Receptor Activator of Nuclear Factor kB (RANK) Is Upregulated in Chronic Myeloid Leukemia Patients Taking Imatinib Mesylate: Can This Be Considered a Drug-Mediated Immune Activation Effect?.
Authors: Albano Francesco , Anelli Luisa , Zagaria Antonella , Guastadisegni Maria , Pannunzio Alessandra , Liso Vincenzo , Rocchi Mariano , Specchia Giorgina 
Published: April 2020

It is known that the receptor activator of nuclear factor kB (RANK) is only identified on progenitor and mature osteoclasts and in dendritic cells. A recent report (Blood107:4334, 2006) described a dose-dependent decrease of RANK expression in osteoclasts when cultured in the presence of imatinib; these data were confirmed in adult mice treated with imatinib, in which a decrease in osteoclasts activity was demonstrated. Therefore, it is speculated that imatinib may have a potential antiresorptive effect. We evaluated bone marrow RANK molecular expression in patients affected by chronic myeloid leukemia (CML) receiving imatinib therapy, to verify the effect of the tyrosine kinases inhibitor on RANK expression.

The study included 13 CML patients (7 males, 6 females, median age 37 yrs). Six were treated with Imatinib at standard dosage (400 mg) and the remaining 7 at higher doses (&gt; 400 mg). The median duration of imatinib therapy was 28 months (range 13 – 44 months). The RANK gene expression level was determined by Real-Time PCR using 1X Platinum SYBR Green qPCR SuperMix-UDG. The RANK gene expression level variation was estimated by comparing the values of 2−Δ Δ Ct obtained in CML patients at diagnosis and during imatinib treatment. For each of the tested cases the sample at diagnosis was utilized as calibrator and 28S rRNA was used as reference gene.

Eleven (85%) patients showed an upregulation of RANK, the gene expression fold increase ranging from 1.17 to 15.88 as compared to the value at diagnosis; all patients treated with high-dose imatinib showed a RANK overexpression, the fold increase ranging from 1.57 to 15.88. Although the median RANK expression fold increase observed in the group of patients treated with high-dose imatinib was higher than in the cases taking standard dosage (2.47 versus 1.34 fold increase, respectively), this difference was not statistically significant. There was no association between the RANK expression level and the duration of imatinib treatment.

Our study reveals that imatinib mesylate is accountable for the molecular overexpression of the RANK gene in CML patients. These data seem to be in conflict with those previously reported (Blood2006;107: 4334). It is possible that the RANK overexpression which we observed was related to the immune (i.e. dendritic cells) and not the bone cells (i.e. osteoclasts). In this regard, a new type of cell has recently been described in mice, that may account for the immune effect of imatinib; the new cell, which seems to be a cross between a dendritic cell and a natural killer cell, has been called an “interferon-producing killer dendritic cell” (Nat Med2:214, 2006; Nat Med2:207, 2006). These studies suggest a new mechanism by which imatinib might exert an antitumor effect, apart from its direct action on chronic myeloid leukemia cells. Therefore, in this context, the RANK upregulation observed in our study could be an expression of the immune effect of imatinib. Further studies are needed to verify if the RANK gene overexpression mediated by imatinib could affect the molecular and cytogenetic response in CML patients.