Correlation of clinical response and response duration with miR-145 induction by lenalidomide in CD34+ cells from patients with del(5q) myelodysplastic syndrome

• Published in: Haematologica (Roma) Vol. 98; no. 3; pp. 409 - 413
• Main Authors: Venner, Christopher P, Woltosz, Joanna Wegrzyn, Nevill, Thomas J, Deeg, H Joachim, Caceres, Gisela, Platzbecker, Uwe, Scott, Bart L, Sokol, Lubomir, Sung, Sandy, List, Alan F, Karsan, Aly
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.03.2013
• Subjects: Animals; Antigens, CD34 - metabolism; Chromosome Deletion; Chromosomes, Human, Pair 5; Gene Expression Regulation - drug effects; Gene Knockdown Techniques; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Mice; MicroRNAs - genetics; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; Thalidomide - therapeutic use; Treatment Outcome
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2012.066068

We examined whether lenalidomide exposure up-regulates miRNAs and mRNAs, previously shown to play a role in the disease phenotype of del(5q) myelodysplastic syndrome, in pre-treatment CD34(+) marrow cells. We hypothesized that increased expression would predict for clinical response. Changes in miR-143, miR-145, miR-146a, miR-146b, miR-378, miR-584, SPARC and RPS14 were examined in del(5q) (n=10) and non-del(5q) (n=18) myelodysplastic syndrome patient samples. Significantly increased expression of miR-143 (1.8-fold and 1.5-fold in del(5q) and non-del(5q), respectively), and miR-145 (1.9-fold and 1.6-fold in del(5q) and non-del(5q), respectively) was observed. In the del(5q) myelodysplastic syndrome cohort, transfusion independence correlated with a 1.3-fold or more increase in miR-145 expression and response over 12 months correlated with a 1.5-fold or more increase. Knockdown of miR-143 and miR-145 in cord blood CD34(+) cells resulted in increased erythroid progenitor activity. Lenalidomide selectively abrogated progenitor activity in cells depleted of miR-143 and miR-145 supporting a key role for miR-143/145 in the sensitivity to lenalidomide of del(5q) myelodysplastic syndrome patients.