Zeroing in on cereblon

Few medicinals, save for arsenic, have had a more redemptive journey than thalidomide and its analogues, the IMiDs. Initially banned after causing devastating birth defects in women who used thalidomide as a sedative during pregnancy, IMiDs now have established roles in multiple myeloma, mantle cell lymphoma, and myelodysplastic syndrome (MDS). The mechanism of action of these drugs, however, has been mysterious, as the downstream effects are quite pleiotropic. In fact, the IMiDs have been found to have antiangiogenic activity, direct cytotoxicity, the ability to disrupt interactions between neoplastic cells and stromal supports as well as immunomodulatory properties in different clinical scenarios. These effects have been attributed more proximately to decreased expression of vascular endothelial growth factor, inhibition of NF-ΚB, and increased secretion of IL-2 and IL-6, to name but a few (reviewed in Ref. 1). A potential unifying key to unraveling the actions of the IMiDs began at the medicinal origin with the relatively recent observation that thalidomide caused phocomelia birth defects by binding to cereblon, a ubiquitously expressed protein that, together with three protein partners, cullin, DNAbinding protein-1, and Ring-box domain protein form a complex with E-3 ubiquitin ligase activity. IMiD binding to cereblon results in recruitment of protein targets to the complex with subsequent degradation through the ubiquitin–proteasome pathway. Two transcription factors, Ikaros (IKZF1) and Aiolos (IKZF3) which play important roles in B cell, T cell, and plasma cell development, were recently shown to be targeted for ubiquitination by the effects of IMiD binding to cereblon (1). Over the past 4 years, links between the therapeutic effects of the IMiDs and cereblon have tightened. Selective suppression of cereblon expression in myeloma cell lines reduced sensitivity to IMiDs but not other agents such as bortezomib, melphalan, or dexamethasone and IMiD-resistant cell lines underexpressed cereblon. Likewise, cereblon RNA levels declined in primary myeloma patient samples in individuals who no longer responded to lenalidomide or pomalidomide, and elevated cereblon RNA levels were found to correlate with response to IMiDs in myeloma patients (1). Although the association between cereblon and IMiDs has not been without controversy in myeloma, two recent reports suggest not only that the actions of the IMiDs are mediated largely through cereblon and that selective inhibition of downstream targets might give a more refined therapeutic effect. Analysis of the crystal structure of lenalidomidebound cereblon strongly suggests that IMiD binding to cereblon results in a new hotspot for cereblon to interact with potential targets creating a neomorphic moiety that does not necessarily interfere with normal cereblon function (2). In this setting, the recent finding in myeloma cell lines that the cytotoxic effect of IMiDs is almost entirely attributable to IMiD-bound cereblon-mediated degradation of IKZF1 and IZKF3 offers the possibility that understanding the downstream, indirect targets of the IMiDs might lead to the identification of new targets that could permit the dissociation of therapeutic and teratogenic effects (3). In this issue of the European Journal of Haematology, Jonasova and colleagues report that response to lenalidomide is tied to cereblon expression, potentially adding MDS to the growing list of IMiD-responsive conditions where at least portion of the effect may be cereblon-mediated (4). They find that patients with MDS characterized by deletion of chromosome 5q (the so-called 5q minus syndrome) have higher levels of cereblon mRNA expression than other patients with lower risk MDS, linking higher levels of a known IMiD target and an MDS subgroup known to be especially sensitive to lenalidomide. They also followed cereblon levels serially in four patients who maintained response to lenalidomide for more than a year and found that cereblon expression in bone marrow and peripheral blood mononuclear cells was relatively stable. In contrast, two patients who had an initial response to lenalidomide that was lost over time experienced a reduction in peripheral blood and bone marrow mononuclear cell cereblon expression that coincided with the loss of response. While these findings are tantalizing, it may be too soon to conclude that cereblon is a major target of lenalidmide in MDS. It should be noted that the number of patients analyzed by Jonasova et al. was small and the patient samples were analyzed retrospectively and are subject to limitations of small, retrospective studies. Further, the serial analysis of patients responding to lenalidomide can be viewed as little more than anecdotal experience. In addition, the cells in which cereblon was measured were not selected MDS progenitor cells but unselected mononuclear marrow and peripheral blood cells that are certainly contaminated by cells that are unlikely to be direct therapeutic targets of cereblon. It is also important to note that cereblon Correspondence Mark L. Heaney, MD, PhD, Columbia University