(PA-309) SETD7 Is a Novel Therapeutic Target for Multiple Myeloma Carrying t(11;14)

Introduction: In refractory hematologic tumors, t(11;14) translocation is frequently observed in 85% of
mantle cell lymphoma, 15-20% of multiple myeloma (MM), and 5% of chronic lymphocytic
leukemia. Of these, the prognosis of MM patients carrying t(11;14) has been controversial
for many years. However, the latest retrospective analysis revealed that t(11;14) was a poor
prognostic factor (Blood Res,60:11,2025). MM cells carrying t(11;14) show an immature
phenotype, such as lymphoplasmacytic morphology, lower CD38 expression, and higher
BCL2 expression. Therefore, proteasome inhibitors and CD38 antibodies are less effective
but a BCL2 inhibitor venetoclax is effective (Cancer Sci,112,3645,2021). However,
venetoclax was not approved for MM due to increased treatment-related deaths. Thus, MM
with t(11;14) refractory to immunomodulatory drugs is an unmet need.

Methods: In this study, we searched for novel therapeutic targets within SET family histone
methyltransferases. Then, we found that SETD7 is highly expressed in MM cells carrying
t(11;14) and is associated with inferior survival. SETD7 acts as a transcriptional activator
via mono- and di-methylation of the lysine 4 residue of histone H3.

Results: ChIP-sequence analysis of SETD7 revealed a lot of peaks, over 70% of which were localized in the vicinity of
transcription start sites (TSSs). Moreover, we found SETD7 binding to the TSSs of the
genes including ARID1A, PRDM1, and c-FOS, which were associated with poor prognosis
of MM. Next, we found that knockdown of SETD7 significantly suppressed the growth of
MM cell lines with t(11;14) but not those without t(11;14). Moreover, a SETD7 inhibitor PFI2
significantly inhibited the growth alone and in combination with pomalidomide via down-
regulation of ARID1A, IRF4, and MYC in vitro and in vivo. The forced expression of MYC
significantly mitigated the cytotoxicity of PFI2.

Conclusions: Although SETD7 can be either an oncogene or a tumor suppressor gene depending on
the type of cancer, there are few data in MM. Based on our findings, we conclude that
SETD7 acts as an oncogene and is a novel therapeutic target for MM. In addition, we found
that ARID1A/IRF4/MYC axis is a critical down-stream pathway and is a bona fide target of
a SETD7 inhibitor. In line with our results, Bolomsky et al. revealed that ARID1A plays an
indispensable role in the expression of IRF4 and MYC in MM (Cancer Cell,42;1,2024).
Therefore, our study provides a molecular basis and rationale for the inclusion of SETD7
inhibitors into current treatment strategies. The clinical use of PFI2 may significantly
improve the treatment outcome of MM carrying t(11;14).