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.
