TY - JOUR
T1 - Blasts from elderly acute myeloid leukemia patients are characterized by low levels of culture- and drug-induced apoptosis
AU - Garrido, Sara M.
AU - Cooper, John J.
AU - Appelbaum, Frederick R.
AU - Willman, Cheryl L.
AU - Kopecky, Kenneth
AU - Banker, Deborah E.
N1 - Funding Information:
This work was supported in part by a grant from the Westlund Supporting Organization (S.M.G.); NIH grants CA18105 and CA18029 (F.R.A.); and NIH UOI CA32102 supporting the Southwest Oncology Group Leukemia Biology Program (C.W.) and a Leukemia Society of America Translational Research grant (D.E.B.). S.A. Garrido provided the concept, design, collected and analyzed the data, drafted the paper, gave critical revision and final approval and provided funding for the project. J.J. Cooper helped to assemble the data and analyze it, provided critical revision and gave final approval. F.R. Appelbaum contributed to the concept, design, provided administrative support and funding, assisted with data analysis and gave final approval after critical revision. C.L. Willman contributed to the concept, design, provided study materials and technical support and interpretation of the data, provided critical review and gave final approval. K. Kopecku provided statistical expertise and data analysis and gave final approval. D.E. Banker contributed to all aspects of the project except for statistical input.
PY - 2001
Y1 - 2001
N2 - Increasing evidence suggests that the biology of acute myeloid leukemia (AML) may differ between older and younger patients, with a higher incidence of antecedent myelodysplasia, unfavorable cytogenetic abnormalities, and multidrug resistance seen in the elderly. Abrogation of apoptosis in response to cytotoxic medications is associated with drug resistance in AML, as is expression of bcl-2, an important anti-apoptotic protein. We hypothesized that blasts from elderly (≥55 years) and young adult AML patients might have different levels of apoptotic and cell cycle responses to chemotherapeutic agents, as well as different levels of proliferation and of bcl-2 protein expression. Therefore, we cultured bone marrow leukemia samples from previously untreated elderly (n = 33) and young (n = 21) AML patients for 48 h and then measured apoptosis, bcl-2 protein levels, cell cycle distributions, and expression of a proliferation marker, proliferating cellular nuclear antigen (PCNA) in multi-parametric flow cytometry assays. In some experiments, leukemia samples were exposed to cytarabine (Ara-C) or daunomycin (DNR) for the last 16-18 h of the culture period. In comparison to samples from young patients, cultured samples from elderly AML patients had a higher fraction of viable cells, as measured by Trypan blue exclusion, higher PCNA expression, and significantly less culture-induced and drug-induced apoptosis. The mean apoptosis after culture was 13% for elderly AML samples, versus 20% for young AML samples (P = 0.009). Similarly, the mean apoptosis after Ara-C was lower in elderly than in young AML samples, 13 versus 28% (P = 0.001), as was the mean apoptosis after DNR, 15 versus 26% (P = 0.012). Diminished apoptotic responses in elderly AML cells were not consistently associated with high bcl-2 levels at thaw or bcl-2 levels increased by culture. These data suggest that new therapies should be developed to overcome abrogated apoptosis, particularly in elderly AML patients.
AB - Increasing evidence suggests that the biology of acute myeloid leukemia (AML) may differ between older and younger patients, with a higher incidence of antecedent myelodysplasia, unfavorable cytogenetic abnormalities, and multidrug resistance seen in the elderly. Abrogation of apoptosis in response to cytotoxic medications is associated with drug resistance in AML, as is expression of bcl-2, an important anti-apoptotic protein. We hypothesized that blasts from elderly (≥55 years) and young adult AML patients might have different levels of apoptotic and cell cycle responses to chemotherapeutic agents, as well as different levels of proliferation and of bcl-2 protein expression. Therefore, we cultured bone marrow leukemia samples from previously untreated elderly (n = 33) and young (n = 21) AML patients for 48 h and then measured apoptosis, bcl-2 protein levels, cell cycle distributions, and expression of a proliferation marker, proliferating cellular nuclear antigen (PCNA) in multi-parametric flow cytometry assays. In some experiments, leukemia samples were exposed to cytarabine (Ara-C) or daunomycin (DNR) for the last 16-18 h of the culture period. In comparison to samples from young patients, cultured samples from elderly AML patients had a higher fraction of viable cells, as measured by Trypan blue exclusion, higher PCNA expression, and significantly less culture-induced and drug-induced apoptosis. The mean apoptosis after culture was 13% for elderly AML samples, versus 20% for young AML samples (P = 0.009). Similarly, the mean apoptosis after Ara-C was lower in elderly than in young AML samples, 13 versus 28% (P = 0.001), as was the mean apoptosis after DNR, 15 versus 26% (P = 0.012). Diminished apoptotic responses in elderly AML cells were not consistently associated with high bcl-2 levels at thaw or bcl-2 levels increased by culture. These data suggest that new therapies should be developed to overcome abrogated apoptosis, particularly in elderly AML patients.
KW - AML
KW - Apoptosis, bcl-2
KW - Elderly
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UR - http://www.scopus.com/inward/citedby.url?scp=0035189487&partnerID=8YFLogxK
U2 - 10.1016/S0145-2126(00)00083-7
DO - 10.1016/S0145-2126(00)00083-7
M3 - Article
C2 - 11137557
AN - SCOPUS:0035189487
SN - 0145-2126
VL - 25
SP - 23
EP - 32
JO - Leukemia Research
JF - Leukemia Research
IS - 1
ER -