Role of Immunomodulatory Drugs in the Treatment of Lymphoid and Myeloid Malignancies

Immunomodulatory drugs (IMiDs) or cereblon (CRBN) binding drugs such as thalidomide, lenalidomide and pomalidomide have similar structures and mechanism of action. Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) has been recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib. Cereblon seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies and has been identified as a direct molecular target for anti-neoplastic activities of IMiDs. Lenalidomide binds to cereblon (CRBN) which acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other component of CRL4CRBN complex, DNA damage binding protein 1 (DDB1) but in the presence of lenalidomide it changes its specificity and ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and degrades them in proteasomes. Both these transcription factors IKZF1 and IKZF3 are important for the viability of MM cells. IKZF1 induces transcription from interferon regulatory factor 4 gene (IRF4) promoter and from MYC gene promoter in B cells. IKZF1/3 repress the interleukin 2 gene (IL-2) promoter in T cells. In such a way, a decline in IKZF1/3 levels explains how IMiDs stimulate the immune system and degrade B cell function. Low CRBN expression correspond with drug resistance in MM cells. CK1α is a serine/threonine kinase and the CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also the survival of malignant plasma cells in MM. Though, the inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful lenalidomide treatment of del(5q) MDS. Bone marrow aspirates of MDS patients who responded to lenalidomide showed before treatment decreased expression of the set of genes needed for erythroid differentiation. Lenalidomide seemed to overcome differentiation block in non-del(5q) low risk MDS patients with decreased expression of these genes compared to the non-responders but this suggestion was not confirmed.

Keywords: Cereblon, Casein kinase 1α1, Cullin 4-containing RING E3 ubiquitin ligase complex, Ikaros family, Immunomodulatory drugs, Lenalidomide, Pomalidomide, Multiple myeloma, Del(5q) MDS, Mantle lymphoma, Proteasome.