title: Prediction of risk of disease recurrence by genome-wide cDNA microarray analysis in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy.
abstract: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) reveals very poor prognosis due to high incidence of relapse when treated with standard chemotherapy. Although >96% of patients with Ph+ALL achieved complete remission (CR) with imatinib-combined chemotherapy in a phase II clinical trial conducted by the Japan Adult Leukemia Study Group (JALSG), 26% of them experienced hematological relapse in a short time after achievement of CR. In this study, to establish a prediction system for risk of relapse, we analyzed gene expression profiles of 23 bone marrow samples from patients with Ph+ALL using cDNA microarray consisting of 27,648 cDNA sequences. Using the 19 randomly-selected test cases, we identified 16 genes that were expressed significantly differently between patients with (n=8) and without (n=11) continuous response; from the list of 16 genes, we selected the 6 'predictive' genes and constructed a numerical scoring system by which the two groups were clearly separated, with positive scores for the former and the negative scores for the latter. Scoring of 4 cases that were reserved from the original 23 cases predicted correctly their clinical responses. In addition, three cases whose BCR-Abl transcript levels failed to reduce sufficiently after induction therapy, also revealed negative scores. We also developed a quantitative reverse transcription-PCR-based prediction system that could be feasible for routine clinical use. Our results suggest that achievement of continuous response with imatinib-combined chemotherapy can be predicted by expression patterns in this set of genes, leading to achievement of 'personalized therapy' for treatment of this disease.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. zembutsh@ims.u-tokyo.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Zembutsu
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Yanada
authors.forename: Asahi
authors.initials: A
authors.lastname: Hishida
authors.forename: Toyomasa
authors.initials: T
authors.lastname: Katagiri
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuruo
authors.forename: Isamu
authors.initials: I
authors.lastname: Sugiura
authors.forename: Jin
authors.initials: J
authors.lastname: Takeuchi
authors.forename: Noriko
authors.initials: N
authors.lastname: Usui
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ohno
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D012008:Recurrence; D012306:Risk
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate