Asunto(s)
Aminoglicósidos , Protocolos de Quimioterapia Combinada Antineoplásica , Gemtuzumab , Leucemia Mieloide Aguda , Humanos , Gemtuzumab/uso terapéutico , Gemtuzumab/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Aminoglicósidos/uso terapéutico , Aminoglicósidos/administración & dosificación , Método Doble Ciego , Masculino , Femenino , Persona de Mediana Edad , Inducción de Remisión , Anciano , Quimioterapia de Inducción , Adulto , Resultado del Tratamiento , Bencimidazoles , Compuestos de FenilureaRESUMEN
Simultaneous inhibition of multiple kinases has been suggested to provide synergistic effects on inhibition of tumour growth and resistance. This study describes the design, synthesis and evaluation of 18 compounds incorporating a pyrrolo[2,3-d]pyrimidine scaffold for dual inhibition of epidermal growth factor receptor kinase (EGFR) and aurora kinase A (AURKA). Compounds 1-18 of this study demonstrate nanomolar inhibition of EGFR and micromolar inhibition of AURKA. Compounds 1-18 allow for a structure-activity relationships (SAR) analysis of the 4-anilino moiety for dual EGFR and AURKA inhibition. Compound 6, a 4-methoxyphenylpyrrolo[2,3-d]pyrimidin-4-amine, demonstrates single-digit micromolar inhibition of both AURKA and EGFR and provides evidence of a single molecule with dual activity against EGFR and AURKA. Compound 2, the most potent inhibitor of EGFR and AURKA from this series, has been further evaluated in four different squamous cell head and neck cancer cell lines for downstream effects resulting from AURKA and EGFR inhibition.
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Aurora Quinasa A/antagonistas & inhibidores , Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Aurora Quinasa A/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCF(Skp2)-directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement.
Asunto(s)
Linfoma de Células B/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Ácidos Anacárdicos/farmacología , Animales , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Análisis por Conglomerados , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma de Células B/genética , Ratones , Ratones Transgénicos , Poliploidía , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal , Sumoilación/efectos de los fármacos , Transcripción Genética , Enzimas Activadoras de Ubiquitina/genética , Enzimas Activadoras de Ubiquitina/metabolismoRESUMEN
To ascertain the genetic basis of a paroxysmal nocturnal hemoglobinuria (PNH) case without somatic mutations in PIGA, we performed deep next-generation sequencing on all exons of known genes of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. We identified a heterozygous germline splice site mutation in PIGT and a somatic 8-MB deletion in granulocytes affecting the other copy of PIGT. PIGA is essential for GPI anchor synthesis, whereas PIGT is essential for attachment of the preassembled GPI anchor to proteins. Although a single mutation event in the X-chromosomal gene PIGA is known to cause GPI-anchored protein deficiency, 2 such hits are required in the autosomal gene PIGT. Our data indicate that PNH can occur even in the presence of fully assembled GPI if its transfer to proteins is defective in hematopoietic stem cells.
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Aciltransferasas/genética , Mutación de Línea Germinal/genética , Hemoglobinuria Paroxística/genética , Mutación/genética , Adulto , Empalme Alternativo/genética , Animales , Células CHO , Estudios de Casos y Controles , Hibridación Genómica Comparativa , Cricetulus , Exones/genética , Femenino , Citometría de Flujo , Genes Ligados a X , Humanos , Hibridación Fluorescente in Situ , Análisis de Secuencia de ADN , Eliminación de SecuenciaRESUMEN
Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.
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Linfocitos B/patología , Regulación Enzimológica de la Expresión Génica/fisiología , Linfoma de Células B/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Apoptosis , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , Linfocitos B/metabolismo , Células 3T3 BALB , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Proliferación Celular , Transformación Celular Neoplásica , Células Cultivadas , Inmunoprecipitación de Cromatina , Ensayo de Cambio de Movilidad Electroforética , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Luciferasas/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , ARN Mensajero/genética , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
How lymphoma cells (LCs) invade the brain during the development of central nervous system lymphoma (CNSL) is unclear. We found that NF-κB-induced gliosis promotes CNSL in immunocompetent mice. Gliosis elevated cell-adhesion molecules, which increased LCs in the brain but was insufficient to induce CNSL. Astrocyte-derived CCL19 was required for gliosis-induced CNSL. Deleting CCL19 in mice or CCR7 from LCs abrogated CNSL development. Two-photon microscopy revealed LCs transiently entering normal brain parenchyma. Astrocytic CCL19 enhanced parenchymal CNS retention of LCs, thereby promoting CNSL formation. Aged, gliotic wild-type mice were more susceptible to forming CNSL than young wild-type mice, and astrocytic CCL19 was observed in both human gliosis and CNSL. Therefore, CCL19-CCR7 interactions may underlie an increased age-related risk for CNSL.
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Envejecimiento/patología , Neoplasias del Sistema Nervioso Central/patología , Quimiocina CCL19/metabolismo , Gliosis/patología , Linfoma/patología , Adolescente , Adulto , Anciano , Animales , Astrocitos/metabolismo , Astrocitos/patología , Barrera Hematoencefálica/citología , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/patología , Línea Celular Tumoral/trasplante , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/cirugía , Quimiocina CCL19/genética , Quimiocina CXCL12 , Modelos Animales de Enfermedad , Femenino , Gliosis/diagnóstico por imagen , Humanos , Microscopía Intravital , Linfoma/diagnóstico por imagen , Linfoma/cirugía , Masculino , Ratones , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica , Persona de Mediana Edad , FN-kappa B/metabolismo , Receptores CCR7/genética , Receptores CCR7/metabolismo , Imagen de Lapso de Tiempo , Adulto JovenRESUMEN
Human metapneumovirus (hMPV) is an important cause of lower respiratory tract infection. In healthy subjects infections are usually mild and rarely necessitate hospitalization. However, more serious outcomes have been described for allogeneic stem cell transplant recipients. This study reports an outbreak of hMPV A2 infection in severely immunocompromised adult hematologic cancer patients in a tertiary care unit. HMPV RNA was detected in bronchoalveolar lavage or produced sputum from patients presenting with typical clinical features. A total of 15 patients were diagnosed in a period of 7 weeks. Molecular subtyping revealed infection with genotype A2a virus, implicating nosocomial transmission. Eleven patients (73%) were treated with intravenous immunoglobulins and ribavirin. Ten patients (65%) presented with severe dyspnea, five (33%) required mechanical ventilation. Four patients (26.6%) died from hMPV-associated pneumonia and consequent multi-organ failure. Thus, hMPV is a critical pathogen for patients with hematologic cancers warranting early detection.
Asunto(s)
Brotes de Enfermedades , Neoplasias Hematológicas/complicaciones , Metapneumovirus , Infecciones por Paramyxoviridae/epidemiología , Infecciones por Paramyxoviridae/etiología , Adulto , Anciano , Antivirales/uso terapéutico , Infección Hospitalaria , Femenino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunidad Celular , Huésped Inmunocomprometido , Inmunoglobulinas Intravenosas , Masculino , Metapneumovirus/genética , Metapneumovirus/inmunología , Metapneumovirus/aislamiento & purificación , Persona de Mediana Edad , Infecciones por Paramyxoviridae/diagnóstico , Infecciones por Paramyxoviridae/tratamiento farmacológico , Análisis de Secuencia de ADN , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Induction high-dose chemotherapy followed by myeloablative melphalan (HD-Mel) treatment and autologous hematopoietic stem-cell support (autoSCT) is a standard treatment for multiple myeloma (MM) either upfront or in relapse after conventional treatment. We performed a retrospective analysis of consecutive patients undergoing a late repeat HD-Mel/autoSCT treatment for MM. METHODS: Data from 24 consecutive patients with MM who underwent a myeloablative treatment with HD-Mel late after completion of upfront first high-dose therapy were assessed for toxicity, response, progression-free survival (PFS) and time to next treatment (TTNT). These data were correlated with the results obtained after the initial high dose therapy and autoSCT. RESULTS: A total of 23 patients were treated with novel drugs (lenalidomide, thalidomide, bortezomib) after relapse to initial autoSCT. The median overall survival (OS) of all patients was 90 months. 19 patients (79%) achieved a very good partial remission (VGPR) or complete remission (CR) after initial autoSCT, compared with 42% after late autoSCT. PFS and TTNT were 19 and 24 months after initial compared with 13 and 21 months after late autoSCT. Univariate analysis identified initial response duration and the achievement of a CR/VGPR after the initial transplantation to be associated with prolonged response after repeat autoSCT. CONCLUSIONS: Our data indicate that late high-dose treatment followed by autoSCT is safe and effective after upfront intensive treatment, can bridge to allogeneic SCT, and encourage collection of an additional graft.
RESUMEN
The Cks1 component of the SCF(Skp2) complex is necessary for p27(Kip1) ubiquitylation and degradation. Cks1 expression is elevated in various B cell malignancies including Burkitt lymphoma and multiple myeloma. We have previously shown that loss of Cks1 results in elevated p27(Kip1) levels and delayed tumor development in a mouse model of Myc-induced B cell lymphoma. Surprisingly, loss of Skp2 in the same mouse model also resulted in elevated p27(Kip1) levels but exhibited no impact on tumor onset. This raises the possibility that Cks1 could have other oncogenic activities than suppressing p27(Kip1). To challenge this notion we have targeted overexpression of Cks1 to B cells using a conditional retroviral bone marrow transduction-transplantation system. Despite potent ectopic overexpression, Cks1 was unable to promote B cell hyperproliferation or B cell malignancies, indicating that Cks1 is not oncogenic when overexpressed in B cells. Since Skp2 overexpression can drive T-cell tumorigenesis or other cancers we also widened the quest for oncogenic activity of Cks1 by ubiquitously expressing Cks1 in hematopoetic progenitors. At variance with c-Myc overexpression, which caused acute myeloid leukemia, Cks1 overexpression did not induce myeloproliferation or leukemia. Therefore, despite being associated with a poor prognosis in various malignancies, sole Cks1 expression is insufficient to induce lymphoma or a myeloproliferative disease in vivo.
Asunto(s)
Quinasas CDC2-CDC28/metabolismo , Proliferación Celular , Regulación Neoplásica de la Expresión Génica/fisiología , Neoplasias Hematológicas/metabolismo , Linfoma de Células B/metabolismo , Neoplasias/fisiopatología , Animales , Médula Ósea/metabolismo , Citometría de Flujo , Proteínas Fluorescentes Verdes/metabolismo , Immunoblotting , Ratones , Ratones Transgénicos , Neoplasias/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , RetroviridaeRESUMEN
Cks1 is an activator of the SCF(Skp2) ubiquitin ligase complex that targets the cell cycle inhibitor p27(Kip1) for degradation. The loss of Cks1 results in p27(Kip1) accumulation and decreased proliferation and inhibits tumorigenesis. We identify here a function of Cks1 in mammalian cell cycle regulation that is independent of p27(Kip1). Specifically, Cks1(-/-); p27(Kip1-/-) mouse embryonic fibroblasts retain defects in the G(1)-S phase transition that are coupled with decreased Cdk2-associated kinase activity and defects in proliferation that are associated with Cks1 loss. Furthermore, concomitant loss of Cks1 does not rescue the tumor suppressor function of p27(Kip1) that is manifest in various organs of p27(Kip1-/-) mice. In contrast, defects in mitotic entry and premature senescence manifest in Cks1(-/-) cells are p27(Kip1) dependent. Collectively, these findings establish p27(Kip1)-independent functions of Cks1 in regulating the G(1)-S transition.
Asunto(s)
Quinasas CDC2-CDC28/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Puntos de Control de la Fase S del Ciclo Celular/fisiología , Animales , Quinasas CDC2-CDC28/deficiencia , Quinasas CDC2-CDC28/genética , Proliferación Celular , Células Cultivadas , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Quinasas Ciclina-Dependientes/metabolismo , Femenino , Fibroblastos/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/fisiología , Puntos de Control de la Fase G2 del Ciclo Celular/fisiología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Proteínas Quinasas Asociadas a Fase-S/metabolismoRESUMEN
Squamous cell cancer of the head and neck (SCCHN) is the sixth leading cause for cancer deaths worldwide. Despite extense knowledge of risk factors and pathogenesis about 50 percent of all patients and essentially every patient with metastatic SCCHN eventually die from this disease. We analyzed the clinical data and performed immunohistochemistry for Epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurora-A) expression in 180 SCCHN patients. Patients characterized by elevated EGFR and elevated Aurora-A protein expression in tumor tissue represent a risk group with poor disease-free and overall survival (EGFR(low)Aurora-A(low) versus EGFR(high)Aurora-A(high), p = 0.024). Treating SCCHN cell lines with a pan-Aurora kinase inhibitor resulted in defective cytokinesis, polyploidy and apoptosis, which was effective irrespective of the EGFR status. Combined Aurora kinase and EGFR targeting using a monoclonal anti-EGFR antibody was more effective compared to single EGFR and Aurora kinase inhibition. Comparing pan-Aurora kinase and Aurora-A targeting hints towards a strong and clinically relevant biological effect mediated via Aurora kinase B. Taken together, our findings characterize a new poor risk group in SCCHN patients defined by elevated EGFR and Aurora-A protein expression. Our results demonstrate that combined targeting of EGFR and Aurora kinases represents a therapeutic means to activate cell cycle checkpoints and apoptosis in SCCHN.
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Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/enzimología , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de Cabeza y Cuello/enzimología , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Línea Celular Tumoral , Cetuximab , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Serina-Treonina Quinasas/metabolismo , Tasa de Supervivencia , Factores de Tiempo , Regulación hacia ArribaAsunto(s)
Diagnóstico por Imagen/métodos , Atrios Cardíacos/patología , Neoplasias Cardíacas/diagnóstico , Linfoma de Células B/diagnóstico , Neoplasias del Mediastino/diagnóstico por imagen , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Diagnóstico Diferencial , Femenino , Fluorodesoxiglucosa F18 , Estudios de Seguimiento , Neoplasias Cardíacas/tratamiento farmacológico , Humanos , Linfoma de Células B/tratamiento farmacológico , Imagen por Resonancia Cinemagnética/métodos , Neoplasias del Mediastino/diagnóstico , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Medición de Riesgo , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoAsunto(s)
Antineoplásicos/uso terapéutico , Everolimus/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Everolimus/administración & dosificación , Everolimus/efectos adversos , Humanos , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/patología , Quimioterapia de Mantención , Resultado del TratamientoRESUMEN
PURPOSE: To assess whether the poor prognosis of ZAP70-positive B-cell chronic lymphocytic leukemia (CLL) is associated with the overexpression of ABC transporter genes that are responsible for pleiotropic drug resistance. MATERIALS AND METHODS: The transcript level of ten drug transporters was analyzed using semiquantitative and quantitative RT-PCR in control hematopoietic cells, in 41 CLL patient samples and in 5 lymphoma cell lines. ZAP70 status was determined by immunoblotting. RESULTS: Of all analyzed transporters, MDR1, MDR2, MRP1, MRP4, MRP5, and MRP7 were expressed at a significantly higher level in B lymphocytes when compared with other hematopoietic cells in peripheral blood. A subgroup of 41 CLL patient samples showed similar or higher expression of these genes than control B cells, and CLL cells exhibited high expression when compared with multiple lymphoma cell lines. No significant correlation between ZAP70 expression and ABC transporter expression was observed. CONCLUSION: The ZAP70 status is independent of the multidrug resistance phenotype in CLL.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteína Tirosina Quinasa ZAP-70/genética , Proteína Tirosina Quinasa ZAP-70/fisiología , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Células Sanguíneas/metabolismo , Células Sanguíneas/patología , Resistencia a Antineoplásicos/genética , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/metabolismo , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Fenotipo , Células Tumorales Cultivadas , Proteína Tirosina Quinasa ZAP-70/metabolismoRESUMEN
The universal cyclin-dependent kinase inhibitor p27(Kip1) functions as a tumor suppressor, and reduced levels of p27(Kip1) connote poor prognosis in several human malignancies. p27(Kip1) levels are predominately regulated by ubiquitin-mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCF(Skp2) complex following its phosphorylation by the cyclin E-cyclin-dependent kinase 2 complex. Binding of phospho-p27(Kip1) is directed by the Skp2 F-box protein, and this is greatly augmented by its allosteric regulator Cks1. We have established that programmed expression of c-Myc in the B cells of Emu-Myc transgenic mice triggers p27(Kip1) destruction by inducing Cks1, that this response controls Myc-driven proliferation, and that loss of Cks1 markedly delays Myc-induced lymphomagenesis and cancels the dissemination of these tumors. Here, we report that elevated levels of Skp2 are a characteristic of Emu-Myc lymphomas and of human Burkitt lymphoma that bear MYC/Immunoglobulin chromosomal translocations. As expected, Myc-mediated suppression of p27(Kip1) was abolished in Skp2-null Emu-Myc B cells. However, the effect of Skp2 loss on Myc-driven proliferation and lymphomagenesis was surprisingly modest compared with the effects of Cks1 loss. Collectively, these findings suggest that Cks1 targets, in addition to p27(Kip1), are critical for Myc-driven proliferation and tumorigenesis.