The goal of our laboratory is to understand the process of oncogenesis in acute myeloid leukemia (AML), and utilize this knowledge to innovate and improve diagnostic and therapeutic strategies.
Ongoing Projects:
1. MOLECULAR MECHANISM AND CLINICAL SIGNIFICANCE OF EVI1 OVEREXPRESSION IN ACUTE MYELOID LEUKEMIA. GENOMIC STRUCTURE AND FUNCTIONAL CHARACTERIZATION OF THE PROMOTER REGION OF THE HUMAN EVI1 GENE
The EVI1 gene codes for a transcription factor with important roles in normal hematopoiesis, and its overexpression is associated with aggressive acute myeloid leukemia (AML). Our aim is to study the mechanisms of overexpression of EVI1, and the role of this gene in the leukemic transformation of patients with AML. We have characterized the transforming properties of EVI1 in cell culture systems, and our analysis has provided insights about new mechanisms of EVI1 in the transformation of AML. In addition, the collaboration with several clinical research groups have allowed us to test our hypotheses in a well clinical characterized series of patients, and to confirm the poor prognosis impact that EVI1 overexpression has in AML. Moreover, we have functionally characterized novel microRNAs involved with EVI1 in leukemia pathways using cell culture studies. The aggressive role that EVI1 plays in human leukemias indicates the need for further research into the molecular events responsible for the activation of this oncogene.
Grants: (1) Ministerio de Ciencia e Innovación (PI081687): 2009-2011. (2) Departamento de Salud del Gobierno de Navarra (14/2008): 2009-2011. (3) Fundación Científica de la Asociación Española contra el Cáncer: 2004-2007. (4) Departamento de Salud del Gobierno de Navarra (8/2004): 2004-2006. (5) Molecular Pathogenesis of Genetic Diseases. Interuniversity Attraction Poles (IAP): 2007-2011.
Scientific Publications: (1) Gómez-Benito et al. (2010) Br J Cancer, 103:1292-6. IF: 4.346. (2) Vázquez et al. (2010) PNAS, 107:E167-8. IF: 9.432. (3) De Weer et al. (2011) Br J Haem. IF: 4.597 (4) Shing et al. (2007) JCI, 117:3696–3707. IF: 16.915. (5) Lahortiga et al. (2005) Hum Genet, 116:476-485. IF: 4.331. (6) Lahortiga et al. (2004) Oncogene, 23:311-6. IF: 6.318. (7) Lahortiga et al. (2004) Genes Chrom Cancer, 40:179-189. IF: 4.276. (8) Vazquez et al. (2004) Leukemia, 18:2041-4. IF: 5.810.
2. GENETIC CHARACTERIZATION OF PATIENTS WITH ACUTE MYELOID LEUKEMIA AND NORMAL KARYOTYPE. MOLECULAR MECHANISM, INCIDENCE, AND CLINICAL SIGNIFICANCE OF GATA2 OVEREXPRESSION
The GATA2 gene codes for a transcription factor with an essential role in normal hematopoiesis. Our aim is to study the prevalence and mechanisms of overexpression of GATA2 in AML, and the role of this gene in the leukemic transformation of this disease.
Grants: (1) Ministerio de Educación y Ciencia (SAF2005/06425): 2005-2008.
Scientific Publications: (1) Vicente et al. (2011) Critical Reviews in Oncology/Hematology, in press. IF: 5.269. (2) Vicente et al. (2007) Leukemia, 21: 2386-2390. IF: 6.924. (3) Suela et al. (2007) Leukemia, 21:1224-1231. IF: 6.924.
3. ROLE OF THE PROTEIN PHOSPHATASE 2A (PP2A) IN ACUTE MYELOID LEUKEMIA
The protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that participates in many mammalian signaling pathways. PP2A regulates the activity of several signaling proteins critical for malignant cell behavior, and has been described as a potential therapeutic target in chronic myeloid leukemia. We have described how SETBP1 protects SET, a potent PP2A inhibitor, from protease cleavage, leading to PP2A inhibition in AML cells. Moreover, we have showed that PP2A inactivation is a recurrent event in AML, and that restoration of PP2A phosphatase activity by treatment with forskolin in AML cells blocks proliferation, induces caspase-dependent apoptosis and affects AKT and ERK1/2 activity. Moreover, treatment with either forskolin or FTY720 had an additive effect with drugs used in standard induction therapy in AML patients. Therefore, our results suggest that functional inactivation of the PP2A tumor suppressor is a recurrent event that seems to represent an important mechanism in the leukemogenic transformation of AML. Although PP2A activators are not still clinically available, these results highlight PP2A as a potential target for future therapies combined with PP2A activators.
Scientific Publications: (1) Cristóbal et al. (2011) Leukemia (25):606-614. IF: 8.296. (2) Cristóbal et al. (2010) Blood, 115:615-25. IF: 10.555.
4. INVESTIGATION OF MYB IN THE PATHOGENESIS OF ACUTE MYELOID LEUKEMIA AND ITS ROLE AS A TARGET FOR THERAPY IN THIS DISEASE
The MYB gene encodes a nuclear transcription factor that is implicated in proliferation, survival and differentiation of hematopoietic progenitor cells. Proper levels of MYB expression are known to be important during hematopoietic cell development. We collaborated with a project that showed that MYB overexpression is directly implicated in the pathogenesis of T-cell acute lymphoblastic leukemia. Our aim is to study the prevalence and mechanisms of overexpression of MYB in AML, and the role of this gene in the leukemic transformation of this disease.
Grant: (1) Molecular Pathogenesis of Genetic Diseases. Interuniversity Attraction Poles (IAP): 2007-2011.
Scientific Publications: (1) Belloni et al. (2011). Leukemia (25):733-736. IF: 8. 296. (2) Lahortiga et al. (2007) Nature Genetics, 39:593-5. IF: 25.556.
