Multidrug resistance in relapsed acute myeloid leukemia: Evidence of biological heterogeneity

Authors

  • Chirayu Patel BA,

    1. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    2. Howard Hughes Medical Institute (HHMI)-National Institutes of Health (NIH) Research Scholars Program, Bethesda, Maryland
    Search for more papers by this author
  • Leif Stenke MD,

    1. Department of Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden
    2. Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden
    Search for more papers by this author
  • Sudhir Varma PhD,

    1. Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, Office of Science Management and Operations, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
    Search for more papers by this author
  • Marita Lagergren Lindberg MD,

    1. Department of Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden
    2. Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden
    Search for more papers by this author
  • Magnus Björkholm MD,

    1. Department of Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden
    Search for more papers by this author
  • Jan Sjöberg MD,

    1. Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden
    Search for more papers by this author
  • Kristina Viktorsson MD,

    1. Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden
    Search for more papers by this author
  • Rolf Lewensohn MD,

    1. Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden
    Search for more papers by this author
  • Ola Landgren MD,

    1. Metabolism Branch, NCI, NIH, Bethesda, Maryland
    Search for more papers by this author
  • Michael M. Gottesman MD,

    Corresponding author
    1. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    • Corresponding author: Michael Gottesman, MD, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 2108, Bethesda, MD 20892-4255; Fax: (301) 402-0450; mgottesman@nih.gov

    Search for more papers by this author
  • Jean-Pierre Gillet PhD

    1. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author

Abstract

BACKGROUND

Studies of mechanisms mediating resistance to chemotherapy led to the discovery of the multidrug transporter ABCB1 (ATP-binding cassette, subfamily B, member 1), often expressed in leukemic cells of patients with acute myeloid leukemia (AML). Most clinical trials evaluating the strategy of inhibiting efflux-mediated chemotherapeutic resistance have been unsuccessful, clearly indicating the need for a better approach.

METHODS

This study investigated the clinical relevance of 380 genes whose expression has been shown to affect the response to chemotherapy, mostly through in vitro studies, in 11 paired samples obtained at AML diagnosis and at relapse. The expression profiling of these 380 genes was performed using TaqMan-based quantitative reverse-transcription polymerase chain reaction. Patients had a median age of 58 years at diagnosis, a median duration of complete remission of 284.5 days, and a median overall survival of 563 days. Cytogenetic abnormalities were detected at diagnosis in 4 patients, whereas 5 displayed a normal karyotype and 2 were not investigated.

RESULTS

Hierarchical clustering shows that samples taken at diagnosis and relapse clustered in pairs for 6 patients of the 11 studied, suggesting recurrence of the same leukemic blast, whereas for the other 5 patients, the data indicate their relapse blasts arose from different origins. A patient-by-patient analysis of the paired samples led to the striking observation that each had a unique gene signature representing different mechanisms of resistance.

CONCLUSIONS

The data underline the need for personalized molecular analysis to tailor treatment for patients with AML. Cancer 2013;119:3076—3083. © 2013 American Cancer Society.

Ancillary