title: Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development.
abstract: The JAK-STAT pathway has a substantial role in lymphoid precursor cell proliferation, survival and differentiation. Nonetheless, the contribution of JAK2 to T-cell lymphoblastic lymphoma (T-LBL) development remains poorly understood. We have identified one activating TEL-JAK2 translocation and four missense mutations accumulated in 2 out of 16 T-LBL samples. Two of them are novel JAK2 mutations and the other two are reported for the first time in T-LBL. Notably, R683G and I682T might have arisen owing to RNA editing. Mutated samples showed different mutated transcripts suggesting sub-clonal heterogeneity. Functional approaches revealed that two JAK2 mutations (H574R and R683G) constitutively activate JAK-STAT signaling in γ2A cells and can drive the proliferation of BaF3-EpoR cytokine-dependent cell line. In addition, aberrant hypermethylation of SOCS3 might contribute to enhance the activation of JAK-STAT signaling. Of utmost interest is that primary T-LBL samples harboring JAK2 mutations exhibited increased expression of LMO2, suggesting a mechanistic link between JAK2 mutations and the expression of LMO2, which was confirmed for the four missense mutations in transfected γ2A cells. We therefore propose that active JAK2 contribute to T-LBL development by two different mechanisms, and that the use of pan-JAK inhibitors in combination with epigenetic drugs should be considered in future treatments.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas- Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.|IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Roncero
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas- Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.|IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: López-Nieva
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas- Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.|IIS-Fundación Jiménez Díaz, Madrid, Spain.|Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Cobos-Fernández
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas- Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.|IIS-Fundación Jiménez Díaz, Madrid, Spain.|Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Villa-Morales
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas- Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.|IIS-Fundación Jiménez Díaz, Madrid, Spain.|Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: L
authors.initials: L
authors.lastname: González-Sánchez
authors.affiliation: IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: López-Lorenzo
authors.affiliation: IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Llamas
authors.affiliation: IIS-Fundación Jiménez Díaz, Madrid, Spain.|Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Ayuso
authors.affiliation: IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: S M
authors.initials: SM
authors.lastname: Rodríguez-Pinilla
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas- Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.|IIS-Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: M C
authors.initials: MC
authors.lastname: Arriba
authors.affiliation: Hospital Universitario Marqués de Valdecilla, Fundación IFIMAV, Santander, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Unidad de Epidemiología Ambiental y Cáncer, Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain.|Consorcio de Investigación Biomédica de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.|IIS Puerta de Hierro, Majadahonda, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Fernández-Navarro
authors.affiliation: Unidad de Epigenética del Cáncer, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-CSIC), Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
authors.forename: A F
authors.initials: AF
authors.lastname: Fernández
authors.affiliation: Unidad de Epigenética del Cáncer, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-CSIC), Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.|Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología (CNB), Madrid, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Fraga
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas- Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.|IIS-Fundación Jiménez Díaz, Madrid, Spain.|Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Santos
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas- Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.|IIS-Fundación Jiménez Díaz, Madrid, Spain.|Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Fernández-Piqueras
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D002881:Chromosomes, Human, Pair 12; D002899:Chromosomes, Human, Pair 9; D019175:DNA Methylation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000502:physiology; D060588:LIM Domain Proteins / Q000235:genetics; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2