title: Chromosomal aberrations in 17p predict in vitro drug resistance and short overall survival in acute myeloid leukemia.
abstract: Chromosomal aberrations are important prognostic parameters in acute myeloid leukemia (AML). Indicators of poor prognosis include del(5q)/-5, del(7q)/-7, abnormal 3q or complex karyotype. In recent years, it has become clear that aberrations in 17p represent one of the indicators of poor prognosis in haematological malignancies. In AML, deletions in 17p have been shown to indicate a dismal prognosis; genetic aberrations in 9p have also been discussed as influencing long-term survival in AML. In this study, we correlated genetic abnormalities in chromosomes 9 and 17 in patients with de novo AML to in vitro cytotoxicity of conventional anti-leukemic drugs, and long-term overall survival. Blast cells were isolated from 387 patients diagnosed with AML. Chromosomal analysis was successful in 336 cases. All samples were tested for in vitro cytotoxicity against fludarabine, amsacrine, mitoxantrone, etoposide, daunorubicin and Ara-C after being cultured for 4 days, using an ATP assay. Among the 336 patients, five main groups were identified. Abnormal chromosome 17 (n = 22), abnormal 9p (n = 13), monosomy 7 or deletion 7q (n = 35), complex karyotype (n = 52) and normal karyotype (n = 132). Patients with abnormalities of chromosome 17 showed significantly greater resistance to all drugs tested and significantly shorter overall survival compared with patients with normal and complex karyotypes (p = 0.0001 and 0.041, respectively). All patients with abnormalities of chromosome 17 died within 11 months of diagnosis. A tendency towards shorter overall survival and greater drug resistance was also noted when comparing chromosome 17 abnormalities with del(7q)/-7, but the differences did not reach statistical significance. Patients with abnormal 9p showed significantly shorter overall survival but did not differ significantly as regards in vitro drug resistance compared with patients presenting with a normal karyotype. Chromosomal abnormalities affecting the p53 pathway have a significant impact on cytostatic drug resistance and survival in AML. Developing new drugs targeting the p53 pathway could be a way to improve treatment of AML.
authors.affiliation: Department of Haematology, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden.
authors.forename: Hareth
authors.initials: H
authors.lastname: Nahi
authors.forename: Sören
authors.initials: S
authors.lastname: Lehmann
authors.forename: Sofia
authors.initials: S
authors.lastname: Bengtzen
authors.forename: Monika
authors.initials: M
authors.lastname: Jansson
authors.forename: Lars
authors.initials: L
authors.lastname: Möllgård
authors.forename: Christer
authors.initials: C
authors.lastname: Paul
authors.forename: Mats
authors.initials: M
authors.lastname: Merup
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000633:toxicity; D001752:Blast Crisis / Q000473:pathology; D002869:Chromosome Aberrations; D002886:Chromosomes, Human, Pair 17; D002899:Chromosomes, Human, Pair 9; D020732:Cytogenetic Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents