title: Novel insights into the biology of myelodysplastic syndromes: excessive apoptosis and the role of cytokines.
abstract: The paradox of myelodysplastic syndromes (MDS) which present with pancytopenias despite cellular bone marrows (BM) was investigated by conducting detailed studies of proliferation and apoptosis in 89 MDS patients. Our results demonstrated a rapid rate of both proliferation as well as apoptosis. Levels of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and interleukin-1 beta (IL-1 beta) were measured in the same patients. High levels of TNF-alpha were found to correlate with high levels of apoptosis in 83 MDS patients (P = 0.0045). We propose a dual role for TNF-alpha (or other cytokines) in the pathogenesis of MDS. On the one hand, TNF-alpha induces apoptosis in the maturing cells causing pancytopenia while on the other, it stimulates the proliferation of the primitive progenitors accounting for the hypercellular BM frequently seen in MDS. A new model for MDS is presented. The initial abnormality probably affects a primitive hemopoietic progenitor which acquires a growth advantage leading to monoclonal hemopoiesis, which in turn makes these cells susceptible towards acquiring additional mutations and appearance of cytogenetically marked (or unmarked) clones. Cytokines such as TNF-alpha whose source is presently unknown, then contribute towards the clinical syndrome of pancytopenia and hypercellularity.
authors: Rush Cancer Institute, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA.
authors: A
authors: A
authors: Raza
authors: S
authors: S
authors: Mundle
authors: V
authors: V
authors: Shetty
authors: S
authors: S
authors: Alvi
authors: H
authors: H
authors: Chopra
authors: L
authors: L
authors: Span
authors: A
authors: A
authors: Parcharidou
authors: S
authors: S
authors: Dar
authors: P
authors: P
authors: Venugopal
authors: R
authors: R
authors: Borok
authors: S
authors: S
authors: Gezer
authors: J
authors: J
authors: Showel
authors: J
authors: J
authors: Loew
authors: E
authors: E
authors: Robin
authors: S
authors: S
authors: Rifkin
authors: D
authors: D
authors: Alston
authors: B
authors: B
authors: Hernandez
authors: R
authors: R
authors: Shah
authors: H
authors: H
authors: Kaizer
authors: S
authors: S
authors: Gregory
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis; D001853:Bone Marrow / Q000473:pathology; D002455:Cell Division; D016207:Cytokines / Q000502:physiology*; D004261:DNA Replication; D018450:Disease Progression; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D007375:Interleukin-1 / Q000097:blood / Q000502:physiology; D007938:Leukemia / Q000209:etiology; D008954:Models, Biological; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000097:blood / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000502:physiology
chemical_list: D018952:Antigens, CD34; D016207:Cytokines; D007375:Interleukin-1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha