A ChIP-seq analysis of the DNA-binding properties of mutant gain-of-function p53 protein compared to wild-type p53 reveals the gain-of-function proteins bind to and activate a distinct set of genes including chromatin modifying enzymes such as the histone methyltransferase MLL; small molecular inhibitors of MLL function may represent a new target for cancers with mutant p53. Wild-type p53 is a tumour suppressor, but mutation of p53 can promote cancer and certain oncogenic forms are gain-of-function (GOF) mutants. Shelley Berger and colleagues compare the genomic binding patterns of wild- type and gain-of-function mutant p53 using ChIP-seq analysis and find that the p53 mutants bind distinct sets of genes compared to the wild-type protein, with key targets including the histone methyltransferases MLL1 and MLL2, as well as other chromatin modifying enzymes. Gain-of-function p53 mutant cells are highly dependent on the MLL pathway for growth and are sensitive to small molecule inhibitors of MLL function, indicating a novel therapeutic avenue for cancers with these p53 mutations. TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a ‘gain-of-function’ (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.

PURPOSE: To report pancreas surveillance outcomes of high-risk individuals within the multicenter Cancer of Pancreas Screening-5 (CAPS5) study and to update outcomes of patients enrolled in prior CAPS studies. METHODS: Individuals recommended for pancreas surveillance were prospectively enrolled into one of eight CAPS5 study centers between 2014 and 2021. The primary end point was the stage distribution of pancreatic ductal adenocarcinoma (PDAC) detected (stage I v higher-stage). Overall survival was determined using the Kaplan-Meier method. RESULTS: Of 1,461 high-risk individuals enrolled into CAPS5, 48.5% had a pathogenic variant in a PDAC-susceptibility gene. Ten patients were diagnosed with PDAC, one of whom was diagnosed with metastatic PDAC 4 years after dropping out of surveillance. Of the remaining nine, seven (77.8%) had a stage I PDAC (by surgical pathology) detected during surveillance; one had stage II, and one had stage III disease. Seven of these nine patients with PDAC were alive after a median follow-up of 2.6 years. Eight additional patients underwent surgical resection for worrisome lesions; three had high-grade and five had low-grade dysplasia in their resected specimens. In the entire CAPS cohort (CAPS1-5 studies, 1,731 patients), 26 PDAC cases have been diagnosed, 19 within surveillance, 57.9% of whom had stage I and 5.2% had stage IV disease. By contrast, six of the seven PDACs (85.7%) detected outside surveillance were stage IV. Five-year survival to date of the patients with a screen-detected PDAC is 73.3%, and median overall survival is 9.8 years, compared with 1.5 years for patients diagnosed with PDAC outside surveillance (hazard ratio [95% CI]; 0.13 [0.03 to 0.50], P = .003). CONCLUSION: Most pancreatic cancers diagnosed within the CAPS high-risk cohort in the recent years have had stage I disease with long-term survival.

Chimeric antigen receptor (CAR) T cells have radically improved the treatment of B cell–derived malignancies by targeting CD19. The success has not yet expanded to treat acute myeloid leukemia (AML). We developed a Sequentially Tumor-Selected Antibody and Antigen Retrieval (STAR) system to rapidly isolate multiple nanobodies (Nbs) that preferentially bind AML cells and empower CAR T cells with anti-AML efficacy. STAR-isolated Nb157 specifically bound CD13, which is highly expressed in AML cells, and CD13 CAR T cells potently eliminated AML in vitro and in vivo. CAR T cells bispecific for CD13 and TIM3, which are upregulated in AML leukemia stem cells, eradicated patient-derived AML, with much reduced toxicity to human bone marrow stem cells and peripheral myeloid cells in mouse models, highlighting a promising approach for developing effective AML CAR T cell therapy.