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55P - Protein expression and clinical significance of the NEDDylation pathway in myelodysplastic syndrome

Presentation Number
55P
Lecture Time
17:10 - 17:10
Speakers
  • Fatemeh Majidi (Düsseldorf, DE)
Session Name
Location
Foyer La Scene, Paris Marriott Rive Gauche, Paris, France
Date
05.03.2018
Time
17:10 - 18:00
Authors
  • Fatemeh Majidi (Düsseldorf, DE)
  • Judith Strapatsas (Düsseldorf, DE)
  • Simon K. Brille (Düsseldorf, DE)
  • Iris Fey (Düsseldorf, DE)
  • Frank Neumann (Cambridge, US)
  • Allison Berger (Cambridge, US)
  • Ulrich Germing (Düsseldorf, DE)
  • Rainer Haas (Düsseldorf, DE)
  • Norbert Gattermann (Düsseldorf, DE)

Abstract

Background

A phase I clinical trial of Pevonedistat (MLN4924), a NEDD8-activating enzyme inhibitor, in AML and MDS showed modest clinical activity as a single agent. A phase II trial with Pevonedistat plus Azacytidine versus single-agent Aza is ongoing. As yet, there is no data regarding activity or dysfunction of the NEDDylation pathway in MDS. We examined NEDDylation pathway protein expression and its prognostic relevance in MDS.

Methods

On a tissue microarray (TMA) with bone marrow biopsies from 119 MDS patients, 40 AML pts, and 11 normal controls, we established immunohistochemistry (IHC) for NEDD8, NAE1 and UBE2M. Semi-quantitative analysis was done according to Remmele-Stegner immunoreactive score (IRS) (0 to 12 points). Clinical follow-up was available for 116 pts.

Results

Of 96 evaluable MDS pts, 46 (39.7%) showed an abnormal karyotype. Ten patients who received disease-modifying treatment prior to biopsy were excluded from survival analysis. On IHC, 100% of 40 AMLs and 11 normal controls were clearly positive (IRS>4) for all three NEDDylation pathway proteins. MDS patients showed a different pattern. While NEDD 8 was positive in the majority (60.6%), NAE1 and UBE2M were expressed in only 30.8% and 29.4%, respectively. For each protein, expression was not correlated with MDS type (WHO 2016), IPSS-R risk group, overall survival or AML transformation. Patients with strong expression of all three proteins survived longer (51 vs. 26 months), but the difference did not reach statistical significance (p = 0.10). Low expression of NAE1 and UBE2M significantly correlated with the presence of karyotype anomalies (p = 0.01 and p = 0.02, respectively).

Conclusions

In contrast to AML, expression of NEDD8 conjugation pathway proteins was low in a substantial proportion of MDS patients. The significant association between low or absent expression of NAE1 and UBE2M, and the presence of karyotype anomalies, suggests that low NEDDylation pathway activity may contribute to chromosomal instability. Nevertheless, since NEDD8 increases DNMT3b-dependent DNA methylation, NEDDylation pathway inhibition may be useful to augment treatment with hypomethylating drugs or counteract resistance to this therapy.

Legal entity responsible for the study

Universitätsklinikum Düsseldorf

Funding

Takeda Pharmaceutical Company

Disclosure

F. Majidi, N. Gattermann: The current research project is funded by Takeda Pharmaceutical Company. All other authors have declared no conflicts of interest.

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