EFFECT OF LENALIDOMIDE TREATMENT ON THE EXPRESSION OF FLI1, EKLF, TP53, HDM2, PU. 1 AND IL-6 GENES IN 5Q- SYNDROME

Sborník

Background. Lenalidomide has improved the treatment of MDS with 5q deletion, inducing a hematologic (erythroid) and cytogenetic response in the majority of patients. The exact mechanisms of lenalidomide action explaining its effects on erythropoiesis are not clear thus far. We recently studied two transcription factors Fli1(Friend leukemia virus integration 1) and EKLF (Erythroid Kruppel like factor) involved in MEP (common megakaryocytic and erythroid progenitor) differentiation in MDS patients and showed significant decrease of EKLF and increase of Fli1 in 5q- syndrome (Neuwirtova et al, ASH 2011). There exists cross-antagonism between Fli1 and EKLF. Fli1 mRNA is target for microRNA-l45 (miR-145) localized in common deleted region of 5q. Haplo-insufficiency of miR-145 in 5qsyndrome stabilizes Fli1 mRNA and increases Fli1. Fli1 is also increased by IL- 6. IL-6 is induced by haplo-insufficiency of miR-145 and miR-146a. Transcription factor PU. 1 is positive regulator of Fli1 gene expression. In mice Fli1 regulates p53 via MDM2 (mouse double minute 2 or HDM2 in humans), an E3 ubiquitin ligase, which promotes p53 degradation in proteasomes. Aims. To study the changes in expression of above mentioned genes, which are conjectured to play a role in the pathogenesis of 5q- MDS, during the lenalidomide therapy course. Methods. We studied the expression of Fli1, EKLF, TP53, HDM2, PU. 1 and IL6 genes, which are supposed to play a role in the pathogenesis of 5q- syndrome, in the course of lenalidomide therapy in mononuclear cells isolated from peripheral blood of twelve MDS patients with 5q- (9 females, 3 males) of a median age of 70 years (range 55-78 years). Informed consent was obtained from all patients. All were transfusion dependent before treatment. Levels of specific mRNAs were determined by quantitative real-time PCR in total RNA isolated from blood. Relative levels of specific mRNAs were calculated to the level of housekeeping GAPDH mRNA. Results. The beneficial effect of lenalidomide was seen in 10 patients. Lenalidomide promoted induction of hemoglobin synthesis, which reflected the increase of EKLF mRNA levels and on the contrary decrease of the Fli1 mRNA. The decline in Fli1 mRNA levels was accompanied with the decrease of the platelet counts. The levels of Fli1 mRNA and EKLF mRNA oscillate after the normalization of hematopoiesis in the course of further lenalidomide therapy. Levels of p53 mRNA surprisingly did not show any clear decrease after lenalidomide treatment. On the contrary, levels of PU. 1 mRNA and IL-6 mRNA consistently increased in the majority of patients. HDM2 mRNA levels were lowered after lenalidomide treatment in most of examined 5q- patients. Conclusions. We can conclude that lenalidomide treatment is associated with elevation of EKLF mRNA levels and with decrease of Fli1 mRNA levels in majority of treatment-sensitive MDS patients with 5q- syndrome, which reflects the improvement of erythropoiesis, increase of hemoglobin and decrease of platelet production. Unexpectedly, we found consistent decrease of HDM2 expression, but any changes in TP53 expression and surprisingly PU. 1 and IL6 expression increased in almost all our patients, contrary to our expectations subsequent to others authors reports.

Haematologica, 2012; 97(s1):  575