title: Genome-wide approach to identify risk factors for therapy-related myeloid leukemia.
abstract: Using a target gene approach, only a few host genetic risk factors for treatment-related myeloid leukemia (t-ML) have been defined. Gene expression microarrays allow for a more genome-wide approach to assess possible genetic risk factors for t-ML. We assessed gene expression profiles (n=12 625 probe sets) in diagnostic acute lymphoblastic leukemic cells from 228 children treated on protocols that included leukemogenic agents such as etoposide, 13 of whom developed t-ML. Expression of 68 probes, corresponding to 63 genes, was significantly related to risk of t-ML. Hierarchical clustering of these probe sets clustered patients into three groups with 94, 122 and 12 patients, respectively; 12 of the 13 patients who went on to develop t-ML were overrepresented in the latter group (P<0.0001). A permutation test indicated a low likelihood that these probe sets and clusters were obtained by chance (P<0.001). Distinguishing genes included transcription-related oncogenes (v-Myb, Pax-5), cyclins (CCNG1, CCNG2 and CCND1) and histone HIST1H4C. Common transcription factor recognition elements among similarly up- or downregulated genes included several involved in hematopoietic differentiation or leukemogenesis (Maz, PU.1, ARNT). This approach has identified several genes whose expression distinguishes patients at risk of t-ML, and suggests targets for assessing germline predisposition to leukemogenesis.
authors.affiliation: Department of Pharmaceutical Sciences, The University of Tennessee, Memphis, TN 38105-2794, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bogni
authors.forename: C
authors.initials: C
authors.lastname: Cheng
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Pfeffer
authors.forename: S
authors.initials: S
authors.lastname: Mukatira
authors.forename: D
authors.initials: D
authors.lastname: French
authors.forename: J R
authors.initials: JR
authors.lastname: Downing
authors.forename: C-H
authors.initials: CH
authors.lastname: Pui
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D002648:Child; D016000:Cluster Analysis; D015331:Cohort Studies; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000209:etiology / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy; D012334:RNA, Neoplasm / Q000235:genetics; D012044:Regression Analysis; D012307:Risk Factors
chemical_list: D012334:RNA, Neoplasm