Cyclin D1 overexpression induces replication stress and microhomology-mediated end-joining dependence in mantle cell lymphoma
Jithma P. Abeykoon, Shuhei Asada, Guangli Zhu, Yuna Hirohashi, Lisa Moreau, Divya Iyer, Sirisha Mukkavalli, Kalindi Parmar, Gabriella Zambrano, Lige Jiang, Dongni Yi, Michelle Manske, Kimberly Gwin, Rebecca L. King, James R. Cerhan, Xiaosheng Wu, Zhenkun Lou, Geoffrey I. Shapiro, Thomas Witzig, Alan D’Andrea
Jithma P. Abeykoon, Shuhei Asada, Guangli Zhu, Yuna Hirohashi, Lisa Moreau, Divya Iyer, Sirisha Mukkavalli, Kalindi Parmar, Gabriella Zambrano, Lige Jiang, Dongni Yi, Michelle Manske, Kimberly Gwin, Rebecca L. King, James R. Cerhan, Xiaosheng Wu, Zhenkun Lou, Geoffrey I. Shapiro, Thomas Witzig, Alan D’Andrea
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Research Article Cell biology Hematology

Cyclin D1 overexpression induces replication stress and microhomology-mediated end-joining dependence in mantle cell lymphoma

Abstract

Oncogene expression can cause replication stress (RS), leading to DNA double-strand breaks (DSBs) that require repair through pathways such as homologous recombination, nonhomologous end-joining, and microhomology-mediated end-joining (MMEJ). Cyclin D1 (encoded by CCND1) is a well-known oncoprotein overexpressed in cancer; however, its role in RS is unknown. Using mantle cell lymphoma (MCL) as a naturally occurring model of cyclin D1 overexpression, we examined the impact of cyclin D1 on RS and DSB repair mechanisms. Cyclin D1 overexpression elevated RS, increased DNA damage, especially during mitosis, and caused specific upregulation of MMEJ. Furthermore, cyclin D1 activated polymerase theta (POLQ) transcription by binding its promoter loci, driving POLΘ-mediated MMEJ that is essential to withstand cyclin D1–induced RS. Moreover, concurrent ATM deficiency further intensified RS, enhanced POLQ expression, and heightened reliance on MMEJ-mediated DNA damage repair. Consequently, inhibition of POLΘ in cyclin D1–overexpressed settings further exacerbated RS, causing single-strand DNA gap accumulations and chromosomal instability, ultimately leading to apoptosis, an effect amplified in ATM-deficient cells. Targeting MMEJ via POLΘ inhibition is therefore an effective strategy in the context of cyclin D1 overexpression and ATM deficiency and may provide a unique therapeutic approach for treating MCL and other malignancies characterized by similar alterations.

Authors

Jithma P. Abeykoon, Shuhei Asada, Guangli Zhu, Yuna Hirohashi, Lisa Moreau, Divya Iyer, Sirisha Mukkavalli, Kalindi Parmar, Gabriella Zambrano, Lige Jiang, Dongni Yi, Michelle Manske, Kimberly Gwin, Rebecca L. King, James R. Cerhan, Xiaosheng Wu, Zhenkun Lou, Geoffrey I. Shapiro, Thomas Witzig, Alan D’Andrea

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Figure 8

POLQ is overexpressed in MCL compared with other NHLs, and its inhibition showed an antitumor effect in primary tumor cells.

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POLQ is overexpressed in MCL compared with other NHLs, and its inhibiti...
(A) Cyclin D1 expression was assessed through IHC in MCL compared with other NHLs (×400 original magnification). (B) Assessment of POLQ expression in MCL compared with other types of NHL primary cells (n = 8 FL, n = 8 DLBCL, n = 17 CLL/SLL, n = 11 MZL, n = 27 MCL; P value was calculated by 1-way ANOVA with Tukey’s post hoc test). (C and D) POLΘ inhibition by ART558 causes a significant antitumor effect in primary MCL patient samples with increased antitumor effect seen in ATM-deficient compared with ATM-proficient primary MCL cells (experiments were done in triplicates, and P value was calculated by t test). (E and F) Concurrent inhibition of ATM and POLΘ increases the antitumor effect compared with POLΘ inhibition alone in primary MCL cells (experiments were done in triplicates). FL, follicular lymphoma; DLBCL, diffuse large B cell lymphoma; MZL, marginal zone lymphoma; PTCL, primary cutaneous T cell lymphoma; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; Pt, patient. Data are shown as the mean ± SEM in B and D and the mean ± SD in C, E, and F. Red triangles in B represent ATM-deficient MCL primary samples. **P < 0.01; ***P < 0.001; ****P < 0.0001.