TRAIL (Apo2L) suppresses growth of primary human leukemia and myelodysplasia progenitors.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, APO2L) has been shown to induce apoptosis in a number of tumor cell lines as well as in some primary tumors whereas cells from most normal tissues are highly resistant to TRAIL-induced apoptosis. We have studied the susceptibility of primary malignant and normal bone marrow hematopoietic progenitors to TRAIL-induced apoptosis. Extracellular domain of human TRAIL with N-terminal His(6) tag (His-TRAIL, amino acids 95-281) was produced in E. coli and its apoptosis-inducing ability was compared with the leucine-zipper containing TRAIL, LZ-TRAIL. Both variants of TRAIL had the same apoptosis-inducing ability. Clonogenic progenitor assays showed that His-TRAIL significantly reduced the number of myeloid colonies (CFU-GM) and clusters from patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). His-TRAIL had no negative effect on the number of CFU-GM colonies and clusters derived from bone marrow cells of AML patients in complete remission, and lymphoma patients without bone marrow involvement, as well as those derived from normal cord blood cells. Moreover, we found that normal human stem cells treated with high doses of His-TRAIL maintain a repopulating potential when transplanted into NOD/SCID mice. To conclude, our data document that TRAIL does not affect normal human hematopoiesis but suppresses the growth of early primary leukemia and myelodysplasia progenitors.
Plasilova
M
M
Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
Zivny
J
J
Jelinek
J
J
Neuwirtova
R
R
Cermak
J
J
Necas
E
E
Andera
L
L
Stopka
T
T
D000208:Acute Disease; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004354:Drug Screening Assays, Antitumor; D006085:Graft Survival; D006131:Growth Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D020014:K562 Cells / Q000187:drug effects; D016350:Leucine Zippers; D007951:Leukemia, Myeloid / Q000473:pathology*; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009190:Myelodysplastic Syndromes / Q000473:pathology*; D022423:Myeloid Cells / Q000187:drug effects*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; C448904:His-TRAIL protein, recombinant; C448905:LZ-TRAIL protein, recombinant; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha