title: Studying the right cell in acute myelogenous leukemia: dynamic changes of apoptosis and signal transduction pathway protein expression in chemotherapy resistant ex-vivo selected "survivor cells".
abstract: We hypothesized that studying protein expression in cells surviving in vitro chemotherapy ("survivor cells", SV), could provide more important insight into the biology of drug-resistant AML cells than analysis of the bulk population of leukemic cells. Leukemia-enriched samples from 79 patients with new or relapsed AML were cultured for four days +/- cytarabine (5-10 microM). Early apoptotic cells were removed to yield purified SV. Expression of BCL2, bax, PKC alpha, ERK2 and pERK2 proteins was measured using laser scanning cytometry. The SV population was enriched for CD34+ stem cells. Protein expression patterns in SV differed considerably from those in controls; culture and reanalysis of protein expression revealed stability, reversion, or new patterns of change. Patterns of pairs or triads of proteins were nonrandomly distributed and appeared at statistically unlikely frequencies, suggesting preferential adoption of certain patterns. The patterns of change were highly predictive of remission attainment, relapse, and survival in univariate and multivariate analysis. We conclude that in vitro SV cells have protein expression patterns distinct from those of the bulk population of leukemic cells and that these patterns are predictive of outcome. Analysis of SV cells may be more informative than analysis of the bulk population of leukemia cells.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4095, USA. skornbla@mdanderson.org
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: Yi Hua
authors.initials: YH
authors.lastname: Qiu
authors.forename: B N
authors.initials: BN
authors.lastname: Bekele
authors.forename: Jenny Straka
authors.initials: JS
authors.lastname: Cade
authors.forename: Xian
authors.initials: X
authors.lastname: Zhou
authors.forename: David
authors.initials: D
authors.lastname: Harris
authors.forename: C Ellen
authors.initials: CE
authors.lastname: Jackson
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000276:immunology; D017209:Apoptosis; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D047569:Laser Scanning Cytometry; D015470:Leukemia, Myeloid, Acute / Q000473:pathology* / Q000517:prevention & control / Q000628:therapy*; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D010641:Phenotype; D016016:Proportional Hazards Models; D012008:Recurrence; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018952:Antigens, CD34; D009363:Neoplasm Proteins