Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma

Wong, Jason P.; Stuhlmiller, Timothy J.; Giffin, Louise; Lin, Carolina; Bigi, Rachele; Zhao, Jichen; Zhang, Weihe; Cruz, Ariana G. Bravo; Park, Steven I; Earp, H. Shelton; Dittmer, Dirk P.; Frye, Stephen V.; Wang, Xiaodong; Johnson, Gary L.; Damania, Blossom

doi:10.1073/pnas.1903991116

Cited by 16 publications

(16 citation statements)

References 75 publications

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“…CRISPRi had no effects on the expression of neighboring genes ( Supplementary Fig. 5a, b) SEs were also present in CFLAR TSS/first intron, TYRO3 loci in all or some PEL cell lines 60 , and long non-coding RNAs, such as NEAT1 and MALAT1 ( Supplementary Fig. 6).…”

Section: Relative Luminiscencementioning

confidence: 99%

Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

Wang

Zhang

et al. 2020

Nat Commun

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Primary effusion lymphoma (PEL) has a very poor prognosis. To evaluate the contributions of enhancers/promoters interactions to PEL cell growth and survival, here we produce H3K27ac HiChIP datasets in PEL cells. This allows us to generate the PEL enhancer connectome, which links enhancers and promoters in PEL genome-wide. We identify more than 8000 genomic interactions in each PEL cell line. By incorporating HiChIP data with H3K27ac ChIP-seq data, we identify interactions between enhancers/enhancers, enhancers/promoters, and promoters/promoters. HiChIP further links PEL super-enhancers to PEL dependency factors MYC, IRF4, MCL1, CCND2, MDM2, and CFLAR. CRISPR knock out of MEF2C and IRF4 significantly reduces MYC and IRF4 super-enhancer H3K27ac signal. Knock out also reduces MYC and IRF4 expression. CRISPRi perturbation of these super-enhancers by tethering transcription repressors to enhancers significantly reduces target gene expression and reduces PEL cell growth. These data provide insights into PEL molecular pathogenesis.

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Section: Relative Luminiscencementioning

confidence: 99%

Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

Wang

Zhang

et al. 2020

Nat Commun

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“…TRex-RTA BCBL-1 cells were intraperitoneally (i.p.) injected into NSG mice, allowing us to visualize the tumor growth upon injection of luciferin (25,32). After four weeks of treatment, the combination of miransertib and sirolimus significantly reduced growth compared to the vehicle (Figures 6C, D).…”

Section: Miransertib Synergizes With Sirolimus To Reduce Tumor Growth In a Pel Xenograft Modelmentioning

confidence: 99%

“…Solid tumors were fixed in 10% formalin vials (Fisher Scientific) for up to 3 days, and sections were processed as previously (25). The pS6 primary antibody was purchased from CST (4858) and used at a dilution of 1:400.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Combined Inhibition of Akt and mTOR Is Effective Against Non-Hodgkin Lymphomas

Rivera-Soto

Dittmer

et al. 2021

Front. Oncol.

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Non-Hodgkin lymphoma (NHL) are a diverse group of hematological malignancies comprised of over 60 subtypes. These subtypes range from indolent to aggressive. The PI3K/Akt/mTOR pathway has been shown to contribute to cell survival and proliferation and is constitutively active in most NHL. MK-7075 (miransertib) and MK-4440 are small molecules that effectively inhibit Akt and have entered clinical development. Using in vitro and in vivo models of NHL, we explored targeting the kinase Akt with miransertib and MK-4440 alone or in combination with the mTORC1 inhibitor, rapamycin (sirolimus). Both Akt inhibitors inhibited the pathway and NHL proliferation in a subtype-dependent manner. However, these compounds had a minimal effect on the viability of primary B-cells. Importantly, the combination of miransertib and sirolimus synergistically reduced cell proliferation in NHL, including in one indolent subtype, e.g., follicular lymphoma (FL), and two aggressive subtypes, e.g., diffuse large B-cell lymphoma (DLBCL) and primary effusion lymphoma (PEL). To establish in vivo efficacy, we used several xenograft models of FL, DLBCL, and PEL. The results obtained in vivo were consistent with the in vitro studies. The FL xenograft was highly sensitive to the inhibition of Akt alone; however, the tumor burden of PEL xenografts was only significantly reduced when both Akt and mTORC1 were targeted. These data suggest that targeting the PI3K/Akt/mTOR pathway with Akt inhibitors such as miransertib in combination with mTOR inhibitors serves as a broadly applicable therapeutic in NHL.

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“…Subsequently, a study by Mohanty et al [ 320 ] revealed everolimus as a multi-targeted therapy that induces apoptosis and downregulates mTOR, STAT-3 and NF-κB signaling in KSHV+ PEL [ 320 ]. Recent kinome profiling of PEL cell lines using kinase inhibitor-conjugated beads to capture kinases followed by quantitative MS revealed Tyro3 as a potential therapeutic target with subsequent analyses revealing that Tyro3 inhibition reduced PEL survival and growth in vitro, and tumor burden in a mouse PEL xenograft model in vivo [ 321 ]. KSHV latency-associated nuclear antigen (LANA) was found to prevent degradation of the oncogene c-Myc in PEL cell lines by inhibiting glycogen synthase kinase-3β (GSK-3β)-mediated phosphorylation of the T58 residue of c-Myc [ 322 ].…”

Section: Lymphomasmentioning

confidence: 99%

Current Methods of Post-Translational Modification Analysis and Their Applications in Blood Cancers

Dunphy

Dowling

Bazou

et al. 2021

Cancers

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Post-translational modifications (PTMs) add a layer of complexity to the proteome through the addition of biochemical moieties to specific residues of proteins, altering their structure, function and/or localization. Mass spectrometry (MS)-based techniques are at the forefront of PTM analysis due to their ability to detect large numbers of modified proteins with a high level of sensitivity and specificity. The low stoichiometry of modified peptides means fractionation and enrichment techniques are often performed prior to MS to improve detection yields. Immuno-based techniques remain popular, with improvements in the quality of commercially available modification-specific antibodies facilitating the detection of modified proteins with high affinity. PTM-focused studies on blood cancers have provided information on altered cellular processes, including cell signaling, apoptosis and transcriptional regulation, that contribute to the malignant phenotype. Furthermore, the mechanism of action of many blood cancer therapies, such as kinase inhibitors, involves inhibiting or modulating protein modifications. Continued optimization of protocols and techniques for PTM analysis in blood cancer will undoubtedly lead to novel insights into mechanisms of malignant transformation, proliferation, and survival, in addition to the identification of novel biomarkers and therapeutic targets. This review discusses techniques used for PTM analysis and their applications in blood cancer research.

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Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma

Cited by 16 publications

References 75 publications

Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

Primary effusion lymphoma enhancer connectome links super-enhancers to dependency factors

Combined Inhibition of Akt and mTOR Is Effective Against Non-Hodgkin Lymphomas

Current Methods of Post-Translational Modification Analysis and Their Applications in Blood Cancers

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