Serum response factor (SRF) is a ubiquitously expressed transcription factor that regulates immediate early genes, cytoskeletal organization, and muscle differentiation. Although SRF plays critical roles in development and cell growth, genomic alterations of SRF have long appeared absent in human neoplasms. Recently, however, recurrent SRF gene rearrangements have been identified in a spectrum of soft tissue tumors with myogenic features, including rhabdomyosarcomas, perivascular tumors, inflammatory myofibroblastic tumors, myoepitheliomas and peripheral nerve sheath tumors. This review summarizes current knowledge on SRF fusion genes and their biological and clinical implications. SRF fusions retain the N-terminal DNA-binding domain while replacing the native transactivation domain with that of a partner protein, frequently a transcription factor or co-activator. This structural configuration leads to constitutive activation of SRF and dysregulation of transcriptional programs related to myogenesis, cytoskeleton organization, and, in some cases, inflammatory signaling. SRF-rearranged tumors predominantly affect children, usually display low-grade behavior, and are often cured by complete surgical resection, although rare recurrences and metastases have been reported. Within perivascular myoid neoplasms, SRF-rearranged tumors show consistent phenotypic and clinical features, supporting their recognition as a distinct tumor entity, whereas SRF fusions identified in rhabdomyosarcomas and rare isolated cases likely represent separate biological contexts. Understanding SRF fusion-driven transcriptional dysregulation provides insights into tumorigenesis and may inform future diagnostic and therapeutic strategies in myoid soft tissue neoplasms. © 2026 The Pathological Society of Great Britain and Ireland.

SRF fusion genes drive the pathogenesis of muscle-related soft tissue tumors, including subsets of perivascular tumors, inflammatory myofibroblastic tumors, and rhabdomyosarcomas. SRF encodes Serum Response Factor, a well-characterized transcription factor that regulates muscle development. We characterized four fusions: SRF::RELA, SRF::FOXO1, SRF::ICA1L, and SRF::PDGFRB. All localized to the nucleus and formed dimers, most likely through the SRF MADS box. SRF::RELA, SRF::FOXO1, and SRF::ICA1L acted as constitutively active transcription factors independent of canonical cofactors, binding SRF target promoters and driving transcription via the partner transactivation domain (TAD). A cryptic TAD was uncovered in ICA1L. These fusions promoted mesenchymal cell growth and upregulated muscle-related genes in mesenchymal stem cells, recapitulating transcriptional signatures of human tumors. In contrast, SRF::PDGFRB acted through its kinase domain, was imatinib-sensitive, activated STAT1 and stimulated inflammation genes, consistent with its inflammatory tumor phenotype. This fusion also transformed Ba/F3 cells, similarly to well-characterized PDGFRB fusions reported in hematological malignancies. Altogether, our data suggest that, except for SRF::PDGFRB, SRF fusions belong to the family of oncogenes acting as hyperactivated transcription factors in human myoid soft tissue tumors.

Heterozygous activating variants in platelet-derived growth factor receptor beta (PDGFRβ) are associated with ultra-rare and clinically heterogeneous conditions, including KOGS (Kosaki Overgrowth Syndrome), PS (Penttinen Syndrome) and related conditons. Tyrosine kinase inhibitors (TKIs), which are widely used in hematological and oncological diseases, are now being explored as potential treatments for these conditions. While four published cases have reported encouraging results, there is still insufficient data available to draw definitive conclusions on the benefit-risk ratio. The international consortium Knowing and Treating KOGS/PS was launched to assess the real-life outcomes of such treatments. The consortium presents four new cases and updates four previously published cases of KOGS/PS treated with TKIs from seven countries. A recent publication was also included in the analysis. Individuals received treatment for between three and a half months and eight years (imatinib N = 8/8, dasatinib N = 3/8, sunitinib N = 1/8), with a mean duration of 44.4 months (SD = 29.8). The age at treatment initiation ranged from 6 to 57 years (six patients treated in childhood and two in adulthood). All individuals showed improvement within weeks/months, with minimal side effects. However, efficacy decreased over time in some cases, prompting a switch to a different TKI. These preliminary findings highlight the potential of TKIs for managing KOGS/PS patients. Standardized follow-up protocols and an electronic Case Report Form (eCRF) have been implemented to enhance monitoring and data collection, enabling systematic comparisons between treated and untreated individuals despite the disorders' rarity.

PURPOSE:The goal of this study was to explore the biological mechanisms that may influence the development of myofibromas, noninvasive soft tissue tumors with a variable clinical course. Although solitary lesions are usually benign, multicentric infantile myofibromatosis can range from indolent disease with spontaneous regression to severe forms with visceral involvement and life-threatening complications. MATERIALS AND METHODS:We analyzed senescence markers, DNA damage, and telomere biology in 33 tumor samples from 28 patients with myofibroma, including both solitary and multicentric forms. DNA damage and senescence markers (53BP1 and p16) were quantified by immunofluorescence and immunohistochemistry, whereas telomere length and maintenance mechanisms were assessed using telomere-specific fluorescence in situ hybridization. ATRX expression was evaluated, and sequencing data were reviewed for chromatin regulator mutations. RESULTS:Tumor tissues exhibited significant p16 overexpression compared with matched normal tissues. DNA damage, reflected by an increased number of 53BP1 nuclear foci, was also significantly higher in tumors, whereas telomere dysfunction-induced foci, measuring telomere-associated DNA damage, showed no notable difference between groups. Telomere length analysis revealed significantly shorter telomeres in tumors, without evidence of an active telomere maintenance mechanism, such as alternative lengthening of telomeres or telomerase reactivation. Loss or downregulation of ATRX protein was frequently observed. Variants in ATRX or DAXX were identified in a subset of cases, including 1 large somatic ATRX deletion and 1 likely pathogenic germline ATRX variant. No significant difference was observed between isolated and multicentric lesions. CONCLUSIONS:Our findings suggest that cellular senescence, characterized by p16 upregulation, increased DNA damage, and telomere shortening, may underlie the spontaneous regression observed in myofibromas. Alterations in ATRX and DAXX may further contribute to chromatin instability. These insights shed light on a possible protective mechanism limiting tumor growth and progression, offering a new perspective on the biology of benign pediatric tumors. Article History.

Tyrosine kinase inhibitors (TKI), such as imatinib, have revolutionized chronic myeloid leukemia (CML) treatment. Despite this success, TKI intolerance and resistance remain significant clinical challenges. A promising therapeutic approach is to simultaneously target the BCR::ABL1 oncogene and other oncogenic drivers. The polycistronic miR-17-92 cluster is known to contribute to CML development and progression, but the specific roles of miR-92a-1-5p within this cluster remain unclear. In this study, we assess the roles of this microRNA and evaluate the therapeutic potential of combining microRNA inhibition with imatinib to improve treatment outcome. Our results show that miR-92a-1-5p is downregulated by imatinib in myeloid cell lines harboring BCR::ABL1 and in CML patient samples. Inhibition of miR-92a-1-5p reduces proliferation and enhances imatinib-induced cell death, while its overexpression increases proliferation and counteracts the effects of imatinib on cell death. This decrease in proliferation caused by miR-92a-1-5p inhibition is rescued after simultaneous inhibition of two newly identified target genes: BNIP3L (NIX) and TP53INP1. We confirm that miR-92a-1-5p regulates proliferation and cell cycle by targeting TP53INP1 and decreases autophagy by targeting BNIP3L. Our data suggest that miR-92a-1-5p plays a role in CML progression, and its inhibition enhances imatinib anti-leukemic efficacy, making it a potential therapeutic target.

The gut microbiota makes critical contributions to host homeostasis, and its role in the treatment of acute myeloid leukemia (AML) has attracted attention. We investigated whether the gut microbiome is affected by AML, and whether such changes are associated with hallmarks of cachexia. Biological samples and clinical data were collected from 30 antibiotic- free AML patients at diagnosis and matched volunteers (1:1) in a multicenter, cross-sectional, prospective study. The composition and functional potential of the fecal microbiota were analyzed using shotgun metagenomics. Fecal, blood, and urinary metabolomics analyses were performed. AML patients displayed muscle weakness, anorexia, signs of altered gut function, and glycemic disorders. The composition of the fecal microbiota differed between patients with AML and control subjects, with an increase in oral bacteria. Alterations in bacterial functions and fecal metabolome support an altered redox status in the gut microbiota, which may contribute to the altered redox status observed in patients with AML. Eubacterium eligens, reduced 3-fold in AML patients, was strongly correlated with muscle strength and citrulline, a marker of enterocyte mass and function. Blautia and Parabacteroides, increased in patients with AML, were correlated with anorexia. Several bacterial taxa and metabolites (e.g., Blautia, Prevotella, phenylacetate, and hippurate) previously associated with glycemic disorders were altered. Our work revealed important perturbations in the gut microbiome of AML patients at diagnosis, which are associated with muscle strength, altered redox status, and anorexia. These findings pave the way for future mechanistic work to explore the function and therapeutic potential of the bacteria identified in this study.

Myxoid glioneuronal tumors (MGNT) are low-grade glioneuronal neoplasms composed of oligodendrocyte-like cells in a mucin-rich stroma. These tumors feature a unique dinucleotide change at codon 385 in the platelet-derived growth factor receptor α (encoded by the PDGFRA gene), resulting in the substitution of lysine 385 into leucine or isoleucine. The functional consequences of these mutations remain largely unexplored. Here, we demonstrated their oncogenic potential in fibroblast and Ba/F3 transformation assays. We showed that the K385I and K385L mutants activate STAT and AKT signaling in the absence of ligand. Co-immunoprecipitations and BRET experiments suggested that the mutations stabilized the active dimeric conformation of the receptor, pointing to a new mechanism of oncogenic PDGF receptor activation. Furthermore, we evaluated the sensitivity of these mutants to three FDA-approved tyrosine kinase inhibitors: imatinib, dasatinib, and avapritinib, which effectively suppressed the constitutive activity of the mutant receptors. Finally, K385 substitution into another hydrophobic amino acid also activated the receptor. Interestingly, K385M was reported in a few cases of brain tumors but not in MGNT. Our results provide valuable insights into the molecular mechanism underlying the activation of PDGFRα by the K385I/L mutations, highlighting their potential as actionable targets in the treatment of myxoid glioneuronal tumors.

Purpose: Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor (PDGF) receptor beta (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.2905-8G>A, in 6 unrelated infants with multifocal myofibromatosis and their relatives. Methods: We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays. Results: All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously described variants. In 4 tumor samples, we identified a second somatic hit at position Asp850 in PDGFRB exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, 2 patients received imatinib without objective response. One of them switched to dasatinib with concomitant improvement. Conclusion: This splice-site PDGFRB variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.

Purpose:To investigate the genetic cause, clinical characteristics, and potential therapeutic targets of infantile corneal myofibromatosis. Design:Case series with genetic and functional in vitro analyses. Participants:Four individuals from 2 unrelated families with clinical signs of corneal myofibromatosis were investigated. Methods:Exome-based panel sequencing for platelet-derived growth factor receptor beta gene (PDGFRB) and notch homolog protein 3 gene (NOTCH3) was performed in the respective index patients. One clinically affected member of each family was tested for the pathogenic variant detected in the respective index by Sanger sequencing. Immunohistochemical staining on excised corneal tissue was conducted. Functional analysis of the individual PDGFRB variants was performed in vitro by luciferase reporter assays on transfected porcine aortic endothelial cells using tyrosine kinase inhibitors. Protein expression analysis of mutated PDGFRB was analyzed by Western blot. Main Outcome Measures:Sequencing data, immunohistochemical stainings, functional analysis of PDGFRB variants, and protein expression analysis. Results:We identified 2 novel, heterozygous gain-of-function variants in PDGFRB in 4 individuals from 2 unrelated families with corneal myofibromatosis. Immunohistochemistry demonstrated positivity for alpha-smooth muscle actin and β-catenin, a low proliferation rate in Ki-67 (< 5%), marginal positivity for Desmin, and negative staining for Caldesmon and CD34. In all patients, recurrence of disease occurred after corneal surgery. When transfected in cultured cells, the PDGFRB variants conferred a constitutive activity to the receptor in the absence of its ligand and were sensitive to the tyrosine kinase inhibitor imatinib. The variants can both be classified as likely pathogenic regarding the American College of Medical Genetics and Genomics classification criteria. Conclusions:We describe 4 cases of corneal myofibromatosis caused by novel PDGFRB variants with autosomal dominant transmission. Imatinib sensitivity in vitro suggests perspectives for targeted therapy preventing recurrences in the future. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease that may involve medium-sized muscular arteries throughout the body. The majority of FMD patients are women. Although a variety of genetic, mechanical, and hormonal factors play a role in the pathogenesis of FMD, overall, its cause remains poorly understood. It is probable that the pathogenesis of FMD is linked to a combination of genetic and environmental factors. Extensive studies have correlated the arterial lesions of FMD to histopathological findings of arterial fibrosis, cellular hyperplasia, and distortion of the abnormal architecture of the arterial wall. More recently, the vascular phenotype of lesions associated with FMD has been expanded to include arterial aneurysms, dissections, and tortuosity. However, in the absence of a string-of-beads or focal stenosis, these lesions do not suffice to establish the diagnosis. While FMD most commonly involves renal and cerebrovascular arteries, involvement of most arteries throughout the body has been reported. Increasing evidence highlights that FMD is a systemic arterial disease and that subclinical alterations can be found in non-affected arterial segments. Recent significant progress in FMD-related research has led to improve our understanding of the disease’s clinical manifestations, natural history, epidemiology, and genetics. Ongoing work continues to focus on FMD genetics and proteomics, physiological effects of FMD on cardiovascular structure and function, and novel imaging modalities and blood-based biomarkers that can be used to identify subclinical FMD. It is also hoped that the next decade will bring the development of multi-centred and potentially international clinical trials to provide comparative effectiveness data to inform the optimal management of patients with FMD.

Penttinen syndrome is a rare progeroid disorder caused by mutations in platelet-derived growth factor (PDGF) receptor beta (encoded by the PDGFRB proto-oncogene) and characterized by a prematurely aged appearance with lipoatrophy, skin lesions, thin hair and acro-osteolysis. Activating mutations in PDGFRB have been associated with other human diseases, including Kosaki overgrowth syndrome, infantile myofibromatosis, fusiform aneurysms, acute lymphoblastic leukaemia and myeloproliferative neoplasms associated with eosinophilia. The goal of the present study was to characterize the PDGFRB p.Val665Ala variant associated with Penttinen syndrome at the molecular level. This substitution is located in a conserved loop of the receptor tyrosine kinase domain. We observed that the mutant receptor was expressed at a lower level but showed constitutive activity. In the absence of ligand, the mutant activated STAT1 and elicited an interferon-like transcriptional response. Phosphorylation of STAT3, STAT5, AKT and phospholipase Cγ was weak or undetectable. It was devoid of oncogenic activity in two cell proliferation assays, contrasting with classical PDGF receptor oncogenic mutants. STAT1 activation was not sensitive to ruxolitinib and did not rely on interferon-JAK2 signalling. Another tyrosine kinase inhibitor, imatinib, blocked signalling by the p.Val665Ala variant at a higher concentration compared with the wild-type receptor. Importantly, this concentration remained in the therapeutic range. Dasatinib, nilotinib and ponatinib also inhibited the mutant receptor. In conclusion, the p.Val665Ala variant confers unique features to PDGF receptor β compared with other characterized gain-of-function mutants, which may in part explain the particular set of symptoms associated with Penttinen syndrome.

Platelet-derived growth factor receptor beta (PDGFRB) is one of the genes associated with primary familial brain calcification (PFBC), an inherited neurological disease (OMIM:173410). Genetic analysis of patients and families revealed at least 13 PDGFRB heterozygous missense variants, including two novel ones described in the present report. Limited experimental data published on five of these variants had suggested that they decrease the receptor activity. No functional information was available on the impact of variants located within the receptor extracellular domains. Here, we performed a comprehensive molecular analysis of PDGFRB variants linked to PFBC. Mutated receptors were transfected in various cell lines to monitor receptor expression, signaling, mitogenic activity and ligand binding. Four mutants caused a complete loss of tyrosine kinase activity in multiple assays. One of the novel variants, p.Pro154Ser, decreased the receptor expression and abolished binding of platelet-derived growth factor (PDGF-BB). Others showed a partial loss of function related to reduced expression or signaling. Combining clinical, genetic and molecular data, we consider nine variants as pathogenic or likely pathogenic, three as benign or likely benign and one as a variant of unknown significance. We discuss the possible relationship between the variant residual activity, incomplete penetrance, brain calcification and neurological symptoms. In conclusion, we identified distinct molecular mechanisms whereby PDGFRB variants may result in a receptor loss of function. This work will facilitate genetic counseling in PFBC.

Somatic point mutations of the FOXO1 transcription factor were reported in non-Hodgkin lymphoma including diffuse large B-cell lymphoma, follicular lymphoma and Burkitt lymphoma. These alterations were associated with a poor prognosis and resistance to therapy. Nearly all amino acid substitutions are localized in two major clusters, affecting either the N-terminal region (Nt mutations) or the forkhead DNA-binding domain (DBD mutations). While recent studies have focused on Nt mutations, we characterized FOXO1 DBD mutants. We analyzed their transcriptional activity, DNA binding, phosphorylation and protein–protein interaction. The majority of DBD mutants showed a decrease in activity and DNA binding, while preserving AKT phosphorylation and interaction with the cytoplasmic ATG7 protein. In addition, we investigated the importance of conserved residues of the α-helix 3 of the DBD. Amino acids I213, R214, H215 and L217 appeared to be crucial for FOXO1 activity. Our data underlined the key role of multiple amino-acid residues of the forkhead domain in FOXO1 transcriptional activity and revealed a new type of FOXO1 loss-of-function mutations in B-cell lymphoma.

Article Tools CASE REPORTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/PO.22.00250 JCO Precision Oncology no. 6 (2022) e2200250. Published online October 6, 2022. PMID: 36201717 Novel Oncogenic PDGFRB Variant in Severe Infantile Myofibromatosis With Response to Imatinib Using Therapeutic Drug Monitoring Abbey Elsbernd , MD1xAbbey ElsberndSearch for articles by this author; Boutaina Boulouadnine , MSc2xBoutaina BoulouadnineSearch for articles by this author; Atif Ahmed , MD3xAtif AhmedSearch for articles by this author; Midhat Farooqi , MD, PhD4,5xMidhat FarooqiSearch for articles by this author; Tracy Sandritter, PharmD6xTracy SandritterSearch for articles by this author; Valentina Shakhnovich , MD6,7,8xValentina ShakhnovichSearch for articles by this author; Darius Blanding, MD1xDarius BlandingSearch for articles by this author, Jean-Baptiste Demoulin , PhD2xJean-Baptiste DemoulinSearch for articles by this author; and Joel Thompson, MD8,9xJoel ThompsonSearch for articles by this author Show More 1Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO2de Duve Institute, University of Louvain, Brussels, Belgium3Department of Laboratory Medicine and Pathology, Seattle Children's Hospital, Seattle, WA4Department of Pathology & Laboratory Medicine, Children's Mercy Hospitals and Clinics, Kansas City, MO5Department of Pathology, University of Missouri-Kansas City School of Medicine, Kansas City, MO6Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, MO7Division of Gastroenterology, Hepatology & Nutrition, Children's Mercy Hospitals and Clinics, Kansas City, MO8Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO9Division of Pediatric Hematology/Oncology/BMT, Children's Mercy Hospitals and Clinics, Kansas City, MO*A.E. and B.B. contributed equally to this work. https://doi.org/10.1200/PO.22.00250 First Page Full Text PDF Figures and Tables Supplements © 2022 by American Society of Clinical OncologySUPPORTSupported by grants from the Belgian Foundation against Cancer. B.B. was supported by a fellowship from the Funds for Scientific Research (FNRS, Belgium).AUTHOR CONTRIBUTIONSConception and design: Boutaina Boulouadnine, Midhat Farooqi, Tracy Sandritter, Valentina Shakhnovich, Jean-Baptiste DemoulinFinancial support: Jean-Baptiste DemoulinProvision of study materials or patients: Atif Ahmed, Valentina ShakhnovichCollection and assembly of data: Abbey Elsbernd, Boutaina Boulouadnine, Atif Ahmed, Midhat Farooqi, Tracy Sandritter, Valentina Shakhnovich, Darius Blanding, Joel ThompsonData analysis and interpretation: Abbey Elsbernd, Boutaina Boulouadnine, Atif Ahmed, Midhat Farooqi, Tracy Sandritter, Valentina Shakhnovich, Jean-Baptiste Demoulin, Joel ThompsonManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Jean-Baptiste DemoulinHonoraria: NovartisNo other potential conflicts of interest were reported.

Introduction The ETV6::NTRK3 fusion is the most common gene alteration in infantile fibrosarcoma, a soft tissue tumor affecting patients under two years of age. Less frequently, these tumors harbor fusions of genes encoding other kinases, such as BRAF, which activates MEK in the mitogen-activated protein kinase pathway. The identification and characterization of these oncogenes are crucial to facilitate diagnosis, validate new treatments, and better understand the pathophysiology of these neoplasms. Methods Herein, we analyzed an ETV6::NTRK3-negative infantile fibrosarcoma from a 5-day-old patient by RNA-sequencing to identify new fusion transcripts. Functional exploration of the fusion of interest was performed by in vitro assays to study its activity, oncogenicity, and sensitivity to the MEK inhibitor trametinib. Results We identified a novel fusion involving the PHIP and BRAF genes. The corresponding fusion protein constitutively activated the mitogen-activated protein kinase pathway, resulting in fibroblast transformation. Treatment of transfected cells with trametinib effectively inhibited signaling by PHIP::BRAF. Conclusion PHIP::BRAF is a novel fusion oncogene that can be targeted by trametinib in infantile fibrosarcoma.

AbstractIntroductionTheETV6::NTRK3fusion is the most common gene alteration in infantile fibrosarcoma, a soft tissue tumor affecting patients under two years of age. Less frequently, these tumors harbor fusions of genes encoding other kinases, such asBRAF, which activates MEK in the mitogen‐activated protein kinase pathway. The identification and characterization of these oncogenes are crucial to facilitate diagnosis, validate new treatments, and better understand the pathophysiology of these neoplasms.MethodsHerein, we analyzed anETV6::NTRK3‐negative infantile fibrosarcoma from a 5‐day‐old patient by RNA‐sequencing to identify new fusion transcripts. Functional exploration of the fusion of interest was performed byin vitroassays to study its activity, oncogenicity, and sensitivity to the MEK inhibitor trametinib.ResultsWe identified a novel fusion involving thePHIPandBRAFgenes. The corresponding fusion protein constitutively activated the mitogen‐activated protein kinase pathway, resulting in fibroblast transformation. Treatment of transfected cells with trametinib effectively inhibited signaling byPHIP::BRAF.ConclusionPHIP::BRAFis a novel fusion oncogene that can be targeted by trametinib in infantile fibrosarcoma.

Cytarabine and daunorubicin are old drugs commonly used in the treatment of acute myeloid leukaemia (AML). Refractory or relapsed disease because of chemotherapy resistance is a major issue. microRNAs (miRNAs) were incriminated in resistance. This study aimed to identify miRNAs involved in chemoresistance in AML patients and to define their target genes. We focused on cytogenetically normal AML patients with wild‐type NPM1 without FLT3‐ITD as the treatment of this subset of patients with intermediate‐risk cytogenetics is not well established. We analysed baseline AML samples by small RNA sequencing and compared the profile of chemoresistant to chemosensitive AML patients. Among the miRNAs significantly overexpressed in chemoresistant patients, we revealed miR‐15a‐5p and miR‐21‐5p as miRNAs with a major role in chemoresistance in AML. We showed that miR‐15a‐5p and miR‐21‐5p overexpression decreased apoptosis induced by cytarabine and/or daunorubicin. PDCD4, ARL2 and BTG2 genes were found to be targeted by miR‐15a‐5p, as well as PDCD4 and BTG2 by miR‐21‐5p. Inhibition experiments of the three target genes reproduced the functional effect of both miRNAs on chemosensitivity. Our study demonstrates that miR‐15a‐5p and miR‐21‐5p are overexpressed in a subgroup of chemoresistant AML patients. Both miRNAs induce chemoresistance by targeting three pro‐apoptotic genes PDCD4, ARL2 and BTG2.

Mitochondrial DNA (mtDNA) has a high mutation rate due at least in part to a lack of protective histones and an inefficient DNA repair system. The most frequently change in mtDNA is the so-called Common Deletion (CD), which accumulates in patients with hetero-plasmic mtDNA mutations and in normal individuals during aging. In this study, wild type mtDNA (WT-mtDNA) and mitochondrial DNA with CD (CD-mtDNA) were quantitatively analyzed in different nasopharynx lesions. A novel type of CD-mtDNA (4981 bp) was de-tected significantly higher in nasopharyngeal carcinoma (NPC) (93%, 54/58) than in naso-pharyngitis (60%, 28/47) and the paired white blood cells (WBC) (26%, 8/31). The ratio of CD-mtDNA to WT-mtDNA in NPC (0.000625, median) was 10 times that in nasopharyngitis (0.000064, median) (P = 0.003), and was significantly higher than that in paired WBC (0.000000, median) (P = 0.000). The CD/WT-mtDNA ratio was 0.000564 (quartile range, 0.000184 - 0.000919) in late stage NPC, which was nearly 3 times the ratio in early stage NPC (0.000164, quartile range, 0.000042 - 0.000353) (P = 0.015, Mann-Whitney Test). In NPC patients with ages °› 48yrs (mean age), the ratio of CD-mtDNA to WT-mtDNA was 0.000625, which was nearly 10 times that in NPC patients with ages < 48yrs (0.000064) (P = 0.005, Mann-Whitney Test). This is the first quantitative study of CD-mtDNA mutations in NPC, which provides evidences that CD-mtDNA mutation might be involved in the devel-opment and progression of NPC.

PDGFRA and PDGFRB are classical proto-oncogenes that encode receptor tyrosine kinases responding to platelet-derived growth factor (PDGF). PDGFRA mutations are found in gastrointestinal stromal tumors (GISTs), inflammatory fibroid polyps and gliomas, and PDGFRB mutations drive myofibroma development. In addition, chromosomal rearrangement of either gene causes myeloid neoplasms associated with hypereosinophilia. Recently, mutations in PDGFRB were linked to several noncancerous diseases. Germline heterozygous variants that reduce receptor activity have been identified in primary familial brain calcification, whereas gain-of-function mutants are present in patients with fusiform aneurysms, Kosaki overgrowth syndrome or Penttinen premature aging syndrome. Functional analysis of these variants has led to the preclinical validation of tyrosine kinase inhibitors targeting PDGF receptors, such as imatinib, as a treatment for some of these conditions. This review summarizes the rapidly expanding knowledge in this field.

Anthracyclines remain a cornerstone of induction chemotherapy for acute myeloid leukemia (AML). Refractory or relapsed disease due to chemotherapy resistance is a major obstacle in AML management. MicroRNAs (miRNAs) have been observed to be involved in chemoresistance. We previously observed that miR-15a-5p was overexpressed in a subgroup of chemoresistant cytogenetically normal AML patients compared with chemosensitive patients treated with daunorubicin and cytarabine. MiR-15a-5p overexpression in AML cells reduced apoptosis induced by both drugs in vitro. This study aimed to elucidate the mechanisms by which miR-15a-5p contributes to daunorubicin resistance. We showed that daunorubicin induced autophagy in myeloid cell lines. The inhibition of autophagy reduced cell sensitivity to daunorubicin. The overexpression of miR-15a-5p decreased daunorubicin-induced autophagy. Conversely, the downregulation of miR-15a-5p increased daunorubicin-induced autophagy. We found that miR-15a-5p targeted four genes involved in autophagy, namely ATG9a, ATG14, GABARAPL1 and SMPD1. Daunorubicin increased the expression of these four genes, and miR-15a-5p counteracted this regulation. Inhibition experiments with the four target genes showed the functional effect of miR-15a-5p on autophagy. In summary, our results indicated that miR-15a-5p induces chemoresistance in AML cells through the abrogation of daunorubicin-induced autophagy, suggesting that miR-15a-5p could be a promising therapeutic target for chemoresistant AML patients.