PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors

Abstract

Majority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms. Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.

Anaplastic Sarcoma of the Kidney With Heterologous Ganglioneuroblastic Differentiation: Another DICER1-Associated Tumor

“…14 However, its presence in ASK has not previously been described in the literature. Similarly, PPM1D mutations have been found in neuroblastoma 15 and medulloblastoma 16 but have not been reported in ASK. Other DICER1-associated tumors have been shown to have other somatic mutations, including TP53, KRAS, NRAS, and NF1.…”

From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma

“…In a recent analysis on 208 tumors with chromosome 17q gain, only three genes revealed to be present in the smallest region of overlap including PPM1D, RAD51C and BRIP1, and these chromosome 17q segmental gains were shown to further accumulate during clonal evolution. Furthermore, a gene fusion of PPM1D and BCAS3 was also found to be present in one NB tumor, subsequently resulting in accumulating PPM1D expression levels [117]. PPM1D is a negative regulator of p53 and positively regulates MDM2 thus further enhancing p53 inhibition (Figure 3, loop 6) [117,146].…”

“…PPM1D is also shown to be a critical regulator of DNA damage response by dephosporylating and inactivating ATM, ATR, CHK1, CHK2 and H2AX. A transgenic mouse model with PPM1D overexpression exposed to irradiation and thus DNA-damaging stress was able to develop PHOX2B-expressing neural crest-derived primary tumors of the adrenal gland phenotypically and genetically similar to NB [117]. Pharmacological inhibition of PPM1D selectively suppressed tumor growth of p53 wildtype NB cell lines [146] and of established NB xenografts in nude mice indicating that PPM1D might be a promising therapeutic target in p53 wild-type NBs [117].…”

“…Furthermore, a gene fusion of PPM1D and BCAS3 was also found to be present in one NB tumor, subsequently resulting in accumulating PPM1D expression levels [117]. PPM1D is a negative regulator of p53 and positively regulates MDM2 thus further enhancing p53 inhibition (Figure 3, loop 6) [117,146]. Using a CRISPR screen, wild-type P53 cell lines were shown to be dependent on PPM1D expression and PPM1D knockdown delayed tumor formation in vivo.…”