales tienen un riesgo elevado de evolución hacia leucemia mieloide aguda (LMA) (1). La estratificación de dicho riesgo en combinación con los requisitos de transfusión, guían el manejo actual de SMD.…”