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1.
Cancer ; 128(24): 4213-4222, 2022 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-36271776

RESUMEN

BACKGROUND: Acute myeloid leukemia (AML) with initial hyperleukocytosis is associated with high early mortality and a poor prognosis. The aims of this study were to delineate the underlying molecular landscape in the largest cytogenetic risk group, cytogenetically normal acute myeloid leukemia (CN-AML), and to assess the prognostic relevance of recurrent mutations in the context of hyperleukocytosis and clinical risk factors. METHODS: The authors performed a targeted sequencing of 49 recurrently mutated genes in 56 patients with newly diagnosed CN-AML and initial hyperleukocytosis of ≥100 G/L treated in the AMLCG99 study. The median number of mutated genes per patient was 5. The most common mutations occurred in FLT3 (73%), NPM1 (75%), and TET2 (45%). RESULTS: The predominant pathways affected by mutations were signaling (84% of patients), epigenetic modifiers (75% of patients), and nuclear transport (NPM1; 75%) of patients. AML with hyperleukocytosis was enriched for molecular subtypes that negatively affected the prognosis, including a high percentage of patients presenting with co-occurring mutations in signaling and epigenetic modifiers such as FLT3 internal tandem duplications and TET2 mutations. CONCLUSIONS: Despite these unique molecular features, clinical risk factors, including high white blood count, hemoglobin level, and lactate dehydrogenase level at baseline, remained the predictors for overall survival and relapse-free survival in hyperleukocytotic CN-AML.


Asunto(s)
Leucemia Mieloide Aguda , Proteínas Nucleares , Humanos , Proteínas Nucleares/genética , Nucleofosmina , Leucemia Mieloide Aguda/terapia , Mutación , Pronóstico , Tirosina Quinasa 3 Similar a fms/genética
2.
Nat Biotechnol ; 40(4): 499-506, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34725502

RESUMEN

Only a fraction of patients with cancer respond to immune checkpoint blockade (ICB) treatment, but current decision-making procedures have limited accuracy. In this study, we developed a machine learning model to predict ICB response by integrating genomic, molecular, demographic and clinical data from a comprehensively curated cohort (MSK-IMPACT) with 1,479 patients treated with ICB across 16 different cancer types. In a retrospective analysis, the model achieved high sensitivity and specificity in predicting clinical response to immunotherapy and predicted both overall survival and progression-free survival in the test data across different cancer types. Our model significantly outperformed predictions based on tumor mutational burden, which was recently approved by the U.S. Food and Drug Administration for this purpose1. Additionally, the model provides quantitative assessments of the model features that are most salient for the predictions. We anticipate that this approach will substantially improve clinical decision-making in immunotherapy and inform future interventions.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias , Biomarcadores de Tumor/genética , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Estudios Retrospectivos
3.
Cancer Discov ; 10(11): 1742-1757, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32669286

RESUMEN

We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells, and PRMT5 inhibition potently reduced MPN cell proliferation ex vivo. PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2V617F+ polycythemia vera and leukocyte and platelet counts, hepatosplenomegaly, and fibrosis in the MPLW515L model of myelofibrosis. Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis in vivo. PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN. SIGNIFICANCE: Expression of PRMT5 and E2F targets is increased in JAK2V617F+ MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2V617F/MPLW515L MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated.This article is highlighted in the In This Issue feature, p. 1611.


Asunto(s)
Factor de Transcripción E2F1/metabolismo , Redes Reguladoras de Genes/genética , Janus Quinasa 2/metabolismo , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Humanos , Metilación , Mutación , Proteína-Arginina N-Metiltransferasas/metabolismo
4.
Cancer Cell ; 38(2): 198-211.e8, 2020 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-32559497

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.


Asunto(s)
Carcinoma Ductal Pancreático/genética , Mutación , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Empalme del ARN , Transducción de Señal/genética , Proteína p53 Supresora de Tumor/genética , Animales , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Línea Celular Tumoral , Células Cultivadas , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Tratamiento con ARN de Interferencia/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
5.
Cell Rep ; 31(5): 107522, 2020 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-32330423

RESUMEN

Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment.


Asunto(s)
Presentación de Antígeno/inmunología , Catepsinas/metabolismo , Linfoma Folicular/metabolismo , Microambiente Tumoral/inmunología , Animales , Antígenos de Diferenciación de Linfocitos B/metabolismo , Citocinas/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Terapia de Inmunosupresión , Linfoma Folicular/patología , Ratones
7.
Nat Med ; 25(12): 1839-1842, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31768065

RESUMEN

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.


Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Histiocitosis/genética , Proteínas Proto-Oncogénicas c-ret/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Adolescente , Adulto , Aminopiridinas/farmacología , Benzotiazoles/farmacología , Niño , Preescolar , Femenino , Genoma Humano , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Histiocitosis/tratamiento farmacológico , Histiocitosis/patología , Humanos , Lactante , Masculino , Mutación , Ácidos Picolínicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Pirroles/farmacología , Proteínas Tirosina Quinasas Receptoras/genética , Gemelos Monocigóticos , Secuenciación del Exoma , Adulto Joven
8.
Nature ; 574(7777): 273-277, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31578525

RESUMEN

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.


Asunto(s)
Empalme Alternativo/genética , Carcinogénesis/genética , Epigénesis Genética , Leucemia Mieloide Aguda/genética , Animales , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN , Proteínas de Unión al ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Mutación/genética , ARN Polimerasa II/metabolismo , Factores de Empalme Serina-Arginina/genética , Transcriptoma
10.
Cancer Discov ; 9(10): 1452-1467, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31285298

RESUMEN

Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer, and XPO1 has been a focus of anticancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1. XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy in vivo. Proteomic characterization identified that mutant XPO1 altered the nucleocytoplasmic distribution of hundreds of proteins in a sequence-specific manner that promoted oncogenesis. XPO1 mutations preferentially sensitized cells to inhibitors of nuclear export, providing a biomarker of response to this family of drugs. These data reveal a new class of oncogenic alteration based on change-of-function mutations in nuclear export signal recognition and identify therapeutic targets based on altered nucleocytoplasmic trafficking. SIGNIFICANCE: Here, we identify that heterozygous mutations in the main nuclear exporter in eukaryotic cells, XPO1, are positively selected in cancer and promote the initiation of clonal B-cell malignancies. XPO1 mutations alter nuclear export signal recognition in a sequence-specific manner and sensitize cells to compounds in clinical development inhibiting XPO1 function.This article is highlighted in the In This Issue feature, p. 1325.


Asunto(s)
Transformación Celular Neoplásica , Señales de Exportación Nuclear , Transporte Activo de Núcleo Celular , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Expresión Génica , Genes bcl-2 , Genes myc , Humanos , Carioferinas/química , Carioferinas/genética , Carioferinas/metabolismo , Leucemia de Células B/genética , Leucemia de Células B/metabolismo , Leucemia de Células B/mortalidad , Leucemia de Células B/patología , Ratones , Mutación , Especificidad de Órganos/genética , Unión Proteica , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Proteína Exportina 1
11.
Nature ; 571(7765): 355-360, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31270458

RESUMEN

Defining the transcriptomic identity of malignant cells is challenging in the absence of surface markers that distinguish cancer clones from one another, or from admixed non-neoplastic cells. To address this challenge, here we developed Genotyping of Transcriptomes (GoT), a method to integrate genotyping with high-throughput droplet-based single-cell RNA sequencing. We apply GoT to profile 38,290 CD34+ cells from patients with CALR-mutated myeloproliferative neoplasms to study how somatic mutations corrupt the complex process of human haematopoiesis. High-resolution mapping of malignant versus normal haematopoietic progenitors revealed an increasing fitness advantage with myeloid differentiation of cells with mutated CALR. We identified the unfolded protein response as a predominant outcome of CALR mutations, with a considerable dependency on cell identity, as well as upregulation of the NF-κB pathway specifically in uncommitted stem cells. We further extended the GoT toolkit to genotype multiple targets and loci that are distant from transcript ends. Together, these findings reveal that the transcriptional output of somatic mutations in myeloproliferative neoplasms is dependent on the native cell identity.


Asunto(s)
Genotipo , Mutación , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Neoplasias/genética , Neoplasias/patología , Transcriptoma/genética , Animales , Antígenos CD34/metabolismo , Calreticulina/genética , Línea Celular , Proliferación Celular , Células Clonales/clasificación , Células Clonales/metabolismo , Células Clonales/patología , Endorribonucleasas/metabolismo , Hematopoyesis/genética , Células Madre Hematopoyéticas/clasificación , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Ratones , Modelos Moleculares , Trastornos Mieloproliferativos/clasificación , FN-kappa B/metabolismo , Neoplasias/clasificación , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Respuesta de Proteína Desplegada/genética
12.
Nature ; 569(7757): 576-580, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31092926

RESUMEN

Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer1. Chronic lymphocytic leukaemia (CLL) is a highly informative model for cancer evolution as it undergoes substantial genetic diversification and evolution after therapy2,3. The CLL epigenome is also an important disease-defining feature4,5, and growing populations of cells in CLL diversify by stochastic changes in DNA methylation known as epimutations6. However, previous studies using bulk sequencing methods to analyse the patterns of DNA methylation were unable to determine whether epimutations affect CLL populations homogeneously. Here, to measure the epimutation rate at single-cell resolution, we applied multiplexed single-cell reduced-representation bisulfite sequencing to B cells from healthy donors and patients with CLL. We observed that the common clonal origin of CLL results in a consistently increased epimutation rate, with low variability in the cell-to-cell epimutation rate. By contrast, variable epimutation rates across healthy B cells reflect diverse evolutionary ages across the trajectory of B cell differentiation, consistent with epimutations serving as a molecular clock. Heritable epimutation information allowed us to reconstruct lineages at high-resolution with single-cell data, and to apply this directly to patient samples. The CLL lineage tree shape revealed earlier branching and longer branch lengths than in normal B cells, reflecting rapid drift after the initial malignant transformation and a greater proliferative history. Integration of single-cell bisulfite sequencing analysis with single-cell transcriptomes and genotyping confirmed that genetic subclones mapped to distinct clades, as inferred solely on the basis of epimutation information. Finally, to examine potential lineage biases during therapy, we profiled serial samples during ibrutinib-associated lymphocytosis, and identified clades of cells that were preferentially expelled from the lymph node after treatment, marked by distinct transcriptional profiles. The single-cell integration of genetic, epigenetic and transcriptional information thus charts the lineage history of CLL and its evolution with therapy.


Asunto(s)
Linaje de la Célula , Epigénesis Genética , Evolución Molecular , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Secuencia de Bases , Relojes Biológicos , Linaje de la Célula/genética , Metilación de ADN , Epigenoma/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Tasa de Mutación , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Transcripción Genética
13.
Blood Adv ; 3(7): 1033-1038, 2019 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-30940638

RESUMEN

The Follicular Lymphoma (FL) International Prognostic Index (FLIPI) and FLIPI-2 are well-described clinical risk models. Age >60 years at diagnosis is a risk factor in both scores. Recently, we showed that older age is not associated with higher risk of disease progression or inferior treatment efficacy. Instead, shorter survival of older patients results mainly from an increased risk of nonrelapse deaths. This questions the value of age as a meaningful component of scores intended to predict disease-specific survival. The newly proposed PRIMA-prognostic index (PRIMA-PI) only includes ß2-microglobulin levels and bone marrow infiltration as risk factors. Here, we independently validate the PRIMA-PI in a clinical trial cohort of 475 patients with advanced FL who uniformly received cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone, and rituximab (R-CHOP) as frontline therapy. The PRIMA-PI separated 3 similar sized risk cohorts with 5-year progression-free survival (PFS) rates of 74%, 59%, and 39%, respectively (P < .0001). Furthermore, we compare the PRIMA-PI with the FLIPI and FLIPI-2. We demonstrate that the PRIMA-PI has the highest specificity to identify high-risk patients (80% for 5-year PFS) because of its superior risk stratification in patients >60 years (73% vs 33% [FLIPI] and 47% [FLIPI-2] for 5-year PFS). Thus, the PRIMA-PI is a promising clinical tool to stringently identify patients at highest risk of poor outcome after frontline R-CHOP for advanced FL, and is particularly useful in patients with older age. Further validation in non-R-CHOP treated cohorts is needed.


Asunto(s)
Factores de Edad , Linfoma Folicular/diagnóstico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/patología , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/mortalidad , Persona de Mediana Edad , Prednisona/uso terapéutico , Pronóstico , Supervivencia sin Progresión , Medición de Riesgo , Factores de Riesgo , Rituximab/uso terapéutico , Vincristina/uso terapéutico , Microglobulina beta-2/análisis
14.
Nat Commun ; 10(1): 1874, 2019 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-31015400

RESUMEN

Cancer evolution is fueled by epigenetic as well as genetic diversity. In chronic lymphocytic leukemia (CLL), intra-tumoral DNA methylation (DNAme) heterogeneity empowers evolution. Here, to comprehensively study the epigenetic dimension of cancer evolution, we integrate DNAme analysis with histone modification mapping and single cell analyses of RNA expression and DNAme in 22 primary CLL and 13 healthy donor B lymphocyte samples. Our data reveal corrupted coherence across different layers of the CLL epigenome. This manifests in decreased mutual information across epigenetic modifications and gene expression attributed to cell-to-cell heterogeneity. Disrupted epigenetic-transcriptional coordination in CLL is also reflected in the dysregulation of the transcriptional output as a function of the combinatorial chromatin states, including incomplete Polycomb-mediated gene silencing. Notably, we observe unexpected co-mapping of typically mutually exclusive activating and repressing histone modifications, suggestive of intra-tumoral epigenetic diversity. Thus, CLL epigenetic diversification leads to decreased coordination across layers of epigenetic information, likely reflecting an admixture of cells with diverging cellular identities.


Asunto(s)
Linfocitos B/metabolismo , Cromatina/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Metilación de ADN , Evolución Molecular , Silenciador del Gen , Genes de las Cadenas Pesadas de las Inmunoglobulinas/genética , Voluntarios Sanos , Código de Histonas/genética , Histonas/genética , Histonas/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Proteínas del Grupo Polycomb/genética , Proteínas del Grupo Polycomb/metabolismo , Regiones Promotoras Genéticas/genética , Análisis de Secuencia de ARN , Análisis de la Célula Individual/métodos , Secuenciación del Exoma
15.
Cancer Cell ; 35(3): 369-384.e7, 2019 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-30799057

RESUMEN

RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML. The effects of RBM39 loss on splicing further resulted in preferential lethality of spliceosomal mutant AML, providing a strategy for treatment of AML bearing RBP splicing mutations.


Asunto(s)
Redes Reguladoras de Genes , Marcación de Gen/métodos , Leucemia Mieloide Aguda/patología , Proteómica/métodos , Proteínas de Unión al ARN/genética , Regulación hacia Arriba , Empalme Alternativo , Animales , Sistemas CRISPR-Cas , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Células HL-60 , Proteínas de Homeodominio/genética , Humanos , Células Jurkat , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Ratones , Trasplante de Neoplasias , Pronóstico , Proteínas de Unión al ARN/metabolismo , Análisis de Secuencia de ARN/métodos , Análisis de Supervivencia
16.
Blood ; 132(16): 1695-1702, 2018 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-30126979

RESUMEN

Duodenal-type follicular lymphoma (DTFL) is a rare and highly indolent follicular lymphoma (FL) variant. It is morphologically and immunophenotypically indistinguishable from typical FL, characterized by restricted involvement of intestinal mucosa, and lacks extraintestinal manifestations. The molecular determinants of this distinct clinical behavior are largely unknown. Thirty-eight diagnostic biopsies from patients with DTFL were evaluated. The 10-year overall survival rate was 100% in clinically evaluable patients (n = 19). We compared the targeted mutation profile of DTFL (n = 31), limited-stage typical FL (LSTFL; n = 17), and advanced-stage typical FL (ASTFL; n = 241). The mutation frequencies of recurrently mutated genes, including CREBBP, TNFRSF14/HVEM, and EZH2 were not significantly different. However, KMT2D was less commonly mutated in DTFL (52%) and LSTFL (24%) as compared with ASTFL (79%). In ASTFL, 41% of KMT2D-mutated cases harbored multiple mutations in KMT2D, as compared with only 12% in LSTFL (P = .019) and 0% in DTFL (P < .0001). Whole exome and targeted sequencing of DTFL revealed high mutation frequencies of EEF1A1 (35%) and HVCN1 (22%). We compared the immune microenvironment gene expression signatures of DTFL (n = 8) and LSTFL (n = 7). DTFL clearly separated from LSTFL by unsupervised, hierarchical clustering of 147 chemokines and cytokines and was enriched for a chronic inflammation signature. In conclusion, the mutational landscape of DTFL is highly related to typical FL. The lower frequency of multiple mutations in KMT2D in DTFL and LSTFL indicates an increasing selection pressure for complete KMT2D loss in ASTFL pathogenesis. The highly dissimilar immune microenvironment of DTFL suggests a central role in the biology of this disease.


Asunto(s)
Biomarcadores de Tumor/genética , Proteínas de Unión al ADN/genética , Neoplasias Duodenales/inmunología , Inflamación/inmunología , Linfoma Folicular/inmunología , Mutación , Proteínas de Neoplasias/genética , Adulto , Anciano , Anciano de 80 o más Años , Citocinas/metabolismo , Análisis Mutacional de ADN , Neoplasias Duodenales/genética , Neoplasias Duodenales/patología , Exoma , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Inflamación/genética , Inflamación/patología , Linfoma Folicular/genética , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Microambiente Tumoral , Adulto Joven
17.
Cancer Cell ; 34(2): 225-241.e8, 2018 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-30107174

RESUMEN

Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 share convergent effects on aberrant splicing of mRNAs that promote nuclear factor κB signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity.


Asunto(s)
Mutación , Neoplasias/genética , Empalmosomas , Animales , Caspasa 8/genética , Femenino , Hematopoyesis , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/fisiología , Fosfoproteínas/genética , Factores de Empalme de ARN/genética , Factores de Empalme Serina-Arginina/genética
18.
Oncogene ; 37(34): 4692-4710, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29755131

RESUMEN

Estrogen receptor alpha (ERα) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERα require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERα control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERα activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERα enhancers. Correspondingly, KMT2C loss impairs estrogen-driven breast cancer proliferation but has no effect on ER- breast cells. Whereas KMT2C loss disrupts estrogen-driven proliferation, it conversely promotes tumor outgrowth under hormone-depleted conditions. In accordance, KMT2C is one of the most frequently mutated genes in ER-positive breast cancer with KMT2C deletion correlating with significantly shorter progression-free survival on anti-estrogen therapy. From a therapeutic standpoint, KMT2C-depleted cells that develop hormone-independence retain their dependence on ERα, displaying ongoing sensitivity to ERα antagonists. We conclude that KMT2C is a key regulator of ERα activity whose loss uncouples breast cancer proliferation from hormone abundance.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Unión al ADN/metabolismo , Receptor alfa de Estrógeno/metabolismo , Estrógenos/metabolismo , Proteínas de Neoplasias/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Proliferación Celular/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Células HEK293 , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Supervivencia sin Progresión , Transducción de Señal/fisiología
19.
J Exp Med ; 215(6): 1729-1747, 2018 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-29643185

RESUMEN

Additional sex combs like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. Chromatin immunoprecipitation followed by next-generation sequencing analysis demonstrated opposing effects of wild-type and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.


Asunto(s)
Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Hematopoyesis , Leucemia/genética , Leucemia/patología , Mutación/genética , Proteínas Represoras/genética , Adulto , Animales , Secuencia de Bases , Epigénesis Genética , Regulación Leucémica de la Expresión Génica , Técnicas de Sustitución del Gen , Genoma Humano , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/patología , Ratones , Mutagénesis/genética , Síndromes Mielodisplásicos/patología , Fenotipo , Unión Proteica , Proteínas Represoras/metabolismo , Transcripción Genética
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