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

Tehranchi, Ramin; Woll, Petter S; Anderson, Kristina; Buza-Vidas, Natalija; Mizukami, Takuo; Mead, Adam J; Åstrand-Grundström, Ingbritt LU ; Strömbeck, Bodil; Biloglav, Andrea LU and Ferry, Helen, et al. (2010) In New England Journal of Medicine 363(11). p.1025-1037
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... (More)
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.) (Less)
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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
in
New England Journal of Medicine
volume
363
issue
11
pages
1025 - 1037
publisher
Massachusetts Medical Society
external identifiers
  • wos:000281609700006
  • pmid:20825315
  • scopus:77956516658
ISSN
0028-4793
DOI
10.1056/NEJMoa0912228
language
English
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yes
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89307a5f-3cce-4fea-b40f-e2a33e6f1182 (old id 1688396)
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http://www.ncbi.nlm.nih.gov/pubmed/20825315?dopt=Abstract
date added to LUP
2010-10-05 10:14:57
date last changed
2018-06-24 04:48:09
@article{89307a5f-3cce-4fea-b40f-e2a33e6f1182,
  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.)},
  author       = {Tehranchi, Ramin and Woll, Petter S and Anderson, Kristina and Buza-Vidas, Natalija and Mizukami, Takuo and Mead, Adam J and Åstrand-Grundström, Ingbritt and Strömbeck, Bodil and Biloglav, Andrea and Ferry, Helen and Dhanda, Rakesh Singh and Hast, Robert and Rydén, Tobias and Vyas, Paresh and Göhring, Gudrun and Schlegelberger, Brigitte and Johansson, Bertil and Hellström, Eva and List, Alan and Nilsson, Lars and Jacobsen, Sten Eirik W},
  issn         = {0028-4793},
  keyword      = {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},
  language     = {eng},
  number       = {11},
  pages        = {1025--1037},
  publisher    = {Massachusetts Medical Society},
  series       = {New England Journal of Medicine},
  title        = {Persistent malignant stem cells in del(5q) myelodysplasia in remission.},
  url          = {http://dx.doi.org/10.1056/NEJMoa0912228},
  volume       = {363},
  year         = {2010},
}