Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells

Abstract

Sickle-cell disease (SCD) and β thalassemia constitute worldwide public health problems. New therapies, including hydroxyurea, have attempted to augment the synthesis of fetal hemoglobin (HbF) and improve current treatment. Lenalidomide and pomalidomide are members of a class of immunomodulators used as anticancer agents. Because clinical trials have demonstrated that lenalidomide reduces or eliminates the need for transfusions in some patients with disrupted blood cell production, we investigated the effects of lenalidomide and pomalidomide on erythropoiesis and hemoglobin synthesis. We used an in vitro erythropoiesis model derived from human CD34 + progenitor cells from normal and SCD donors. We found that both compounds slowed erythroid maturation, increased proliferation of immature erythroid cells, and regulated hemoglobin transcription, resulting in potent induction of HbF without the cytotoxicity associated with other HbF inducers. When combined with hydroxyurea, pomalidomide and, to a lesser extent, lenalidomide were found to have synergistic effects on HbF upregulation. Our results elucidate what we believe to be a new mechanism of action of pomalidomide and lenalidomide and support the hypothesis that pomalidomide, used alone or in combination with hydroxyurea, may improve erythropoiesis and increase the ratio of fetal to adult hemoglobin. These findings support the evaluation of pomalidomide as an innovative new therapy for β-hemoglobinopathies.

Pomalidomide and Lenalidomide Induce p21WAF-1 Expression in Both Lymphoma and Multiple Myeloma through a LSD1-Mediated Epigenetic Mechanism

“…Total RNAs were purified from cells using the RNeasy Kit (Qiagen). Reverse transcription-PCR and quantification of RNA transcripts were done as previously described (10).…”

“…Myelodysplastic syndrome patients receiving lenalidomide therapy experience a significant erythroid response characterized by a cytogenetic reduction of the malignant clone and restoration of bone marrow function that leads to transfusion independence (7,9). Pomalidomide is currently under evaluation for the treatment of hematologic cancers (10). We previously reported that lenalidomide and pomalidomide induce G 0 -G 1 growth arrest in the Burkitt's lymphoma Namalwa cells and multiple myeloma LP-1 and U266 cells by increasing the levels of p21 WAF-1 RNA and protein.…”

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

“…[5][6][7][8][9] In non-del(5q) MDS patients, lenalidomide appears to function by a distinct mechanism to induce erythropoiesis although the clinical response is much less robust. [10][11][12] In patients harboring the del(5q) anomaly, the activity of lenalidomide may correlate with effects on genes found on the remaining sister chromosome thereby recapitulating the normal diploid state. Reinduction of the tumor suppressor gene SPARC has been documented following lenalidomide exposure.…”

Sickle Cell Disease – Current Treatment and New Therapeutical Approaches

“…Moutouh-de Parseval et al (2008) have shown that pomalidomide and lenalidomide induce HbF synthesis and modulate erythrocyte differentiation, and these effects were improved when the authors combined the treatment with HU. The combination of HU with pomalidomide was more effective that its combination with lenalidomide [62]. In vivo studies of these two agents in transgenic animals have shown increased HbF expression, without any myelosuppressive effect, at levels similar to those in the HU-treated controls [63].…”