Persistent malignant stem cells in del(5q) myelodysplasia in remission.

Research output: Contribution to journalArticle

Abstract

BACKGROUND: The in vivo clinical significance of malignant stem cells remains unclear. METHODS: Patients who have the 5q deletion (del[5q]) myelodysplastic syndrome (interstitial deletions involving the long arm of chromosome 5) have complete clinical and cytogenetic remissions in response to lenalidomide treatment, but they often have relapse. To determine whether the persistence of rare but distinct malignant stem cells accounts for such relapses, we examined bone marrow specimens obtained from seven patients with the del(5q) myelodysplastic syndrome who became transfusion-independent while receiving lenalidomide treatment and entered cytogenetic remission. RESULTS: Virtually all CD34+, CD38+ progenitor cells and stem cells that were positive for CD34 and CD90, with undetectable or low CD38 (CD38−/low), had the 5q deletion before treatment. Although lenalidomide efficiently reduced these progenitors in patients in complete remission, a larger fraction of the minor, quiescent, CD34+,CD38-/low, CD90+ del(5q) stem cells as well as functionally defined del(5q) stem cells remained distinctly resistant to lenalidomide. Over time, lenalidomide resistance developed in most of the patients in partial and complete remission, with recurrence or expansion of the del(5q) clone and clinical and cytogenetic progression. CONCLUSIONS: In these patients with the del(5q) myelodysplastic syndrome, we identified rare and phenotypically distinct del(5q) myelodysplastic syndrome stem cells that were also selectively resistant to therapeutic targeting at the time of complete clinical and cytogenetic remission. (Funded by the EuroCancerStemCell Consortium and others.)

Details

Authors
  • Ramin Tehranchi
  • Petter S Woll
  • Kristina Anderson
  • Natalija Buza-Vidas
  • Takuo Mizukami
  • Adam J Mead
  • Ingbritt Åstrand-Grundström
  • Bodil Strömbeck
  • Andrea Biloglav
  • Helen Ferry
  • Rakesh Singh Dhanda
  • Robert Hast
  • Tobias Rydén
  • Paresh Vyas
  • Gudrun Göhring
  • Brigitte Schlegelberger
  • Eva Hellström
  • Alan List
  • Lars Nilsson
  • Sten Eirik W Jacobsen
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Medical Genetics

Keywords

  • Myelodysplastic Syndromes: genetics, Myelodysplastic Syndromes: drug therapy, Drug Resistance: genetics, Pair 5: genetics, Human, Chromosomes, Antineoplastic Agents: therapeutic use, Antineoplastic Agents: pharmacology, Thy-1: analysis, Antigens, CD34: analysis, CD38: analysis, Thalidomide: pharmacology, Thalidomide: therapeutic use, Thalidomide: analogs & derivatives, Neoplastic Stem Cells: immunology, Neoplastic Stem Cells: drug effects, Myelodysplastic Syndromes: pathology
Original languageEnglish
Pages (from-to)1025-1037
JournalNew England Journal of Medicine
Volume363
Issue number11
Publication statusPublished - 2010
Publication categoryResearch
Peer-reviewedYes