title: BCR-JAK2 drives a myeloproliferative neoplasm in transplanted mice.
abstract: BCR-JAK2 is an infrequent gene fusion found in chronic/acute, myeloid/lymphoid Philadelphia chromosome-negative leukaemia. In this study, we demonstrated that in vivo expression of BCR-JAK2 in mice induces neoplasia, with fatal consequences. Transplantation of BCR-JAK2 bone marrow progenitors promoted splenomegaly, with megakaryocyte infiltration and elevated leukocytosis of myeloid origin. Analysis of peripheral blood revealed the presence of immature myeloid cells, platelet aggregates and ineffective erythropoiesis. A possible molecular mechanism for these observations involved inhibition of apoptosis by deregulated expression of the anti-apoptotic mediator Bcl-xL and the serine/threonine kinase Pim1. Together, these data provide a suitable in vivo molecular mechanism for leukaemia induction by BCR-JAK2 that validates the use of this model as a relevant preclinical tool for the design of new targeted therapies in Philadelphia chromosome-negative leukaemia involving BCR-JAK2-driven activation of the JAK2 pathway.
authors: Molecular Biology Unit, Instituto de Investigación Sanitaria Princesa (IIS-P, UAM), Hospital Universitario de La Princesa, Madrid, Spain.
authors: Álvaro
authors: Á
authors: Cuesta-Domínguez
authors: Division of Haematopoietic Innovative Therapies, CIEMAT/CIBERER, Madrid, Spain.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain.
authors: Diego
authors: D
authors: León-Rico
authors: Division of Haematopoietic Innovative Therapies, CIEMAT/CIBERER, Madrid, Spain.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain.
authors: Lara
authors: L
authors: Álvarez
authors: Division of Haematopoietic Innovative Therapies, CIEMAT/CIBERER, Madrid, Spain.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain.
authors: Begoña
authors: B
authors: Díez
authors: Molecular Biology Unit, Instituto de Investigación Sanitaria Princesa (IIS-P, UAM), Hospital Universitario de La Princesa, Madrid, Spain.
authors: Irene
authors: I
authors: Bodega-Mayor
authors: Division of Haematopoietic Innovative Therapies, CIEMAT/CIBERER, Madrid, Spain.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain.
authors: Rocío
authors: R
authors: Baños
authors: Division of Haematopoietic Innovative Therapies, CIEMAT/CIBERER, Madrid, Spain.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain.
authors: Miguel Ángel
authors: MÁ
authors: Martín-Rey
authors: Molecular Biology Unit, Instituto de Investigación Sanitaria Princesa (IIS-P, UAM), Hospital Universitario de La Princesa, Madrid, Spain.
authors: Matilde
authors: M
authors: Santos-Roncero
authors: Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII), Majadahonda, Spain.
authors: María Luisa
authors: ML
authors: Gaspar
authors: Servicio de Anatomía Patológica, Hospital Universitario Puerta de Hierro, Majadahonda, Spain.
authors: Paloma
authors: P
authors: Martín-Acosta
authors: Division of Haematopoietic Innovative Therapies, CIEMAT/CIBERER, Madrid, Spain.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain.
authors: Elena
authors: E
authors: Almarza
authors: Division of Haematopoietic Innovative Therapies, CIEMAT/CIBERER, Madrid, Spain.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain.
authors: Juan A
authors: JA
authors: Bueren
authors: Division of Haematopoietic Innovative Therapies, CIEMAT/CIBERER, Madrid, Spain.|Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD, UAM), Madrid, Spain.
authors: Paula
authors: P
authors: Río
authors: Molecular Biology Unit, Instituto de Investigación Sanitaria Princesa (IIS-P, UAM), Hospital Universitario de La Princesa, Madrid, Spain.
authors: Elena
authors: E
authors: Fernández-Ruiz
mesh_terms: D000818:Animals; D005260:Female; D015321:Gene Rearrangement; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000502:physiology; D053614:Janus Kinase 2 / Q000235:genetics / Q000502:physiology*; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000235:genetics* / Q000401:mortality; D007964:Leukocytosis / Q000209:etiology; D008297:Male; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000502:physiology*; D012190:Retroviridae; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013163:Splenomegaly / Q000209:etiology; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes
chemical_list: D050799:STAT5 Transcription Factor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr
keywords: BCR-JAK2; JAK2; extramedullary haematopoiesis; myeloproliferative neoplasm; retroviral vector; transplanted mice