Advanced

Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q-syndrome patients

Pellagatti, Andrea; Jaedersten, Martin; Forsblom, Ann-Mari; Cattan, Helen; Christensson, Birger; Emanuelsson, Emma K.; Merup, Mats; Nilsson, Lars LU ; Samuelsson, Jan and Sander, Birgitta, et al. (2007) In Proceedings of the National Academy of Sciences 104(27). p.11406-11411
Abstract
Myelodysplastic syndromes (MDSs) are a group of hematopoietic stem cell disorders characterized by ineffective hernatopoiesis and peripheral blood cytopenias. Lenalidomide has dramatic therapeutic effects in patients with low-risk MDS and a chromosome 5q31 deletion, resulting in complete cytogenetic remission in >60% of patients. The molecular basis of this remarkable drug response is unknown. To gain insight into the molecular targets of lenaliclomide we investigated its in vitro effects on growth, maturation, and global gene expression in isolated erythroblast cultures from MDS patients with clel(5)(q3l). Lenalidomide inhibited growth of differentiating del(5q) erythroblasts but did not affect cytogenetically normal cells. Moreover,... (More)
Myelodysplastic syndromes (MDSs) are a group of hematopoietic stem cell disorders characterized by ineffective hernatopoiesis and peripheral blood cytopenias. Lenalidomide has dramatic therapeutic effects in patients with low-risk MDS and a chromosome 5q31 deletion, resulting in complete cytogenetic remission in >60% of patients. The molecular basis of this remarkable drug response is unknown. To gain insight into the molecular targets of lenaliclomide we investigated its in vitro effects on growth, maturation, and global gene expression in isolated erythroblast cultures from MDS patients with clel(5)(q3l). Lenalidomide inhibited growth of differentiating del(5q) erythroblasts but did not affect cytogenetically normal cells. Moreover, lenalidomide significantly influenced the pattern of gene expression in del(5q) intermediate erythroblasts, with the V51G4, PPIC, TPBG, activin A, and SPARC genes up-regulated by >2-fold in all samples and many genes involved in erythropoiesis, including HBA2, GYPA, and KLF1, down-regulated in most samples. Activin A, one of the most significant differentially expressed genes between lenalidomide-treated cells from MDS patients and healthy controls, has pleiotropic functions, including apoptosis of hematopoietic cells. Up-regulation and increased protein expression of the tumor suppressor gene SPARC is of particular interest because it is anti proliferative, antiadhesive, and antiangiogenic and is located at 5q3l-q32, within the commonly deleted region in MDS 5q- syndrome. We conclude that lenalidomide inhibits growth of del(5q) erythroid progenitors and that the up-regulation of SPARC and activin A may underlie the potent effects of lenalidomide in MDS with clel(5)(q3l). SPARCmay play a role in the pathogenesis of the 5q- syndrome. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
microarray, gene expression profiling, myelodysplastic syndromes, erythropoiesis, osteonectin
in
Proceedings of the National Academy of Sciences
volume
104
issue
27
pages
11406 - 11411
publisher
National Acad Sciences
external identifiers
  • wos:000247900000051
  • scopus:34547474047
ISSN
1091-6490
DOI
10.1073/pnas.0610477104
language
English
LU publication?
yes
id
e4f7a50b-7a25-4582-8ae7-558a06413a1f (old id 689813)
date added to LUP
2007-12-19 12:49:58
date last changed
2017-11-05 03:35:59
@article{e4f7a50b-7a25-4582-8ae7-558a06413a1f,
  abstract     = {Myelodysplastic syndromes (MDSs) are a group of hematopoietic stem cell disorders characterized by ineffective hernatopoiesis and peripheral blood cytopenias. Lenalidomide has dramatic therapeutic effects in patients with low-risk MDS and a chromosome 5q31 deletion, resulting in complete cytogenetic remission in >60% of patients. The molecular basis of this remarkable drug response is unknown. To gain insight into the molecular targets of lenaliclomide we investigated its in vitro effects on growth, maturation, and global gene expression in isolated erythroblast cultures from MDS patients with clel(5)(q3l). Lenalidomide inhibited growth of differentiating del(5q) erythroblasts but did not affect cytogenetically normal cells. Moreover, lenalidomide significantly influenced the pattern of gene expression in del(5q) intermediate erythroblasts, with the V51G4, PPIC, TPBG, activin A, and SPARC genes up-regulated by >2-fold in all samples and many genes involved in erythropoiesis, including HBA2, GYPA, and KLF1, down-regulated in most samples. Activin A, one of the most significant differentially expressed genes between lenalidomide-treated cells from MDS patients and healthy controls, has pleiotropic functions, including apoptosis of hematopoietic cells. Up-regulation and increased protein expression of the tumor suppressor gene SPARC is of particular interest because it is anti proliferative, antiadhesive, and antiangiogenic and is located at 5q3l-q32, within the commonly deleted region in MDS 5q- syndrome. We conclude that lenalidomide inhibits growth of del(5q) erythroid progenitors and that the up-regulation of SPARC and activin A may underlie the potent effects of lenalidomide in MDS with clel(5)(q3l). SPARCmay play a role in the pathogenesis of the 5q- syndrome.},
  author       = {Pellagatti, Andrea and Jaedersten, Martin and Forsblom, Ann-Mari and Cattan, Helen and Christensson, Birger and Emanuelsson, Emma K. and Merup, Mats and Nilsson, Lars and Samuelsson, Jan and Sander, Birgitta and Wainscoat, James S. and Boultwood, Jacqueline and Helistroem-Lindberg, Eva},
  issn         = {1091-6490},
  keyword      = {microarray,gene expression profiling,myelodysplastic syndromes,erythropoiesis,osteonectin},
  language     = {eng},
  number       = {27},
  pages        = {11406--11411},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q-syndrome patients},
  url          = {http://dx.doi.org/10.1073/pnas.0610477104},
  volume       = {104},
  year         = {2007},
}