Page 272 - 2021_06-Haematologica-web

Letters to the Editor
MK2 is a therapeutic target for high-risk multiple
myeloma
Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by heterogeneous genetic diversity. Although the development of proteasome inhibitors and immumodulatory drugs combined with autologous stem cell transplantation (ASCT) have achieved advanced improvement for MM treatment, the majority of MM patients ultimately relapse.1,2 One hypothesis for relapse is the cytogenetic evolution of drug-resistant MM cells and the generation of more aggressively proliferative subclones over the patients’ dis- ease course. Recent studies support this hypothesis and demonstrate that the existence of intraclonal heterogene- ity in MM and genome of high-risk patients with poor outcome and survival present more changes over the dis- ease course.3 The progression of modern high-through- put genomic and proteomic analytical technique such as gene expression profile (GEP) and whole exome or genome sequencing combined with bioinformatic and bio-statistic approaches has aided the investigation of these MM clinical samples.4,5 Based on GEP analysis of sequential MM primary samples during the disease course, characterized by serial cycles of response, remis- sion, and relapse combined with health donor control, our group identified a serial of genes inluding NEK2, RARα2, which induce MM proliferation and drug-resis- tance resulting in MM relapse and poor outcome.6
MAPKAPK2 (MK2), a major substrate of p38, is regu- lated through direct phosphorylation by p38 MAP kinase, and participates in many cellular processes such as stress and inflammatory responses, cell proliferation and gene expression regulation.7,8 To date, abnormality of MK2 is associated with a broad range of cancers, including glioblastoma, lung and bladder cancer.9 Intriguingly, p38-
MK2-Hsp27 signaling maintains survival of cancer stem cells,10 which is regarded as an obstacle of MM treatment and the resource for MM relapse in clinics suggesting MK2 is a promising therapeutic target in MM. However, MK2 has received little attention in MM.
In order to explore the role of MK2 in MM, we exam- ined MK2 expression of normal plasma cells (NP) (n=22), monoclonal gammopathy of undetermined significance cells (MGUS) (n=44) and newly diagnosed myeloma patient plasma cells (n=351) using our GEP database col- lected from the National Institutes of Health Gene Expression Omnibus GSE2658 and the result showed sig- nificantly increased MK2 expression in MM cells com- pared to NP and MGUS cells (data not shown).11 Following analysis of array-based comparative genomic hybridiza- tion (aCGH) data, GSE4452, collected from 67 MM patients indicated that the MK2 locus was frequently amplified in MM patient samples relative to normal con- trol (data not shown).12 We further observed elevation of MK2 expression in high-risk MM patients compared to low-risk patients (Figure 1A). The expression of MK2 in the PR (high proliferation) and MS (MMSET transloca- tion) groups, the worst two subgroups in MM patients, was dramatically elevated compared to the other six groups13 (Figure 1B). Upon correlation analyses of MK2 with clinical characteristics, MK2 expression performed as an independent factor associated with parameters like C-reactive protein at least 4.0 mg/L (P<0.05), chromoso- mal abnormalities (by G-banding) (P<0.05), and magnetic resonance imaging focal bone lesions, at least three lesions, which were acknowledged as a poor diagnosed markers in MM (data not shown).
We further tested MK2 mRNA expression in MM patients from APEX trials which evaluated the response to standard therapies (bortezomib or dexamethasone).14 A pronounced elevation of average MK2 expression was observed in the no-response treatment group compared
ABC
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Figure 1. MK2 is a poor prognostic marker or a high-risk gene in multiple myeloma. (A) MK2 expression in the TT2 high and low group based 70-gene model. (B) A box-plot exhibited the average MK2 expression in eight multiple myeloma (MM) subgroups of the TT2 cohort. (C) A box-plot showed MK2 expression in patients categorized by unresponsive (No Response) or responsive (Response) to treatment with dexamethasone and/or bortezomib. (D) Kaplan-Meier analysis on the MM patients’ survival in APEX cohort divided by different MK2 expression. (E and F) Kaplan-Meier curve on relapsed MM patients’ event free survival (E) and overall survival (F) in the TT2 cohort divided by MK2 expression.
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haematologica | 2021; 106(6)