Persistent malignant stem cells in del(5q) myelodysplasia in remission.
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.)
Tehranchi
Ramin
R
Hematopoietic Stem Cell Laboratory, Lund Stem Cell Center, Lund University, Lund, Sweden.
Woll
Petter S
PS
Anderson
Kristina
K
Buza-Vidas
Natalija
N
Mizukami
Takuo
T
Mead
Adam J
AJ
Astrand-Grundström
Ingbritt
I
Strömbeck
Bodil
B
Horvat
Andrea
A
Ferry
Helen
H
Dhanda
Rakesh Singh
RS
Hast
Robert
R
Rydén
Tobias
T
Vyas
Paresh
P
Göhring
Gudrun
G
Schlegelberger
Brigitte
B
Johansson
Bertil
B
Hellström-Lindberg
Eva
E
List
Alan
A
Nilsson
Lars
L
Jacobsen
Sten Eirik W
SE
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology; D010641:Phenotype; D012074:Remission Induction; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018800:Thy-1 Antigens / Q000032:analysis
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D018800:Thy-1 Antigens; D013792:Thalidomide; D051997:ADP-ribosyl Cyclase 1; D000077269:Lenalidomide