HDM4 (HDMX) is widely expressed in adult pre-B acute lymphoblastic leukemia and is a potential therapeutic target

Han, Xin; McDonnell, Timothy J.; Lozano, Guillermina; Medeiros, L. Jeffrey; Xiao, Lianchun; Rosner, Gary L.; Nguyen, Martin; Fernández, Michael; Valentin-Vega, Yasmine A.; Barboza, Juan; Jones, Daniel M.; Rassidakis, Georgios Z.; Kantarjian, Hagop M.; Bueso‐Ramos, Carlos E.

doi:10.1038/modpathol.3800727

Cited by 37 publications

(37 citation statements)

References 25 publications

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“…In keeping with this hypothesis, it is frequently overexpressed in human cancers that retain wildtype p53 (14)(15)(16)(17)(18). Recent data suggest that even modest variation in Mdm4 levels in mice cause measurable perturbations of p53 tumor suppressive function (19).…”

Section: Introductionmentioning

confidence: 86%

An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity

et al. 2010

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Overexpression of MDM4 (also known as MDMX or HDMX) is thought to promote tumorigenesis by decreasing p53 tumor suppressor function. Even modest decrease in Mdm4 levels affects tumorigenesis in mice, suggesting that genetic variants of MDM4 might have similar effects in humans. We sequenced the MDM4 gene in a series of ovarian cancer cell lines and carcinomas to identify mutations and/or single nucleotide polymorphisms (SNPs). We identified an SNP (SNP34091) in the 3 0 -UTR of MDM4 that creates a putative target site for hsa-miR-191, a microRNA that is highly expressed in normal and tumor tissues. Biochemical evidence supports specific miR-191-dependent regulation of the MDM4-C, but not MDM4-A, variant. Consistently, the A-allele was associated with statistically significant increased expression of MDM4 mRNA and protein levels in ovarian carcinomas. Importantly, the wild-type genotype (A/A) is more frequent (57.8% vs. 42.2% for A/C and C/C, respectively) in patients with high-grade carcinomas than in patients with low-grade carcinomas (47.2% vs. 52.5% for A/A and A/C þ C/C, respectively). Moreover, A/A patients who do not express the estrogen receptor had a 4.2-fold [95% confidence interval (CI) ¼ 1.2-13.5; P ¼ 0.02] increased risk of recurrence and 5.5-fold (95% CI ¼ 1.5-20.5; P ¼ 0.01) increased risk of tumor-related death. Unexpectedly, the frequency of p53 mutations was not significantly lower in A/A patients. We conclude that acquisition of an illegitimate miR-191 target site causes downregulation of MDM4 expression, thereby significantly delaying ovarian carcinoma progression and tumor-related death. Importantly, these effects appear to be, at least partly, independent of p53. Cancer Res; 70(23); 9641-9. Ó2010 AACR.

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Section: Introductionmentioning

confidence: 86%

An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity

et al. 2010

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“…This mutation has also been found in five patients with B-lymphoblastic leukemia/lymphoma in our previous studies (four have 119C4G, one has 119C4S). 24 It is located in the Loop-L1 of the central core domain, which contains the sequencespecific DNA-binding activity of the p53 protein (residues 102-292). 34 It is been reported that most p53 mutations occur in this region and result in loss of DNA binding.…”

Section: Discussionmentioning

confidence: 99%

“…The RT-PCR reaction products were sequenced and the presence of a HDM4 variant with a short internal deletion of 68 base pairs (bp) was confirmed as shown earlier. 2,24 The expression of both splicing variants, HDM4-S (containing only the p53-binding domain) and HDM4-FL, was increased compared with that of normal CD19 þ B-cells. The HDM4-S to HDM4-FL ratio was significantly increased compared with that of normal CD19 þ B-cells (Po0.02) (Figure 3b).…”

Section: Hdm4 Transcripts Are Aberrantly Overexpressed In Mantle Cellmentioning

confidence: 99%

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HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis

et al. 2010

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In mouse models and cell lines, murine double minute 2 (MDM2) and MDM4 have been shown to synergistically promote proteasome-mediated degradation of p21 and p53. MDM4 also inhibits p53-mediated transcriptional activation of p21. p53 expression results in increased p21 expression, a negative cell-cycle regulatory protein and an inhibitor of cyclin D1. As mantle cell lymphoma is characterized by cyclin D1 overexpression, we assessed for human homolog of MDM4 (HDM4) expression and its effect on p21 in mantle cell lymphoma. Using immunohistochemical methods, in reactive lymph nodes (n ¼ 19) germinal center cells strongly expressed HDM4 in the nucleus and the cytoplasm, but mantle zone B-cells were only dimly positive. In mantle cell lymphoma tumors, aberrant HDM4 nuclear expression was observed in 18 of 19 (95%) cases. In contrast, HDM4 in other B-cell non-Hodgkin lymphoma types retained its normal pattern of expression. To further characterize the differential upregulation of HDM4 in mantle cell lymphoma, HDM4 was assessed by quantitative real-time polymerase chain reaction in four mantle cell lymphoma cell lines (Granta 519, Z-138, SP-53, and Mino) and six mantle cell lymphoma tumors. Both the splicing variant HDM4-S, containing only the p53-binding domain, and full length HDM4 were increased compared with normal CD19 þ B-cells (Po0.05). Using small interfering RNA to inhibit HDM4 in the SP53 and Mino cell lines showed increased p21 and active caspase-3, the latter indicating increased apoptosis. Our results show that HDM4 is overexpressed in mantle cell lymphoma and, at least in part, exerts its effect by suppressing p21 expression, thereby enhancing cell-cycle progression. Inhibition of HDM4 may serve as a potential approach in the design of therapy for patients with mantle cell lymphoma.

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“…Stronger MDMX nuclear than cytoplasmic immunostaining has been found in various tumor histotypes [32][33][34] and, despite its lack of a nuclear signal localization domain (Supplementary Figure 3), 35 it has also been reported that MDMX-S localizes in the nucleus and the cytoplasm. 16 Using an antibody that recognizes only full-length MDMX, stronger nuclear than cytoplasmic labeling was demonstrated by means of IHC in matched FFPE samples of both the WD and the DD components (Figure 3c).…”

Section: Mdmx Protein Expressionmentioning

confidence: 99%

In vitro and in silico studies of MDM2/MDMX isoforms predict Nutlin-3A sensitivity in well/de-differentiated liposarcomas

Bozzi

Conca

Laurini

et al. 2013

Laboratory Investigation

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The molecular marker of well-differentiated/de-differentiated liposarcomas is MDM2 gene amplification coupled with protein overexpression and wild-type TP53. MDMX is a recently identified MDM2 homolog and its presence in this tumor is unexplored. Our aim was to investigate the role of full-length MDM2 and MDMX proteins and their isoforms in surgical specimens of well-differentiated/de-differentiated liposarcomas in view of Nutlin-3A (a MDM2 inhibitor) treatment. Frozen and matched formalin-fixed, paraffin-embedded material from surgical specimens was examined by means of: (1) fluorescence in situ hybridization to determine MDM2 and MDMX gene copy numbers; (2) RT-PCR and densitometry to analyze alternative splicing forms of mdm2 and mdmx; (3) immunoblotting and immunohistochemistry to assess the corresponding translated proteins; and (4) in vitro and in silico assays to determine their affinity for Nutlin-3A. All these cases showed MDM2 gene amplification with an MDMX disomic pattern. In all cases, the full-length mdm2 transcript was associated with the mdm2-b transcript, with ratios ranging from 0.07 to 5.6, and both were translated into protein; mdmx and mdmx-s were co-transcripted, with ratios ranging from 0.1 to 5.6. MDMX-S was frequently more upregulated than MDMX at both transcriptional and protein level. Each case showed different amounts of mdm2, mdm2-b, mdmx, and mdmx-s transcripts and the corresponding proteins. In vitro assays showed that Nutlin-3A was ineffective against MDM2-B and was unable to disrupt the MDMX/TP53 and MSMX-S/TP53 complexes. Molecular simulations confirmed these in vitro findings by showing that MDM2 has high Nutlin-3A affinity, followed by MDMX-S, MDMX, and MDM2-B. Nutlin-3A is predicted to be a good therapeutic option for well-differentiated/de-differentiated liposarcomas. However, our findings predict heterogeneous responses depending on the relative expression of mdm2, mdm2-b, mdmx, and mdmx-s transcripts and proteins. Well-differentiated/de-differentiated (WD/DD) liposarcomas (LPS) account for 40% of all liposarcomas. With a few exceptions, 1,2 the DD component is defined as a usually abrupt and generally a phenotypic time-dependent transition to a non-lipogenic sarcoma.WD/DD LPS characteristically involve the retroperitoneum and are characterized by a high rate of local recurrences. The inability of even aggressive surgery to obtain negative margins leads to high local failure rates, worsening the long-term prognosis of WD/DD patients and favors the use of multiple treatment modalities albeit with limited benefit. 3,4 The molecular hallmark of WD/DD LPS is MDM2 gene amplification coupled with protein overexpression and wild-type TP53, 5-7 which provides the rationale supporting the therapeutic potential of the MDM2 antagonist Nutlin-3A. MDM2 is an E3 ubiquitin ligase that, in addition to targeting TP53 for proteasomal degradation, blocks TP53

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HDM4 (HDMX) is widely expressed in adult pre-B acute lymphoblastic leukemia and is a potential therapeutic target

Cited by 37 publications

References 25 publications

An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity

An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity

HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis

In vitro and in silico studies of MDM2/MDMX isoforms predict Nutlin-3A sensitivity in well/de-differentiated liposarcomas

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