MDM4 (MDMX) is overexpressed in chronic lymphocytic leukaemia (CLL) and marks a subset of p53^wild‐type CLL with a poor cytotoxic response to Nutlin‐3

Abstract

Cutaneous manifestations of cryoglobulinemia: clinical and histopathologic study of seventy-two patients. Journal of the American Academy of Dermatology, 25, 21-27. Kern, J., Untergasser, G., Zenzmaier, C., Sarg, B., Gastl, G., Gunsilius, E. & Steurer, M. (2009) Although about one-third of patients with B-cell chronic lymphocytic leukaemia (CLL) never require treatment, in other patients the disease progresses at a variable rate and requires treatment regimens by alkylating agents, purine analogs, monoclonal antibodies or combinations thereof. Despite improvements in response rates using chemo-immunotherapy combinations, patients refractory to fludarabine and/or monoclonal antibodies or patients that have suffered multiple disease relapses have a poor outlook.In cells with functional p53, the p53 activity is primarily inhibited through direct and tonic interaction with the human homolog of the murine double minute 2 (MDM2) protein.After the original description of the small molecule Nutlin-3 as a potent and selective inhibitor of p53/MDM2 interaction (Vassilev et al, 2004), subsequent studies first demonstrated that Nutlin-3 induced ex-vivo cytotoxic cell death of most p53 wild-type (p53 wt ) CLL samples (Coll-Mulet et al, 2006;Secchiero et al, 2006) and is able to determine a comparable accumulation of p53 and degree of apoptosis in CLL cells from bad prognosis CLL subsets, i.e. bearing an unmutated IGHV status, or high levels of the 70 kDa f-associated protein (ZAP-70). However, we have recently demonstrated that cells of a minority of p53 wt CLL cases do not respond to Nutlin-3 treatment and fail to display the canonical signature associated with in-vitro Nutlin-3 exposure (Zauli et al, 2009). According to this background, the present study sought to identify and validate the relevant genes associated with resistance of p53 wt CLL cells to the in-vitro Nutlin-3 effects.To do this, the constitutive gene expression signature associated with the reduced response of p53 wt CLL cells to in-vitro Nutlin-3 exposure was investigated by comparing the gene expression profile (GEP) of CLL cells from 13 Nutlin-3 'responder' versus 3 Nutlin-3 'non-responder' cases, as identified by previous studies (Zauli et al, 2009), all of which displayed a p53 wt phenotype. The main clinical and biological features of CLL samples utilized for this purpose are listed in Table SI. Patients provided informed consent in accordance with the local institutional review board requirements and the declaration of Helsinki. Problems associated with bioinformatic analyses of such an unbalanced datasets (13 vs. 3 cases) were overcome by applying a purposely set-up modified version of significance analysis of microarrays (SAM), named multi-SAM (see Appendix S1). By means of this approach, we were able to select 278 differentially expressed genes, of which 149 up-regulated and 129 down-regulated in 'non-responder' p53 wt CLL, correlated with the lack of response to Nutlin-3 (Table SII). A hierarchical clustering using the 278 genes separated the ...

FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of MdmX

“…First, this further supports the notion that MdmX depletion is a critical mechanism to inactivate oncogenic Mdm2–MdmX E3 complex and accordingly activates p53 signaling in cells (39), because MdmX stimulates Mdm2-mediated p53 monoubiquitination and is required for p53 polyubiquitination (36, 38). Second, FL118 can be used as an MdmX-depleting agent in MdmX-targeting therapies for a subgroup of patients with cancer (i.e., a type of personalized medicine) such as in chronic lymphocytic leukemia (49) and melanomas (50), in which MdmX overexpression confers treatment resistance. Our studies provided evidence that FL118 inhibits growth of MdmX-overexpressing cells better than non–MdmX-overexpressing cells (Fig.…”

Pharmacological activation of wild-type p53 in the therapy of leukemia

“…Although trisomy 12 is the most common cytogenetic change in CLL, trisomy 12 has not been associated with overexpression of MDM2. MDMX overexpression has also been reported in CLL [19]. ATM, which is activated in response to DNA double-strand breaks, synchronizes DNA repair with the induction of p53-dependent apoptosis.…”

“…It has been reported that increased expression of MDM2 predicts higher cell sensitivity to MDM2 inhibitors [30, 58]. On the other hand, cells with MDMX overexpression or TP53 mutations generally show poor inhibitor sensitivity [19, 29–35]. By interrogating high-throughput cell line and patient-derived tumor xenograft sensitivity data with genomic profiling data, a gene expression signature consisting of 13 p53 transcriptional target genes has been identified that predicts sensitivity to the MDM2 inhibitor NVP-CGM097 [72].…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…104 Interestingly, MDM4 overexpression has been associated with lack of response to the MDM2 antagonist nutlin in chronic lymphoma cells in vitro. 105 In a recent phase I study exploring an MDM2 antagonist administered as monotherapy to patients with liposarcomas, for which most were amplified for MDM2, one patient achieved a partial tumour response while several had stable disease, 106 advocating further studies in concert with chemotherapy.…”