Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation

Hing, Zachary A.; Walker, J. T.; Whipp, Ethan; Brinton, Lindsey T.; Cannon, Matthew; Zhang, Pu; Sher, Steven; Cempre, Casey B.; Brown, Fiona; Smith, Porsha L.; Agostinelli, Claudio; Pileri, Stefano; Skinner, Jordan; Williams, Katie; Phillips, Hannah; Shaffer, Jami; Beaver, Larry; Pan, Alexander; Kyle, Shin,; Gregory, Charles T.; Özer, Gülçin; Yilmaz, Selen; Harrington, Bonnie K.; Lehman, Amy; Yu, Lianbo; Coppola, Vincenzo; Yan, Pearlly S.; Scherle, Peggy; Wang, Min; Philip, Pitis,; Chaoyi, Xu,; Vaddi, Kris; Chen‐Kiang, Selina; Woyach, Jennifer A.; Blachly, James S.; Alinari, Lapo; Yang, Yiping; Byrd, John C.; Baiocchi, Robert A.; Blaser, Bradley W.; Lapalombella, Rosa

doi:10.1038/s41467-022-35778-1

Cited by 13 publications

(9 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In vitro anti-MCL activity was demonstrated in 9 cell lines, which showed IC50s ranging from 44.8 to 1905.5 nM, with the maximal effect occurring on day 9 ( Figure 1 A; supplemental Figure 1 B). This compound was found to be more potent than EPZ015666 (GSK3235025), a well-described PRMT5 inhibitor 58 ( supplemental Figure 1 C). In vivo, PRT382 demonstrated a favorable oral bioavailability and pharmacokinetic profile in mice (area under curve, 1175 h∗kg∗ng/mL per mg at 10 mg/kg) ( supplemental Figure 1 D).…”

Section: Resultsmentioning

confidence: 92%

“…To selectively target PRMT5 activity in MCL, we used PRT382 (Prelude Therapeutics), a novel S-adenosyl methionine competitive, selective small-molecule inhibitor of PRMT5 enzymatic activity 58 ( supplemental Figure 1 A). In vitro anti-MCL activity was demonstrated in 9 cell lines, which showed IC50s ranging from 44.8 to 1905.5 nM, with the maximal effect occurring on day 9 ( Figure 1 A; supplemental Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma

Brown-Burke,

Hwang,

Sloan

et al. 2023

Blood Advances

Self Cite

View full text Add to dashboard Cite

Mantle cell lymphoma (MCL) is an incurable B cell malignancy, comprising up to 6% of non-Hodgkin lymphomas diagnosed annually and is associated with a poor prognosis. The average overall survival of patients with MCL is five years and for the majority of patients who progress on targeted agents, survival remains at a dismal 3-8 months. There is a major unmet need to identify new therapeutic approaches that are well tolerated to improve treatment outcomes and quality of life. The protein arginine methyltransferase 5 (PRMT5) enzyme is overexpressed in MCL and promotes growth and survival. Inhibition of PRMT5 drives anti-tumor activity in MCL cell lines and preclinical murine models. PRMT5 inhibition reduced the activity of pro-survival AKT signaling which led to nuclear translocation of FOXO1 and modulation of its transcriptional activity. Chromatin immunoprecipitation and sequencing (ChIP-seq) identified multiple pro-apoptotic BCL-2 family members as FOXO1-bound genomic loci. We identified BAX as a direct transcriptional target of FOXO1 and demonstrated its critical role in the synergy observed between the selective PRMT5 inhibitor, PRT382 and the BCL-2 inhibitor, venetoclax. Single agent and combination treatment was performed in nine MCL lines. Loewe synergy scores showed significant levels of synergy in the majority of MCL lines tested. Preclinical, in vivo evaluation of this strategy in multiple MCL models showed therapeutic synergy with combination venetoclax/PRT382 treatment with increased survival advantage in two PDX models (p=<0.0001, p=<0.0001). Our results provide mechanistic rationale for combination PRMT5 inhibition and venetoclax to treat patients with MCL.

show abstract

Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma

Brown-Burke,

Hwang,

Sloan

et al. 2023

Blood Advances

Self Cite

View full text Add to dashboard Cite

show abstract

“…The molecular mechanisms driving the pathogenesis and progression of CLL have not been fully elucidated. A subset of patients experience an aggressive disease course in the absence of known high-risk genetic alterations, which indicates that there are still many undiscovered factors promoting the progression of CLL [ 20 ]. For example, Hortal et al recently identified that the overexpression of the wild type oncogene RRAS2 is behind the development of CLL, the most frequent leukemia in the western world [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

SYT7 regulates the progression of chronic lymphocytic leukemia through interacting and regulating KNTC1

Jiang

Tang

et al. 2023

Biomark Res

View full text Add to dashboard Cite

Background Chronic lymphocytic leukemia (CLL) is one of the most frequent occurring types of leukemia. It typically occurs in elderly patients and has a highly variable clinical course. At present, the molecular mechanism driving the pathogenesis and progression of CLL is not fully understood. The protein Synaptotagmin 7 (SYT7) encoded by the SYT7 gene has been found to be closely related to the development of various solid tumors, but its role in CLL is unclear. In this study, we investigated the function and molecular mechanism of SYT7 in CLL. Methods The expression level of SYT7 in CLL was determined by immunohistochemical staining and qPCR. The role of SYT7 in promoting CLL development was verified by in vivo and in vitro experiments. The molecular mechanism of SYT7 in CLL was elucidated by methods such as GeneChip analysis and Co-immunoprecipitation assay. Results Malignant behaviors such as proliferation, migration, and anti-apoptosis of CLL cells were significantly inhibited after SYT7 gene knockdown. In contrast, SYT7 overexpression promoted CLL development in vitro. Consistently, the knockdown of SYT7 also inhibited xenograft tumor growth of CLL cells. Mechanistically, SYT7 promoted CLL development by inhibiting SYVN1-mediated KNTC1 ubiquitination. The KNTC1 knockdown also attenuated the effects of SYT7 overexpression on development of CLL. Conclusions SYT7 regulates the progression of CLL through SYVN1-mediated KNTC1 ubiquitination, which has potential value for molecular targeted therapy of CLL.

show abstract

“…Another study utilizing scRNA-seq on spleen- and LN-derived CLL cells from Eμ-TCL1 Akt-C mice in a model of RT pointed to the importance of sustained Akt signaling for maintaining a pro-proliferative and anti-apoptotic microenvironment through aberrant NOTCH1 activation ( 115 ). scRNA-seq was also instrumental in identifying the epigenetic modifier PRMT5 as a potential mediator of RT, in patient tissues as well as in an experimental model employing Eμ-PRMT5/TCL1 mice ( 116 ).…”

Section: Deciphering Clonal Heterogeneity and Evolution In Cllmentioning

confidence: 99%

Recent revelations and future directions using single-cell technologies in chronic lymphocytic leukemia

et al. 2023

View full text Add to dashboard Cite

Chronic lymphocytic leukemia (CLL) is a clinically and biologically heterogeneous disease with varying outcomes. In the last decade, the application of next-generation sequencing technologies has allowed extensive mapping of disease-specific genomic, epigenomic, immunogenetic, and transcriptomic signatures linked to CLL pathogenesis. These technologies have improved our understanding of the impact of tumor heterogeneity and evolution on disease outcome, although they have mostly been performed on bulk preparations of nucleic acids. As a further development, new technologies have emerged in recent years that allow high-resolution mapping at the single-cell level. These include single-cell RNA sequencing for assessment of the transcriptome, both of leukemic and non-malignant cells in the tumor microenvironment; immunogenetic profiling of B and T cell receptor rearrangements; single-cell sequencing methods for investigation of methylation and chromatin accessibility across the genome; and targeted single-cell DNA sequencing for analysis of copy-number alterations and single nucleotide variants. In addition, concomitant profiling of cellular subpopulations, based on protein expression, can also be obtained by various antibody-based approaches. In this review, we discuss different single-cell sequencing technologies and how they have been applied so far to study CLL onset and progression, also in response to treatment. This latter aspect is particularly relevant considering that we are moving away from chemoimmunotherapy to targeted therapies, with a potentially distinct impact on clonal dynamics. We also discuss new possibilities, such as integrative multi-omics analysis, as well as inherent limitations of the different single-cell technologies, from sample preparation to data interpretation using available bioinformatic pipelines. Finally, we discuss future directions in this rapidly evolving field.

show abstract

Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation

Cited by 13 publications

References 83 publications

PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma

PRMT5 inhibition drives therapeutic vulnerability to combination treatment with BCL-2 inhibition in mantle cell lymphoma

SYT7 regulates the progression of chronic lymphocytic leukemia through interacting and regulating KNTC1

Recent revelations and future directions using single-cell technologies in chronic lymphocytic leukemia

Contact Info

Product

Resources

About