Sleeping Beauty transposon screen identifies signaling modules that cooperate with STAT5 activation to induce B-cell acute lymphoblastic leukemia.

Heltemes-Harris, L M; Larson, J D; Starr, T K; Hubbard, G K; Sarver, A L; Largaespada, D A; Farrar, M A

Heltemes-Harris, L M; Larson, J D; Starr, T K; Hubbard, G K; Sarver, A L; Largaespada, D A; Farrar, M A.

Afiliación

Heltemes-Harris LM; Center for Immunology, University of Minnesota, Minneapolis, MN, USA.
Larson JD; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
Starr TK; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Hubbard GK; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Sarver AL; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA.
Largaespada DA; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Farrar MA; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA.

Oncogene ; 35(26): 3454-64, 2016 06 30.

Article en En | MEDLINE | ID: mdl-26500062

RESUMEN

Signal transducer and activator of transcription 5 (STAT5) activation occurs frequently in human progenitor B-cell acute lymphoblastic leukemia (B-ALL). To identify gene alterations that cooperate with STAT5 activation to initiate leukemia, we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice in which a mutagenic Sleeping Beauty transposon (T2/Onc) was mobilized only in B cells. Stat5b-CA mice typically do not develop B-ALL (<2% penetrance); in contrast, 89% of Stat5b-CA mice in which the T2/Onc transposon had been mobilized died of B-ALL by 3 months of age. High-throughput sequencing approaches were used to identify genes frequently targeted by the T2/Onc transposon; these included Sos1 (74%), Kdm2a (35%), Jak1 (26%), Bmi1 (19%), Prdm14 or Ncoa2 (13%), Cdkn2a (10%), Ikzf1 (8%), Caap1 (6%) and Klf3 (6%). Collectively, these mutations target three major cellular processes: (i) the Janus kinase/STAT5 pathway (ii) progenitor B-cell differentiation and (iii) the CDKN2A tumor-suppressor pathway. Transposon insertions typically resulted in altered expression of these genes, as well as downstream pathways including STAT5, extracellular signal-regulated kinase (Erk) and p38. Importantly, expression of Sos1 and Kdm2a, and activation of p38, correlated with survival, further underscoring the role these genes and associated pathways have in B-ALL.

Asunto(s)

Linfocitos B/metabolismo; Elementos Transponibles de ADN/genética; Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética; Factor de Transcripción STAT5/genética; Animales; Western Blotting; Transformación Celular Neoplásica/genética; Transformación Celular Neoplásica/metabolismo; Regulación Leucémica de la Expresión Génica; Factor de Transcripción Ikaros/genética; Factor de Transcripción Ikaros/metabolismo; Janus Quinasa 1/genética; Janus Quinasa 1/metabolismo; Histona Demetilasas con Dominio de Jumonji/genética; Histona Demetilasas con Dominio de Jumonji/metabolismo; Estimación de Kaplan-Meier; Ratones Endogámicos C57BL; Ratones Transgénicos; Mutagénesis Insercional; Mutación; Complejo Represivo Polycomb 1/genética; Complejo Represivo Polycomb 1/metabolismo; Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo; Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología; Proteínas Proto-Oncogénicas/genética; Proteínas Proto-Oncogénicas/metabolismo; Reacción en Cadena de la Polimerasa de Transcriptasa Inversa; Proteína SOS1/genética; Proteína SOS1/metabolismo; Factor de Transcripción STAT5/metabolismo; Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos B / Elementos Transponibles de ADN / Leucemia-Linfoma Linfoblástico de Células Precursoras B / Factor de Transcripción STAT5 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

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