Deficient cell cycle control in myeloid cells of patients with newly diagnosed chronic myeloid leukemia.
Cell cycle control subsequent to gamma irradiation or growth factor starvation has been studied in immative hematopoietic cells of 19 previously untreated chronic myeloid leukemia (CML) patients in chronic phase compared with 18 normal controls. CD34-positive cells were cultured for seven days in the presence of optimal concentrations of appropriate growth factors. At day 7 of culture both S-phase fraction and differentiation were identical in normal and leukemic cells. In normal cells the proportion of S-phase cells was reduced by irradiation with 500 rad from 40 +/- 3% to 16 +/- 2%. In contrast, in CML cells a reduction of S-phase cells from 35 +/- 2% to 25 +/- 3% was observed. Moreover, irradiated CML cells arrested at a smaller number of cells in G2. Similarly, a significantly higher proportion of CML cells remained in S phase after withdrawal of growth factors. Semiquantitative PCR of p21 (waf1/cip1) induction by gamma irradiation provided no evidence for a major functional deficiency of p53 response to irradiation in these cells. Our results demonstrate an abnormal cell cycle arrest in chronic-phase CML cells both after gamma irradiation and after growth factor removal. This observation might have important implications for understanding the pathogenesis of both hyperplasia of chronic phase and the development of blast crisis in CML. The molecular mechanisms underlying these abnormalities in bcr-abl-positive cells remain to be clarified.
Schwab
R
R
IIIrd Medical Department, Medical School of the Johannes, Gutenberg University, Mainz, Germany.
Peschel
C
C
Desprès
D
D
Derigs
G
G
Fischer
T
T
Huber
C
C
Aulitzky
W E
WE
D000199:Actins / Q000096:biosynthesis; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D001853:Bone Marrow / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology* / Q000528:radiation effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005720:Gamma Rays; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000528:radiation effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000473:pathology*; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011506:Proteins; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D000097642:GADD45 Proteins
D000199:Actins; D015703:Antigens, CD; D018952:Antigens, CD34; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D000097642:GADD45 Proteins; C493956:CDKN1A protein, human