PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation

Khadka, Prasidda; Reitman, Zachary J.; Lu, Sophie D.; Buchan, Graham; Gionet, Gabrielle; Dubois, Frank; Carvalho, Diana; Shih, Juliann; Zhang, Shu; Greenwald, Noah F.; Zack, Travis I.; Shapira, Ofer; Pelton, Kristine; Hartley, Rachel; Bear, Heather; Georgis, Yohanna; Jarmale, Spandana; Melanson, Randy; Bonanno, Kevin; Schoolcraft, Kathleen; Miller, Peter G.; Condurat, Alexandra L.; Gonzalez, Elizabeth M.; Qian, Kenin; Morin, Eric; Langhnoja, Jaldeep; Lupien, Leslie; Rendo, Verónica; Digiacomo, Jeromy J.; Wang, Dayle K.; Zhou, Kevin N.; Kumbhani, Rushil; Garcia, María E. Guerra; Sinai, Claire; Becker, Sarah; Schneider, Rachel; Vogelzang, Jayne; Krug, Karsten; Goodale, Amy; Abid, Tanaz; Kalani, Zohra; Piccioni, Federica; Beroukhim, Rameen; Persky, Nicole S.; Root, David E.; Carcaboso, Ángel M.; Ebert, Benjamin L.; Fuller, Christine; Babur, Özgün; Kieran, Mark W.; Jones, Chris; Keshishian, Hasmik; Ligon, Keith L.; Carr, Steven A.; Phoenix, Timothy N.; Bandopadhayay, Pratiti

doi:10.1038/s41467-022-28198-8

Cited by 35 publications

(35 citation statements)

References 76 publications

(133 reference statements)

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“…In previous studies, we showed that these IUE-based brainstem tumors are similar to their human counterparts at the transcriptomic level. 24 , 41 Here, we further demonstrate that these IUE-transformed murine tumor cells recapitulate patient-derived cell sensitivity to Panobinostat, one of the most extensively studied compounds in (pre)clinical DMG studies. We have also recently shown that the vasculature of IUE-based DMG mouse models closely resembles the minimally disrupted blood-brain barrier of patient-derived xenograft models, indicating that the models developed in this study are suitable surrogates for testing drug penetration and efficacy of other therapeutics.…”

Section: Discussionsupporting

confidence: 54%

“… 43–46 Future work to increase the genetic diversity of available allograft mouse models will further enhance the utility of this system to complement the growing catalog of PDOX models. This could include models that substitute PPM1D mutations for loss of TP53 function 41 or expression of wild-type PDGFRA, mutant FGFR1 or other MAPK pathway mutations 47 to replace the use of constitutively active Pdgfra-D842V mutations.…”

Section: Discussionmentioning

confidence: 99%

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Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

Chatinier

Meel

Das

et al. 2022

Neuro-Oncology Advances

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Background Diffuse midline gliomas (DMG) are highly malignant incurable pediatric brain tumors. A lack of effective treatment options highlights the need to investigate novel therapeutic strategies. This includes the use of immunotherapy, which has shown promise in other hard-to-treat tumors. To facilitate preclinical immunotherapeutic research, immunocompetent mouse models that accurately reflect the unique genetic, anatomical, and histological features of DMG patients are warranted. Methods We established cell cultures from primary DMG mouse models (C57BL/6) that were generated by brainstem targeted intra-uterine electroporation (IUE). We subsequently created allograft DMG mouse models by orthotopically implanting these tumor cells into syngeneic mice. Immunohistochemistry and -fluorescence, mass cytometry, and cell-viability assays were then used to verify that these murine tumors recapitulated human DMG. Results We generated three genetically distinct allograft models representing histone 3 wildtype (H3 WT) and K27M-mutant DMG (H3.3 K27M and H3.1 K27M). These allograft models recapitulated the histopathologic phenotype of their human counterparts, including their diffuse infiltrative growth and expression of DMG-associated antigens. These murine pontine tumors also exhibited an immune microenvironment similar to human DMG, characterized by considerable myeloid cell infiltration and a paucity of T-lymphocytes and NK cells. Finally, we show that these murine DMG cells display similar sensitivity to histone deacetylase (HDAC) inhibition as patient-derived DMG cells. Conclusions We created and validated an accessible method to generate immunocompetent allograft models reflecting different subtypes of DMG. These models adequately recapitulated the histopathology, immune microenvironment, and therapeutic response of human DMG, providing useful tools for future preclinical studies.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

Chatinier

Meel

Das

et al. 2022

Neuro-Oncology Advances

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“…Brainstem gliomas contain therapeutically important alterations in Phosphatase and tensin homolog ( PTEN) and its molecular pathway, and frequent mutations in TP53 . PTEN is a tumor suppressor that is recurrently inactivated by focal or chromosomal deletions of chromosome 10 and/or loss-of-function mutation in 6–27% of diffuse midline gliomas [ 1 , 2 , 3 , 4 , 5 , 6 ]. PTEN functions in the phosphoinositol-3-kinase (PI3K) molecular pathway.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma

Stewart

Guerra-García

Luo

et al. 2022

Cancers

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Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia–telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.

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“…PTEN is a tumor suppressor that is recurrently inactivated by focal or chromosomal deletions of chromosome 10 and/or loss-of-function mutation in 6-27% of diffuse midline gliomas (1)(2)(3)(4)(5)(6). PTEN functions in the phosphoinositol-3-kinase (PI3K) molecular pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Brainstem gliomas contain therapeutically important alterations in Phosphatase and tensin homolog ( PTEN) and its molecular pathway, and frequent mutations in TP53. PTEN is a tumor suppressor that is recurrently inactivated by focal or chromosomal deletions of chromosome 10 and/or loss-of-function mutation in 6-27% of diffuse midline gliomas (1-6). PTEN functions in the phosphoinositol-3-kinase (PI3K) molecular pathway.…”

Section: Introductionmentioning

confidence: 99%

Atm loss does not radiosensitize a primary mouse model of Pten-deleted brainstem glioma

Stewart

Garcia

Luo

et al. 2022

Preprint

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Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase ataxia telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if Atm inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by Atm deletion, which may guide the design of future clinical trials.

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PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation

Cited by 35 publications

References 76 publications

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma

The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma

Atm loss does not radiosensitize a primary mouse model of Pten-deleted brainstem glioma

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