The Myc bHLH-ZIP transcription factor is deregulated by most cancers. As a heterodimer with the bHLH-ZIP protein Max, Myc regulates target genes that contribute to metabolism and proliferation. This “Myc Network” cross-talks with the “Mlx Network” comprised of the Myc-like bHLH-ZIP proteins MondoA and ChREBP and the Max-like bHLH-ZIP protein Mlx. This “Extended Myc Network” regulates genes with both common and distinct functions. We have generated hepatocytes lacking Mlx (mlxKO) or Mlx+Myc (double KO or DKO) and quantified their abilities to replace dying hepatocytes in a murine model of Type I tyosinemia. We find that this function deteriorates as the Extended Myc Network is progressively dismantled. Genes dysregulated in mlxKO and DKO hepatocytes include those involved in translation and mitochondrial function. The Myc and Mlx Networks thus cross-talk with the latter playing a disproportionate role. mycKO and mlxKO mice also develop non-alcoholic fatty liver disease and mlxKO and DKO mice develop extensive hepatic adenomatosis not observed in wild-type, mycKO, chrebpKO or mycKOxchrebpKO mice. In addition to demonstrating cooperation between the Myc and Mlx Networks, this study reveals the latter to be more important in maintaining metabolic and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis.

The pediatric liver cancer hepatoblastoma (HB) often expresses mutant forms of β-catenin and deregulates the Hippo tumor suppressor pathway. Murine HBs can be generated by co-expressing these β-catenin mutants and the constitutively active Hippo effector YAPS127A. Some HBs and other human cancers also express mutant forms of NFE2L2/NRF2 (NFE2L2), a bHLH transcription factor that tempers oxidative and electrophilic stress. In doing so, NFE2L2 either suppresses or facilitates tumorigenesis in a context- and time-dependent manner. We show here that two patient-derived NFE2L2 missense mutants, L30P and R34P, markedly accelerate HB growth in association with widespread cyst formation, an otherwise uncommon feature of human HB. Surprisingly, we found that any two members of the mutant β-catenin-YAPS127A-L30P/R34P triad were tumorigenic, thus providing direct evidence for NFE2L2's role as an oncoprotein. Each tumor group displayed distinct features but shared a similarly deregulated set of 22 transcripts, 10 of which perfectly correlated with survival in human HBs. 17 transcripts also correlated with survival in multiple other adult cancers. One of the most highly deregulated transcripts encoded serpin E1, a serine protease inhibitor with roles in fibrinolysis, tumor growth and extracellular matrix formation. The combination of mutant β-catenin, YAPS127A and Serpin E1, while not accelerating tumor growth or generating cysts, did promote the wide-spread necrosis previously associated with the cysts of mutant β-catenin-YAPS127A-L30P/R34P tumors. These findings establish the direct oncogenicity of NFE2L2 mutants and identify key transcripts, including serpin E1, that drive specific HB features.

PURPOSE-The identification of new therapies for high-risk (HR) hepatoblastoma (HB) is challenging. Children's Oncology Group Study AHEP0731 included a HR stratum to explore the efficacy of novel agents. We report the response rate to vincristine/irinotecan and the outcome of high-risk HB patients.

The evolution of SARS-CoV2 virus has led to the emergence of variants of concern (VOC). Children, particularly <12 years old not yet eligible for vaccines, continue to be important reservoirs of SARS-CoV-2 yet VOC prevalence data in this population is lacking. We report data from a genomic surveillance program that includes 9 U.S. children's hospitals. Analysis of SARS-CoV-2 genome from 2119 patients <19 years old between 03/20 to 04/21 identified 252 VOCs and 560 VOC signature mutations, most from 10/20 onwards. From 02/21 to 04/21, B.1.1.7 prevalence increased from 3.85% to 72.22% corresponding with the decline of B.1.429/B.1.427 from 51.82% to 16.67% at one institution. 71.74% of the VOC signature mutations detected were in children <12 years old, including 33 cases of B.1.1.7 and 119 of B.1.429/B.1.427. There continues to be a need for ongoing genomic surveillance, particularly among young children who will be the last groups to be vaccinated.

Background Survival for children with metastatic hepatoblastoma (HB) remains suboptimal. We report the response rate and outcome of two courses of vincristine/irinotecan/temsirolimus (VIT) in children with high‐risk (HR)/metastatic HB. Procedures Patients with newly diagnosed HB received HR window chemotherapy if they had metastatic disease or a serum alpha‐fetoprotein (AFP) level less than 100 ng/mL. Patients received vincristine (days 1 and 8), irinotecan (days 1–5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30% decrease using RECIST (Response Evaluation Criteria in Solid Tumors) criteria OR a 90% (>1 log10 decline) AFP decline after two cycles. Responders received two additional cycles of VIT intermixed with six cycles of cisplatin/doxorubicin/5‐fluorouracil/vincristine (C5VD). Nonresponders received six cycles of C5VD alone. Results Thirty‐six eligible patients enrolled on study. The median age at enrollment was 27 months (range: 7–170). Seventeen of 36 patients were responders (RECIST and AFP = 3, RECIST only = 4, AFP only = 10). The median AFP at diagnosis was 222,648 ng/mL and the median AFP following two VIT cycles was 19,262 ng/mL. Three‐year event‐free survival was 47% (95% confidence interval [CI]: 30%–62%), while overall survival was 67% (95% CI: 49%–80%). Conclusion VIT did not achieve the study efficacy endpoint. Temsirolimus does not improve the response rate seen in patients treated with vincristine and irinotecan (VI) alone as part of the initial treatment regimen explored in this study. Additionally, AFP response may be a more sensitive predictor of disease response than RECIST in HB.