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ABSTRACT: Sterile alpha motif and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate triphosphohydrolase with ara-CTPase activity that confers cytarabine (ara-C) resistance in several hematological malignancies. Targeting SAMHD1's ara-CTPase activity has recently been demonstrated to enhance ara-C efficacy in acute myeloid leukemia. Here, we identify the transcription factor SRY-related HMG-box containing protein 11 (SOX11) as a novel direct binding partner and first known endogenous inhibitor of SAMHD1. SOX11 is aberrantly expressed not only in mantle cell lymphoma (MCL), but also in some Burkitt lymphomas. Coimmunoprecipitation of SOX11 followed by mass spectrometry in MCL cell lines identified SAMHD1 as the top SOX11 interaction partner, which was validated by proximity ligation assay. In vitro, SAMHD1 bound to the HMG box of SOX11 with low-micromolar affinity. In situ crosslinking studies further indicated that SOX11-SAMHD1 binding resulted in a reduced tetramerization of SAMHD1. Functionally, expression of SOX11 inhibited SAMHD1 ara-CTPase activity in a dose-dependent manner resulting in ara-C sensitization in cell lines and in a SOX11-inducible mouse model of MCL. In SOX11-negative MCL, SOX11-mediated ara-CTPase inhibition could be mimicked by adding the recently identified SAMHD1 inhibitor hydroxyurea. Taken together, our results identify SOX11 as a novel SAMHD1 interaction partner and its first known endogenous inhibitor with potentially important implications for clinical therapy stratification.
Assuntos
Linfoma de Célula do Manto , Proteína 1 com Domínio SAM e Domínio HD , Fatores de Transcrição SOXC , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Humanos , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Proteína 1 com Domínio SAM e Domínio HD/genética , Animais , Camundongos , Fatores de Transcrição SOXC/metabolismo , Fatores de Transcrição SOXC/genética , Ligação Proteica , Linhagem Celular Tumoral , Citarabina/farmacologiaRESUMO
Osteosarcoma is the most prevalent malignant bone tumour in children, adolescents and young adults. Despite a multitude of aberrations present in osteosarcoma genomes, no recurrent driver mutations have been identified to date. In addition, unlike for other sarcoma entities, no functional fusion proteins resulting from chromosomal rearrangements have been reported. Part of the genetic complexity of osteosarcoma might, however, be explained by the association of osteosarcoma with germline and somatic mutations of the major tumour suppressor TP53 that safeguards genomic integrity. By demonstrating that TP53 promoter translocations resulting in transcriptionally active fusion genes are a recurrent event in osteosarcoma, long-learnt paradigms are challenged by a recent publication by Saba, Difilippo et al. Osteosarcoma no longer appears to be a fusion-negative tumour, and by hardwiring cellular stress responses that transactivate the TP53 promoter to an oncogenic fusion partner, TP53 can be subverted and turned into an oncogene.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Regiões Promotoras Genéticas , Translocação Genética , Proteína Supressora de Tumor p53 , Osteossarcoma/genética , Osteossarcoma/patologia , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologiaRESUMO
CONTEXT: There is an increasing population of childhood cancer survivors (CCS) at risk for treatment-related toxicities, including skeletal morbidities. Bone mineral density (BMD) is a proxy for bone health and reductions are associated with osteoporosis and fractures. OBJECTIVE: To investigate bone health in CCS by conducting a systematic review and meta-analysis of BMD after completed treatments. DATA SOURCES: We searched Medline, Embase, Cochrane, and Web of Science in May 2019 and updated in May 2023. STUDY SELECTION: Studies reporting BMD Z-scores measured with dual-energy x-ray absorptiometry in CCS after treatment completion. DATA EXTRACTION: We performed a pooled analysis of studies reporting BMD Z-scores and thereafter we analyzed studies comparing BMD in survivors and healthy controls. All analyses were performed based on the site of BMD measurement. RESULTS: Of 4243 studies, 84 were included (N = 8106). The mean time off-treatment across the studies ranged from 2 months to 24 years. The overall pooled mean Z-score was -0.57 (95% confidence interval [CI] -0.59 to -0.55) in the whole-body, -0.84 (95% CI -0.86 to -0.83) in the lumbar spine, -0.79 (95% CI -0.81 to -0.77) in the femoral neck and -0.14 (95% CI -0.18 to -0.11) in the total hip. When comparing survivors with controls, BMD was significantly lower in survivors at all sites. LIMITATIONS: English publications, study-level meta-analysis. CONCLUSIONS: We showed a significant reduction of BMD Z-scores in CCS. Given the increased fracture risk already within -1 SD, these results emphasize the need for BMD surveillance and secondary prevention in CCS.
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Densidade Óssea , Sobreviventes de Câncer , Neoplasias , Humanos , Criança , Osteoporose/epidemiologia , Osteoporose/etiologia , Absorciometria de Fóton , AdolescenteRESUMO
Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors. Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients. Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35). Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients. Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.