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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Andrea Pellagatti
  • Martin Jaedersten
  • Ann-Mari Forsblom
  • Helen Cattan
  • Birger Christensson
  • Emma K. Emanuelsson
  • Mats Merup
  • Lars Nilsson
  • Jan Samuelsson
  • Birgitta Sander
  • James S. Wainscoat
  • Jacqueline Boultwood
  • Eva Helistroem-Lindberg
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • microarray, gene expression profiling, myelodysplastic syndromes, erythropoiesis, osteonectin
Original languageEnglish
Pages (from-to)11406-11411
JournalProceedings of the National Academy of Sciences
Volume104
Issue number27
Publication statusPublished - 2007
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematopoietic Stem Cell Laboratory (013022012)