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PPM1D mutations are oncogenic drivers of de novo Diffuse Midline Glioma formation

ABSTRACT: Khadka P, Reitman ZJ, Lu S, Buchan G, Gionet G, Dubois F, Carvalho DM, Shih J, Zhang S, Greenwald N, Zack T, Shapira O, Pelton K, Hartley R, Bear H, Georgis Y, Jarmale S, Melanson R, Bonano K, Schoolcraft K, Miller PG, Condurat AL, Gonzalez E, Qian K, Morin E, Langhnoja J, Lupien L, Rendo V, Digiacomo J, Wang D, Zhou K, Kumbhani R, Guerra-Garcia ME, Sinai CE, Becker S, Schneider R, Vogelzang J, Krug K, Babur O, Goodale A, Abid T, Kalani Z, Piccioni F, Beroukhim R, Perskey N, Root D, Carcaboso AM, Ebert BL, Fuller C, Kieran MW, Jones C, Keshishian H, Ligon KL, Carr SA, Phoenix TN, and Bandopadhayay P. 2021. The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genomes sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of novel DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we applied integrative phosphoproteomic and functional genomics assays and found that the oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Steven A. Carr

PROVIDER: MSV000088404 | MassIVE | Wed Nov 17 14:38:00 GMT 2021

REPOSITORIES: MassIVE

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Project description:Streptococcus pneumoniae is a human commensal bacterium that causes serious diseases. Peptidoglycan (PG) is the critical component of bacteria that maintains cell shape, size, chaining, and turgor resistance. Because of its surface exposure and eubacterial-specific mechanism of biosynthesis, PG biosynthesis remains an outstanding target for discovery of new antibiotics to resistant “superbugs,” like S. pneumoniae. Pneumococcal PG biosynthesis is carried out by a balance of septal and peripheral (side-wall-like) PG synthesis mediated by bPBP2x and bPBP2b, respectively, that emanates from midcell regions. We selected for additional suppressor mutations, besides mltG, that eliminate the requirement for essential bPBP2b in peripheral PG synthesis. We found that mutations that inactivate a putative RNA binding protein, designated KhpA, suppressed the requirement for some, but not all of the essential proteins required for peripheral PG synthesis. KhpA was used as bait in co-IP experiments to demonstrate interactions with a second RNA binding protein, designated KhpB, in cells. Mutations in khpA or khpB phenocopy each other and result in slower growth rates, smaller cell size with normal aspect ratios, and induction of cell wall stress responses. RIP-Seq analyses confirmed KhpAB as RNA binding protein in cells. Another suppressor of Δpbp2b implicated induction of a cell division operon as a way to bypass the requirement for bPBP2b. We show that increased expression of this cell division operon occurs in ΔkhpAB mutants and that this induction is necessary and sufficient to account for suppression of Δpbp2b. Comparisons of relative transcript amounts and protein levels indicate that induction of this cell division operon in ΔkhpAB mutants occurs primarily at the post-transcriptional level. Together, our results show that KhpAB, which are virulence factors in S. pneumoniae and are conserved in other Gram-positive pathogens, acts as a new class of RNA binding protein, with properties analogous to Hfq in Gram-negative bacteria.

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PPM1D mutations are oncogenic drivers of de novo Diffuse Midline Glioma formation

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