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Myeloma Genomics and Microenvironment and immune profiling

Category: Myeloma Genomics and Microenvironment and immune profiling

Immunomodulatory Drugs (IMiDs) induce the expression of long non-coding RNAs NEAT1 and NEAT1_2 in myeloma cells

(PA-238) Immunomodulatory Drugs (IMiDs) induce the expression of long non-coding RNAs NEAT1 and NEAT1_2 in myeloma cells

Wednesday, September 17, 2025

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Miri Kitamura, Clinical Laboratory Technologist

Trainee
Graduate School of Health Sciences, Gunma University

Introduction: NEAT1 is a long non-coding RNA with its gene locus on chromosome 11q13, and has two isoforms designated NEAT1_1 and NEAT1_2. It has been demonstrated that NEAT1_2 plays a central role in the formation of the nuclear structure paraspeckle, and that it serves a significant function in responses to stress such as viral infection. Furthermore, its expression is upregulated in numerous cancer cells, and p53 induces its expression. We previously confirmed that NEAT1 is highly expressed in multiple myeloma (MM) cells, and that its expression is induced by p53, as previously reported, in a Tet-on wild-p53 expression MM cell line. Moreover, we discovered that it is induced by anti-MM drugs such as Bortezomib, and that this induction is mediated by HSF1 in the heat shock pathway. In this study, we investigated the effects of IMiDs on the expression of NEAT1 and NEAT1_2 and the regulatory mechanisms governing their expression.

Methods:   Lenalidomide, pomalidomide and iberdomide were administered to the MM cell lines, and after 72 hours, the expression of NEAT1, NEAT1_2, p53, p21, HSF1 and HSP were quantified by RT-qPCR. To elucidate the involvement of HSF1 in NEAT1, we additionally employed MM cell line that had been transfected with Tet-on shHSF1.

Results:   Lenalidomide (10 µM) increased NEAT1 expression 3.63-fold in MM.1S, 2.78-fold in MM.1S-Shp53, 0.65-fold in KMS11, 0.96-fold in KMS12PE, and NEAT1_2 was 4.93-fold in MM.1S, 4.22-fold in MM.1S-Shp53, 0.49-fold in KMS11, and 1.29-fold in KMS12PE. Administration of 10 µM pomalidomide resulted in a 5.73-fold increase in NEAT1 in MM.1S, an 8.50-fold increase in MM.1S-Shp53, a 6.80-fold increase in KMS11, and a 1.71-fold increase in KMS12PE. Furthermore, NEAT1_2 expression was 12.01-fold in MM.1S, 15.08-fold in MM.1S-Shp53, 15.48-fold in KMS11, and 1.89-fold in KMS12PE. When 10 µM iberdomide was added, the expression level of NEAT1 was 4.21-fold in MM.1S, 4.84-fold in MM.1S-Shp53, 2.13-fold in KMS11, and 2.14-fold in KMS12PE. The expression level of NEAT1_2 was 7.83-fold in MM.1S, 10.72-fold in MM.1S-Shp53, 4.72-fold in KMS11, and 2.69-fold in KMS12PE. However, the addition of lenalidomide, pomalidomide, or iberdmide did not increase the expression levels of p53, p21, HSF1, or HSP in any of the MM cell lines. Unlike NEAT1 induced by PI and cytotoxic drugs, NEAT1 expression induced by IMiDs was not suppressed even when HSF1 was knocked down in the MM cell line with Tet-on shHSF1.

Conclusions:   These findings demonstrate that pomalidomide and iberdomide, the members of the IMiD class, exhibit significantly higher efficacy in inducing NEAT1 expression compared to lenalidomide. Furthermore, the results indicate that the well-established p53 and heat shock pathways are not implicated in this mechanism. It is imperative to investigate the unidentified expression control mechanisms and elucidate the significance of NEAT1 expression induction by IMiDs.