RESUMEN
Internal tandem duplication mutations in fms-like tyrosine kinase 3 (FLT3-ITD) are recurrent in acute myeloid leukemia (AML) and increase the risk of relapse. Clinical responses to FLT3 inhibitors (FLT3i) include myeloid differentiation of the FLT3-ITD clone in nearly half of patients through an unknown mechanism. We identified enhancer of zeste homolog 2 (EZH2), a component of polycomb repressive complex 2 (PRC2), as a mediator of this effect using a proteomic-based screen. FLT3i downregulated EZH2 protein expression and PRC2 activity on H3K27me3. FLT3-ITD and loss-of-function mutations in EZH2 are mutually exclusive in human AML. We demonstrated that FLT3i increase myeloid maturation with reduced stem/progenitor cell populations in murine Flt3-ITD AML. Combining EZH1/2 inhibitors with FLT3i increased terminal maturation of leukemic cells and reduced leukemic burden. Our data suggest that reduced EZH2 activity following FLT3 inhibition promotes myeloid differentiation of FLT3-ITD leukemic cells, providing a mechanistic explanation for the clinical observations. These results demonstrate that in addition to its known cell survival and proliferation signaling, FLT3-ITD has a second, previously undefined function to maintain a myeloid stem/progenitor cell state through modulation of PRC2 activity. Our findings support exploring EZH1/2 inhibitors as therapy for FLT3-ITD AML.
Asunto(s)
Leucemia Mieloide Aguda , Proteínas Tirosina Quinasas , Humanos , Animales , Ratones , Proteínas Tirosina Quinasas/genética , Complejo Represivo Polycomb 2/genética , Proteómica , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/uso terapéuticoRESUMEN
PURPOSE: DNMT3A mutations confer a poor prognosis in acute myeloid leukemia (AML), but the molecular mechanisms downstream of DNMT3A mutations in disease pathogenesis are not completely understood, limiting targeted therapeutic options. The role of miRNA in DNMT3A-mutant AML pathogenesis is understudied. EXPERIMENTAL DESIGN: DNA methylation and miRNA expression was evaluated in human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. The treatment efficacy and molecular mechanisms of TLR7/8-directed therapies on DNMT3A-mutant AML were evaluated in vitro on human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. RESULTS: miR-196b is hypomethylated and overexpressed in DNMT3A-mutant AML and is associated with poor patient outcome. miR-196b overexpression in DNMT3A-mutant AML is important to maintain an immature state and leukemic cell survival through repression of TLR signaling. The TLR7/8 agonist resiquimod induces dendritic cell-like differentiation with costimulatory molecule expression in DNMT3A-mutant AML cells and provides a survival benefit to Dnmt3a/Flt3-mutant AML mice. The small molecule bryostatin-1 augments resiquimod-mediated AML growth inhibition and differentiation. CONCLUSIONS: DNMT3A loss-of-function mutations cause miRNA locus-specific hypomethylation and overexpression important for mutant DNMT3A-mediated pathogenesis and clinical outcomes. Specifically, the overexpression of miR-196b in DNMT3A-mutant AML creates a novel therapeutic vulnerability by controlling sensitivity to TLR7/8-directed therapies.
Asunto(s)
Leucemia Mieloide Aguda , MicroARNs , Animales , Brioestatinas/uso terapéutico , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Metilasas de Modificación del ADN/genética , Humanos , Inmunidad Innata , Leucemia Mieloide Aguda/tratamiento farmacológico , Ratones , MicroARNs/genética , MicroARNs/uso terapéutico , Mutación , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/uso terapéuticoRESUMEN
Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML. SIGNIFICANCE: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a "writer-reader" epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587.
Asunto(s)
Leucemia Mieloide Aguda , Oncogenes , Cromatina/genética , Epigénesis Genética , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas de Neoplasias , Proteínas Nucleares , Factores de TranscripciónRESUMEN
PURPOSE OF REVIEW: Clonal heterogeneity is a significant obstacle to successful treatment of patients with acute myeloid leukemia (AML). Here, we review new advances in the understanding of genetic heterogeneity in AML using single-cell DNA-sequencing technology. RECENT FINDINGS: New genomics and immunologic discovery tools have provided single-cell resolution maps of the clonal architecture of AML. The use of these technologies reveals the mutational landscape of AML at diagnosis, during treatment, and at relapse has an enormous degree of clonal complexity and diversity that is poised to adapt and evolve under environmental pressures. SUMMARY: AML is a complex ecosystem of competing and cooperating clones undergoing constant evolution and selection.
Asunto(s)
Evolución Clonal , Heterogeneidad Genética , Leucemia Mieloide Aguda/genética , Animales , Análisis Mutacional de ADN , Humanos , Mutación , Análisis de Secuencia de ARN , Análisis de la Célula IndividualRESUMEN
Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later1-3. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.
Asunto(s)
Células Clonales/patología , Análisis Mutacional de ADN , Mutación , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Análisis de la Célula Individual , Separación Celular , Células Clonales/metabolismo , Humanos , InmunofenotipificaciónAsunto(s)
Leucemia , MicroARNs , Humanos , Inflamación , Células Progenitoras Mieloides , FN-kappa BRESUMEN
We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell-like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2-containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.
Asunto(s)
Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , MicroARNs/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Diferenciación Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Cromosomas Humanos Par 11/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Ciclinas/metabolismo , Células Madre Embrionarias/metabolismo , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Mieloide Aguda/genética , Ratones Endogámicos C57BL , MicroARNs/genética , Oncogenes , ARN Interferente Pequeño/metabolismoRESUMEN
UNLABELLED: Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3(ITD)) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3(ITD)/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3(ITD) myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation. SIGNIFICANCE: DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3(ITD)-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501-15. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 461.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/genética , Haploinsuficiencia , Leucemia Mieloide Aguda/etiología , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Penetrancia , Secuencias Repetidas en Tándem , Tirosina Quinasa 3 Similar a fms/genética , Animales , Biopsia , Médula Ósea , Transformación Celular Neoplásica/genética , Análisis por Conglomerados , Metilación de ADN , ADN Metiltransferasa 3A , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Sitios Genéticos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Cariotipo , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Ratones , Ratones Transgénicos , MutaciónRESUMEN
In this issue of Blood, the articles by Shaham et al and Wang et al are the first to identify microRNA 486 (miR-486) as a requisite oncomiR and credible therapeutic target in myeloid leukemia of Down syndrome (ML-DS) and chronic myeloid leukemia (CML) by showing that these 2 leukemias co-opt miR-486 functions in normal erythroid progenitor progrowth and survival activity.
Asunto(s)
Proliferación Celular/genética , Síndrome de Down/genética , Resistencia a Antineoplásicos/genética , Eritropoyesis/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Células Progenitoras de Megacariocitos y Eritrocitos/fisiología , MicroARNs/fisiología , Animales , HumanosRESUMEN
Hox genes are key regulators of development. In mammals, the study of these genes is greatly confounded by their large number, overlapping functions and interspersed shared enhancers. Here, we describe the use of a novel recombineering strategy to introduce simultaneous frameshift mutations into the flanking Hoxa9, Hoxa10 and Hoxa11 genes, as well as their paralogs on the HoxD cluster. The resulting Hoxa9,10,11 mutant mice displayed dramatic synergistic homeotic transformations of the reproductive tracts, with the uterus anteriorized towards oviduct and the vas deferens anteriorized towards epididymis. The Hoxa9,10,11 mutant mice also provided a genetic setting that allowed the discovery of Hoxd9,10,11 redundant reproductive tract patterning function. Both shared and distinct Hox functions were defined. Hoxd9,10,11 play a crucial role in the regulation of uterine immune function. Non-coding non-polyadenylated RNAs were among the key Hox targets, with dramatic downregulation in mutants. We observed Hox cross-regulation of transcription and splicing. In addition, we observed a surprising anti-dogmatic apparent posteriorization of the uterine epithelium. In caudal regions of the uterus, the normal simple columnar epithelium flanking the lumen was replaced by a pseudostratified transitional epithelium, normally found near the more posterior cervix. These results identify novel molecular functions of Hox genes in the development of the male and female reproductive tracts.
Asunto(s)
Genes Homeobox , Ingeniería Genética/métodos , Proteínas de Homeodominio/metabolismo , Útero/metabolismo , Conducto Deferente/metabolismo , Animales , Tipificación del Cuerpo , Cromosomas Artificiales Bacterianos/genética , Epitelio/metabolismo , Femenino , Fertilidad , Mutación del Sistema de Lectura , Proteínas de Homeodominio/genética , Masculino , Ratones , Mutagénesis , Útero/embriología , Útero/inmunología , Conducto Deferente/embriologíaRESUMEN
The coding single nucleotide polymorphism GFI136N in the human gene growth factor independence 1 (GFI1) is present in 3%-7% of whites and increases the risk for acute myeloid leukemia (AML) by 60%. We show here that GFI136N, in contrast to GFI136S, lacks the ability to bind to the Gfi1 target gene that encodes the leukemia-associated transcription factor Hoxa9 and fails to initiate histone modifications that regulate HoxA9 expression. Consistent with this, AML patients heterozygous for the GFI136N variant show increased HOXA9 expression compared with normal controls. Using ChipSeq, we demonstrate that GFI136N specific epigenetic changes are also present in other genes involved in the development of AML. Moreover, granulomonocytic progenitors, a bone marrow subset from which AML can arise in humans and mice, show a proliferative expansion in the presence of the GFI136N variant. In addition, granulomonocytic progenitors carrying the GFI136N variant allele have altered gene expression patterns and differ in their ability to grow after transplantation. Finally, GFI136N can accelerate a K-RAS driven fatal myeloproliferative disease in mice. Our data suggest that the presence of a GFI136N variant allele induces a preleukemic state in myeloid precursors by deregulating the expression of Hoxa9 and other AML-related genes.
Asunto(s)
Proteínas de Unión al ADN/genética , Epigénesis Genética , Proteínas de Homeodominio/genética , Trastornos Mieloproliferativos/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Transcripción/genética , Animales , Análisis por Conglomerados , Proteínas de Unión al ADN/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Hematopoyesis/genética , Histonas/metabolismo , Humanos , Ratones , Ratones Transgénicos , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/patología , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/mortalidad , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factores de Transcripción/metabolismoRESUMEN
MicroRNA (miRNA) play important roles in the development and physiological function of hematopoietic stem/progenitor and mature cell lineages. In addition, deregulated miRNA expression and subsequent gene expression changes are associated with hematologic diseases including myelodysplastic syndromes and acute myeloid leukemia. This review focuses on myelopoiesis as a model to highlight the involvement of miRNA in the regulation of normal and malignant cellular signaling pathways. By incorporating miRNA regulation into well-established myeloid signal transduction pathways, we hope to shed light on targetable factors both upstream and downstream of miRNA signaling. These pathway-specific miRNA functions suggest scenarios wherein miRNA-based therapeutics may be beneficial either alone or in combination with current therapies.
Asunto(s)
MicroARNs/metabolismo , Células Mieloides/metabolismo , Transducción de Señal/fisiología , Animales , Hematopoyesis/fisiologíaRESUMEN
K-RAS mutations are found in approximately 30% of lung cancers. The transcription factor Krüppel-like Factor 5 (KLF5) has been shown to mediate cellular transformation signaling events downstream of oncogenic RAS in other cancers, but a role for KLF5 in lung tumorigenesis has not been defined. We show here that knockdown of KLF5 expression significantly decreased anchorage-independent growth, but did not affect proliferation of human lung adenocarcinoma cells. Moreover, Klf5 is not required for lung tumor formation in an inducible oncogenic K-Ras(G12D) mouse model of lung tumorigenesis, and non-small cell lung cancer patients expressing high levels of KLF5 (21/258) have a significantly better disease-specific survival than those with intermediate to no KLF5 expression. Further, KLF5 knockdown in K-RAS-mutant human lung cancer cells resulted in a fivefold increase in ATP-binding cassette, subfamily G (WHITE), member 2 (ABCG2), an anthracycline drug transporter, which lead to significantly increased resistance to doxorubicin treatment, a chemotherapeutic agent clinically used to treat lung cancer. In summary, while KLF5 is not required for oncogenic mutant K-Ras-induced lung tumorigenesis, KLF5 regulation of ABCG2 expression may be important for chemotherapeutic resistance and patient survival.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas ras/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/genética , Análisis de Varianza , Animales , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Células Cultivadas , Inmunoprecipitación de Cromatina , Supervivencia sin Enfermedad , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Factores de Transcripción de Tipo Kruppel/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Matrices Tisulares , Proteínas ras/genéticaRESUMEN
The CHEK2 (Chk2 in mice) polymorphic variant, CHEK2*1100delC, leads to genomic instability and is associated with an increased risk for breast cancer. The Ron receptor tyrosine kinase is overexpressed in a large fraction of human breast cancers. Here, we asked whether the low penetrance Chk2*1100delC allele alters the tumorigenic efficacy of Ron in the development of mammary tumors in a mouse model. Our data demonstrate that Ron overexpression on a Chk2*1100delC background accelerates the development of mammary tumors, and shows that pathways mediated by a tyrosine kinase receptor and a regulator of the cell cycle can act to hasten tumorigenesis in vivo.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Mamarias Animales/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Animales , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Ciclo Celular , División Celular , Línea Celular Tumoral , Quinasa de Punto de Control 2 , Femenino , Variación Genética , Humanos , Inmunohistoquímica , Neoplasias Mamarias Animales/patología , Ratones , Polimorfismo Genético , Factores de Riesgo , Eliminación de SecuenciaRESUMEN
The Ron receptor tyrosine kinase is expressed in normal breast tissue and is overexpressed in approximately 50% of human breast cancers. Despite the recent studies on Ron in breast cancer, nothing is known about the importance of this protein during breast development. To investigate the functional significance of Ron in the normal mammary gland, we compared mammary gland development in wild-type mice to mice containing a targeted ablation of the tyrosine kinase (TK) signaling domain of Ron (TK-/-). Mammary glands from RonTK-/- mice exhibited accelerated pubertal development including significantly increased ductal extension and branching morphogenesis. While circulating levels of estrogen, progesterone, and overall rates of epithelial cell turnover were unchanged, significant increases in phosphorylated MAPK, which predominantly localized to the epithelium, were associated with increased branching morphogenesis. Additionally, purified RonTK-/- epithelial cells cultured ex vivo exhibited enhanced branching morphogenesis, which was reduced upon MAPK inhibition. Microarray analysis of pubertal RonTK-/- glands revealed 393 genes temporally impacted by Ron expression with significant changes observed in signaling networks regulating development, morphogenesis, differentiation, cell motility, and adhesion. In total, these studies represent the first evidence of a role for the Ron receptor tyrosine kinase as a critical negative regulator of mammary development.
Asunto(s)
Glándulas Mamarias Animales/fisiología , Morfogénesis/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Transducción de Señal/fisiología , Animales , Adhesión Celular/fisiología , Movimiento Celular/fisiología , Células Cultivadas , Femenino , Regulación del Desarrollo de la Expresión Génica , Glándulas Mamarias Animales/crecimiento & desarrollo , Ratones , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
The Ron receptor tyrosine kinase is overexpressed in approximately half of all human colon cancers. Increased Ron expression positively correlates with tumor progression, and reduction of Ron levels in human colon adenocarcinoma cells reverses their tumorigenic properties. Nearly all colon tumors demonstrate loss of the adenomatous polyposis coli (APC) tumor suppressor, an early initiating event, subsequently leading to beta-catenin stabilization. To understand the role of Ron in early stage intestinal tumorigenesis, we generated Apc-mutant (Apc(Min/+)) mice with and without Ron signaling. Interestingly, we report here that significantly more Apc(Min/+) Ron-deficient mice developed higher tumor burden than Apc(Min/+) mice with wild-type Ron. Even though baseline levels of intestinal crypt proliferation were increased in the Apc(Min/+) Ron-deficient mice, loss of Ron did not influence tumor size or histological appearance of the Apc(Min/+) adenomas, nor was beta-catenin localization changed compared to Apc(Min/+) mice with Ron. Together, these data suggest that Ron may be important in normal intestinal tissue homeostasis, but that the expression of this receptor is not required for the formation and growth of adenomas in Apc(Min/+) mice.