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1.
Ann Hematol ; 99(11): 2611-2617, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980888

RESUMO

EP300-ZNF384 fusion is a rare recurrent cytogenetic abnormality associated with B cell acute lymphoblastic leukemia (B-ALL), which was rarely studied in Chinese patient cohort. Here, we used a customized RNA fusion gene panel to investigate gene fusions in 56 selected acute leukemia patients without conventional genetic abnormalities. Two EP300-ZNF384 fusion forms were detected in ten cases, which were in-frame fusions of EP300 exon 6 fused with exon 3 or 2 of ZNF384. The fusions led to the lack of most functional domains of EP300. We firstly reported EP300-ZNF384 fusion in a mixed-phenotype acute leukemia (MPAL) patient whose CD33 and CD13 were negative. The rest nine B-ALL patients with EP300-ZNF384 fusion expressed CD33 and/or CD13. Fifty-six percent of B-ALL patients (5/9) with EP300-ZNF384 fusion were positive with CD10. After the diagnosis of EP300-ZNF384 fusion, 70% of the patients achieved remission after chemotherapy. Our observations indicated that EP300-ZNF384 fusion consists of a distinct subgroup of B-ALL with a characteristic immunophenotype. These patients are sensitive to current chemotherapy regimen and have an excellent outcome.


Assuntos
Proteína p300 Associada a E1A , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras , RNA Neoplásico , Análise de Sequência de RNA , Transativadores , Adulto , Estudos de Coortes , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Feminino , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transativadores/genética , Transativadores/metabolismo
2.
Nat Commun ; 11(1): 3339, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620764

RESUMO

Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.


Assuntos
Cromatina/metabolismo , Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Doença Aguda , Antígenos Nucleares/genética , Antígenos Nucleares/metabolismo , Cromatina/genética , Dissulfiram/farmacologia , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Leucemia Mieloide/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Dedos de Zinco PHD/genética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteína 2 de Ligação ao Retinoblastoma/genética , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Translocação Genética/efeitos dos fármacos , Translocação Genética/genética
3.
J Vis Exp ; (160)2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32658189

RESUMO

Many cancers are characterized by chromosomal translocations which result in the expression of oncogenic fusion transcription factors. Typically, these proteins contain an intrinsically disordered domain (IDD) fused with the DNA-binding domain (DBD) of another protein and orchestrate widespread transcriptional changes to promote malignancy. These fusions are often the sole recurring genomic aberration in the cancers they cause, making them attractive therapeutic targets. However, targeting oncogenic transcription factors requires a better understanding of the mechanistic role that low-complexity, IDDs play in their function. The N-terminal domain of EWSR1 is an IDD involved in a variety of oncogenic fusion transcription factors, including EWS/FLI, EWS/ATF, and EWS/WT1. Here, we use RNA-sequencing to investigate the structural features of the EWS domain important for transcriptional function of EWS/FLI in Ewing sarcoma. First shRNA-mediated depletion of the endogenous fusion from Ewing sarcoma cells paired with ectopic expression of a variety of EWS-mutant constructs is performed. Then RNA-sequencing is used to analyze the transcriptomes of cells expressing these constructs to characterize the functional deficits associated with mutations in the EWS domain. By integrating the transcriptomic analyses with previously published information about EWS/FLI DNA binding motifs, and genomic localization, as well as functional assays for transforming ability, we were able to identify structural features of EWS/FLI important for oncogenesis and define a novel set of EWS/FLI target genes critical for Ewing sarcoma. This paper demonstrates the use of RNA-sequencing as a method to map the structure-function relationship of the intrinsically disordered domain of oncogenic transcription factors.


Assuntos
Perfilação da Expressão Gênica , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/química , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/química , Proteína EWS de Ligação a RNA/metabolismo , Relação Estrutura-Atividade , Sítios de Ligação , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Humanos , Mutação , Proteínas de Fusão Oncogênica/genética , Domínios Proteicos , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia
4.
Prostate ; 80(13): 1097-1107, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32628300

RESUMO

BACKGROUND: Kallikrein-related peptidase 2 (KLK2)-like KLK3 (prostate-specific antigen [PSA])-belongs to the highly conserved serine proteases of the glandular kallikrein protein family (KLK family). Studies suggested that measurement of KLK2 serum levels advanced the predictive accuracy of PSA testing in prostate cancer. METHODS: To clarify the potential utility of KLK2 as a prognostic tissue biomarker, KLK2 expression was analyzed by immunohistochemistry in more than 12 000 prostate cancers. RESULTS: Normal epithelium cells usually showed weak to moderate KLK2 immunostaining, whereas KLK2 was negative in 23%, weak in 38%, moderate in 35%, and strong in 4% of 9576 analyzable cancers. Lost or reduced KLK2 immunostaining was associated with advanced tumor stage, high Gleason score, lymph node metastasis, increased cell proliferation, positive resection margin, and early PSA recurrence (P < .0001). Comparison with previously analyzed molecular alterations revealed a strong association of KLK2 loss and presence of TMPRSS2:ERG fusion (P < .0001), most of all analyzed common deletions (9 of 11; P ≤ .03), and decreased PSA immunostaining (P < .0001 each). Cancers with combined negative or weak immunostaining of KLK2 and PSA showed worse prognosis than cancers with at least moderate staining of one or both proteins (P < .0001). Multivariate analyses including established preoperative and postoperative prognostic parameters showed a strong independent prognostic impact of KLK2 loss alone or in combination of PSA, especially in erythroblast transformation-specific-negative cancers (P ≤ .006). CONCLUSIONS: Loss of KLK2 expression is a potentially useful prognostic marker in prostate cancer. Analysis of KLK2 alone or in combination with PSA may be useful for estimating cancer aggressiveness at the time of biopsy.


Assuntos
Calicreínas/biossíntese , Neoplasias da Próstata/enzimologia , Idoso , Humanos , Imuno-Histoquímica , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fenótipo , Prognóstico , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Regulador Transcricional ERG/biossíntese , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismo
5.
Nat Commun ; 11(1): 2977, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532995

RESUMO

Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Glicoproteínas de Membrana/genética , Oncogenes/genética , Isoformas de RNA/genética , Processamento de RNA , Receptor trkB/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Células Cultivadas , Perfilação da Expressão Gênica , Ontologia Genética , Glioma/metabolismo , Glioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Células NIH 3T3 , Células-Tronco Neurais/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de RNA/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais/genética
6.
PLoS One ; 15(6): e0234243, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502203

RESUMO

The presence of the chimeric EWSR1-FLI1 oncoprotein is the main and initiating event defining Ewing sarcoma (ES). The dysregulation of epigenomic and proteomic homeostasis induced by the oncoprotein contributes to a wide variety of events involved in oncogenesis and tumor progression. Attempts at studying the effects of EWSR1-FLI1 in non-tumor cells to understand the mechanisms underlying sarcomagenesis have been unsuccessful to date, as ectopic expression of EWSR1-FLI1 blocks cell cycle progression and induces apoptosis in the tested cell lines. Therefore, it is essential to find a permissive cell type for EWSR1-FLI1 expression that allows its endogenous molecular functions to be studied. Here we have demonstrated that HeLa cell lines are permissive to EWSR1-FLI1 ectopic expression, and that our model substantially recapitulates the endogenous activity of the EWSR1-FLI1 fusion protein. This model could contribute to better understanding ES sarcomagenesis by helping to understand the molecular mechanisms induced by the EWSR1-FLI1 oncoprotein.


Assuntos
Carcinogênese/genética , Expressão Ectópica do Gene , Proteínas de Fusão Oncogênica/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Sítios de Ligação , DNA/metabolismo , Células HeLa , Humanos , Proteínas de Fusão Oncogênica/metabolismo
7.
Nat Commun ; 11(1): 2423, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415069

RESUMO

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments including 3D and PDX models, we discover that constitutively high SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic vulnerability toward the oxidative stress-inducing drug Elesclomol.Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/metabolismo , Estresse Oxidativo , Sarcoma de Ewing/patologia , Adulto , Animais , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , Condrócitos/metabolismo , Metilação de DNA , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Hidrazinas/química , Células-Tronco Mesenquimais/metabolismo , Camundongos , Repetições de Microssatélites , Mitocôndrias/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Oncogenes , Interferência de RNA , Fatores de Transcrição SOXD/metabolismo , Sarcoma/genética
8.
PLoS One ; 15(4): e0232036, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32343715

RESUMO

The NUP98 and NUP214 nucleoporins (NUPs) are recurrently fused to heterologous proteins in leukemia. The resulting chimeric oncoproteins retain the phenylalanine-glycine (FG) repeat motifs of the NUP moiety that mediate interaction with the nuclear export receptor Crm1. NUP fusion leukemias are characterized by HOXA gene upregulation; however, their molecular pathogenesis remains poorly understood. To investigate the role of Crm1 in mediating the leukemogenic properties of NUP chimeric proteins, we took advantage of the Sequestosome-1 (SQSTM1)-NUP214 fusion. SQSTM1-NUP214 retains only a short C-terminal portion of NUP214 which contains FG motifs that mediate interaction with Crm1. We introduced point mutations targeting these FG motifs and found that the ability of the resulting SQSTM1-NUP214FGmut protein to interact with Crm1 was reduced by more than 50% compared with SQSTM1-NUP214. Mutation of FG motifs affected transforming potential: while SQSTM1-NUP214 impaired myeloid maturation and conferred robust colony formation to transduced hematopoietic progenitors in a serial replating assay, the effect of SQSTM1-NUP214FGmut was considerably diminished. Moreover, SQSTM1-NUP214 caused myeloid leukemia in all transplanted mice, whereas none of the SQSTM1-NUP214FGmut reconstituted mice developed leukemia. These oncogenic effects coincided with the ability of SQSTM1-NUP214 and SQSTM1-NUP214FGmut to upregulate the expression of Hoxa and Meis1 genes in hematopoietic progenitors. Indeed, chromatin immunoprecipitation assays demonstrated that impaired SQSTM1-NUP214 interaction with Crm1 correlated with impaired binding of the fusion protein to Hoxa and Meis1 genes. These findings highlight the importance of Crm1 in mediating the leukemogenic properties of SQSTM1-NUP214, and suggest a conserved role of Crm1 in recruiting oncoproteins to their effector genes.


Assuntos
Proteínas de Homeodomínio/genética , Carioferinas/metabolismo , Leucemia/metabolismo , Proteína Meis1/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína Sequestossoma-1/genética , Motivos de Aminoácidos , Animais , Linhagem Celular , Regulação Neoplásica da Expressão Gênica , Leucemia/genética , Leucemia/patologia , Camundongos , Mutagênese Sítio-Dirigida , Transplante de Neoplasias , Complexo de Proteínas Formadoras de Poros Nucleares/química , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/genética , Mutação Puntual , Regulação para Cima
9.
Am J Hematol ; 95(7): 824-833, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32279331

RESUMO

We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1-JAK2, n = 8; BCR-JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6-ABL1, n = 9). On ruxolitinib (median 24 months, range 2-36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4-78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6-ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3-60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6-ABL1 positive patients.


Assuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Proteínas de Fusão Oncogênica , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/enzimologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/enzimologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/mortalidade , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Taxa de Sobrevida
10.
Nat Commun ; 11(1): 2056, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345963

RESUMO

Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. By RNA-seq analysis, we identify a RET rearrangement in the tumour material of a patient who does not harbour any known RAS or BRAF mutations. This new gene fusion involves exons 1-4 from the 5' end of the Trk fused Gene (TFG) fused to the 3' end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinase-dependent manner. TFG-RET oligomerises in a PB1 domain-dependent manner and oligomerisation of TFG-RET is required for oncogenic transformation. Quantitative proteomic analysis reveals the upregulation of E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and metastatic lesions, which is further confirmed in additional patients. Expression of TFG-RET leads to the upregulation of HUWE1 and inhibition of HUWE1 significantly reduces RET-mediated oncogenesis.


Assuntos
Proteínas de Fusão Oncogênica/genética , Proteínas/genética , Proteogenômica , Proteínas Proto-Oncogênicas c-ret/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Transformação Celular Neoplásica/patologia , Humanos , Concentração Inibidora 50 , Metástase Linfática/patologia , Mutação/genética , Proteínas de Fusão Oncogênica/metabolismo , Multimerização Proteica , Proteínas/química , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Regulação para Cima
11.
Mol Cell ; 78(1): 112-126.e12, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32243828

RESUMO

Delineating how chromosomes fold at length scales beyond one megabase remains obscure relative to smaller-scale folding into TADs, loops, and nucleosomes. We find that rather than simply unfolding chromatin, histone hyperacetylation results in interactions between distant genomic loci separated by tens to hundreds of megabases, even in the absence of transcription. These hyperacetylated "megadomains" are formed by the BRD4-NUT fusion oncoprotein, interact both within and between chromosomes, and form a specific nuclear subcompartment that has elevated gene activity with respect to other subcompartments. Pharmacological degradation of BRD4-NUT results in collapse of megadomains and attenuation of the interactions between them. In contrast, these interactions persist and contacts between newly acetylated regions are formed after inhibiting RNA polymerase II initiation. Our structure-function approach thus reveals that broad chromatin domains of identical biochemical composition, independent of transcription, form nuclear subcompartments, and also indicates the potential of altering chromosome structure for treating human disease.


Assuntos
Núcleo Celular/genética , Cromatina/metabolismo , Cromossomos de Mamíferos/química , Acetilação , Linhagem Celular , Núcleo Celular/metabolismo , Cromatina/química , Cromatina/efeitos dos fármacos , Cromossomos de Mamíferos/metabolismo , Expressão Gênica , Humanos , Masculino , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/metabolismo
12.
Semin Oncol ; 47(1): 73-84, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32201016

RESUMO

Soft-tissue sarcomas (STS) are a group of rare mesenchymal tumors that constitutes ∼1% of all solid tumors. It remains a rare tumor which lacks effective treatment options. Precision oncology may be of interest in this regard by identifying potential targets for emerging novel therapies. Neurotrophic receptor tyrosine kinase (NTRK) fusions are rare oncogenic driver mutations found in a broad range of common and rare tumor subtypes including STS. The recent approvals of NTRK inhibitors (larotrectinib and entrectinib) represent new therapeutic options in the drug armamentarium especially valuable in advanced STS given the paucity of treatment options and the generally poor prognosis of these tumors. We review the methods used to detect NTRK fusions in STS with focus on incidence, diagnosis and management of these rare and intriguing oncogenic targets.


Assuntos
Biomarcadores Tumorais , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sarcoma/tratamento farmacológico , Sarcoma/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Testes Genéticos , Humanos , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Sarcoma/diagnóstico , Sarcoma/epidemiologia , Resultado do Tratamento
13.
Nat Commun ; 11(1): 1406, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179749

RESUMO

Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML.


Assuntos
Cromatina/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Acetilação , Animais , Diferenciação Celular , Sobrevivência Celular , Feminino , Proteína HMGN1/genética , Proteína HMGN1/metabolismo , Células-Tronco Hematopoéticas/citologia , Histonas/genética , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo
14.
Nat Commun ; 11(1): 1407, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179751

RESUMO

Leukaemogenic mutations commonly disrupt cellular differentiation and/or enhance proliferation, thus perturbing the regulatory programs that control self-renewal and differentiation of stem and progenitor cells. Translocations involving the Mll1 (Kmt2a) gene generate powerful oncogenic fusion proteins, predominantly affecting infant and paediatric AML and ALL patients. The early stages of leukaemogenic transformation are typically inaccessible from human patients and conventional mouse models. Here, we take advantage of cells conditionally blocked at the multipotent haematopoietic progenitor stage to develop a MLL-r model capturing early cellular and molecular consequences of MLL-ENL expression based on a clear clonal relationship between parental and leukaemic cells. Through a combination of scRNA-seq, ATAC-seq and genome-scale CRISPR-Cas9 screening, we identify pathways and genes likely to drive the early phases of leukaemogenesis. Finally, we demonstrate the broad utility of using matched parental and transformed cells for small molecule inhibitor studies by validating both previously known and other potential therapeutic targets.


Assuntos
Transformação Celular Neoplásica , Histona-Lisina N-Metiltransferase/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Células-Tronco Hematopoéticas/metabolismo , Histona-Lisina N-Metiltransferase/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
Leuk Res ; 91: 106316, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32114371
16.
Yonsei Med J ; 61(3): 262-266, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32102128

RESUMO

The World Health Organization 2016 edition assigned anaplastic lymphoma kinase (ALK) rearrangement-associated renal cell carcinoma (ALK-RCC) as an emerging renal tumor entity. Identifying ALK-RCC is important because ALK inhibitors have been shown to be effective in treatment. Here, we report the case of a 14-year-old young man with ALK-RCC. Computed tomography revealed a well-demarcated 5.3-cm enhancing mass at the upper pole of the left kidney. There was no further history or symptoms of the sickle-cell trait. The patient underwent left radical nephrectomy. Pathologically, the mass was diagnosed as an unclassified RCC. Targeted next-generation sequencing identified a TPM3-ALK fusion gene. The present report and literature review demonstrate that TPM3-ALK RCC may be associated with distinct clinicopathological features. Microscopically, the tumors showed diffuse growth and tubulocystic changes with inflammatory cell infiltration. Tumor cells were dis-cohesive and epithelioid with abundant eosinophilic cytoplasm and cytoplasmic vacuoles. If morphological features and TFE3 expression are present in adolescent and young patients, molecular tests for ALK translocation should be performed. This awareness is critically important, because ALK rearrangement confers sensitivity to ALK inhibitors.


Assuntos
Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Adolescente , Adulto , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Criança , Feminino , Rearranjo Gênico , Humanos , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Tomografia Computadorizada por Raios X
17.
Biochim Biophys Acta Gene Regul Mech ; 1863(3): 194503, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32061883

RESUMO

The highly leukemogenic MLL fusion proteins have a unique mechanism of action. This review summarizes the current knowledge of how MLL fusions interact with the transcriptional machinery and it proposes a hypothesis how these proteins modify transcriptional control to act as transcriptional amplifiers causing runaway production of certain RNAs that transform hematopoietic cells.


Assuntos
Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Transcrição Genética , Cromatina/metabolismo , Ativação Transcricional
18.
Cytotherapy ; 22(3): 127-134, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32024607

RESUMO

Enhanced interleukin-1ß (IL-1ß) signaling is a common event in patients with acute myeloid leukemia (AML). It was previously demonstrated that chronic IL-1ß exposure severely impaired hematopoietic stem cell (HSC) self-renewal capability in mice and promoted leukemia cell growth in primary AML cells. However, the role of IL-1ß in the murine bone marrow (BM) niche remains unclear. Here, we explored the role of IL-1ß in the BM niche in Il-1r1-/- mice, chronic IL-1ß exposure mice and mixed lineage leukemia-AF9 fusion gene (MLL-AF9)-induced AML mice models. We demonstrated that IL-1R1 deficiency did not affect the function of HSCs or niche cells under steady-state conditions or during transplantation. Chronic exposure to IL-1ß decreased the expansion of Il-1r1-/- hematopoietic cells in Il-1r1+/+ recipient mice. These results indicated that IL-1ß exposure impaired the ability of niche cells to support hematopoietic cells. Furthermore, we revealed that IL-1R1 deficiency in niche cells prolonged the survival of MLL-AF9-induced AML mice. The results of our study suggest that inhibition of the IL-1ß/IL-1R1 signaling pathway in the niche might be a non-cell-autonomous therapy strategy for AML.


Assuntos
Medula Óssea/patologia , Progressão da Doença , Células-Tronco Hematopoéticas/metabolismo , Interleucina-1beta/metabolismo , Leucemia Mieloide Aguda/patologia , Nicho de Células-Tronco , Animais , Medula Óssea/metabolismo , Proliferação de Células , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Proteínas de Fusão Oncogênica/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo
19.
Cancer Genomics Proteomics ; 17(2): 161-168, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32108038

RESUMO

BACKGROUND/AIM: Osteoblastoma is a rare benign tumor of the bones in which recurrent rearrangements of FOS have been found. Our aim was to investigate two osteoblastomas for possible genetic aberrations. MATERIALS AND METHODS: Cytogenetic, RNA sequencing, and molecular analyses were performed. RESULTS: A FOS-ANKH transcript was found in the first tumor, whereas a FOS-RUNX2 was detected in the second. Exon 4 of FOS fused with sequences either from intron 1 of ANKH or intron 5 of RUNX2. The fusion events introduced a stop codon and removed sequences involved in the regulation of FOS. CONCLUSION: Rearrangements and fusions of FOS show similarities with those of HMGA2 (a feature of leiomyomas and lipomas) and CSF1 (tenosynovial giant cell tumors). The replacement of a 3'-untranslated region, controlling the gene's expression, by a new sequence is thus a common pathogenetic theme shared by FOS, HMGA2, and CSF1 in many benign connective tissue tumors.


Assuntos
Neoplasias Ósseas/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Osteoblastoma/genética , Proteínas de Transporte de Fosfato/genética , Sequência de Bases , Neoplasias Ósseas/metabolismo , Criança , Subunidade alfa 1 de Fator de Ligação ao Core/deficiência , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Feminino , Expressão Gênica , Humanos , Cariótipo , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Osteoblastoma/metabolismo , Proteínas de Transporte de Fosfato/metabolismo
20.
Nat Commun ; 11(1): 44, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896750

RESUMO

Sclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic-phenotypic correlation in ovarian neoplasms.


Assuntos
Proteínas com Homeodomínio LIM/genética , Proteínas Musculares/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias Ovarianas/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Fatores de Transcrição/genética , Proteína Gli2 com Dedos de Zinco/genética , Adolescente , Adulto , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Ovarianas/patologia , Esclerose , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Células Estromais/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
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