Dysregulated human myeloid nuclear differentiation antigen expression in myelodysplastic syndromes: evidence for a role in apoptosis.
Reduced levels of human myeloid nuclear differentiation antigen (MNDA) gene transcripts have been detected in both familial and sporadic cases of myelodysplastic syndromes (MDS). Numerous reports implicate elevated apoptosis/programmed cell death and death ligands and their receptors in the pathogenesis of MDS. MNDA and related proteins contain the pyrin domain that functions in signaling associated with programmed cell death and inflammation. We tested the hypothesis that MNDA is involved in the regulation of programmed cell death in human myeloid hematopoietic cells. Clones of K562 cells (MNDA-null) that expressed ectopic MNDA protein were established using retroviral transduction. MNDA-expressing K562 clones were resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis, but were not protected from programmed cell death induced with genotoxic agents or H(2)O(2). MNDA protein expression assessed in control and intermediate and high-grade MDS marrows showed several patterns of aberrant reduced MNDA. These variable patterns of dysregulated MNDA expression may relate to the variable pathophysiology of MDS. We propose that MNDA has a role regulating programmed cell death in myeloid progenitor cells, and that its down-regulation in MDS is related to granulocyte-macrophage progenitor cell sensitivity to TRAIL-induced programmed cell death.
Briggs
Robert C
RC
Departments of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. bob.briggs@vanderbilt.edu
Shults
Keith E
KE
Flye
Leanne A
LA
McClintock-Treep
Sara A
SA
Jagasia
Madan H
MH
Goodman
Stacey A
SA
Boulos
Fouad I
FI
Jacobberger
James W
JW
Stelzer
Greg T
GT
Head
David R
DR
D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D015536:Down-Regulation; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D008562:Membrane Glycoproteins / Q000494:pharmacology; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D023461:Myeloid Progenitor Cells / Q000166:cytology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015214:Antigens, Differentiation, Myelomonocytic; D051017:Apoptosis Regulatory Proteins; C075373:MNDA protein, human; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha