ABSTRACT
TEN-ELEVEN-TRANSLOCATION-2 (TET2) and DNA-METHYLTRANSFERASE-3A (DNMT3A), both encoding proteins involved in regulating DNA methylation, are mutated in hematological malignancies affecting both myeloid and lymphoid lineages. We previously reported an association of TET2 and DNMT3A mutations in progenitors of patients with angioimmunoblastic T-cell lymphomas (AITL). Here, we report on the cooperative effect of Tet2 inactivation and DNMT3A mutation affecting arginine 882 (DNMT3A(R882H)) using a murine bone marrow transplantation assay. Five out of eighteen primary recipients developed hematological malignancies with one mouse developing an AITL-like disease, two mice presenting acute myeloid leukemia (AML)-like and two others T-cell acute lymphoblastic leukemia (T-ALL)-like diseases within 6 months following transplantation. Serial transplantations of DNMT3A(R882H) Tet2(-/-) progenitors led to a differentiation bias toward the T-cell compartment, eventually leading to AITL-like disease in 9/12 serially transplanted recipients. Expression profiling suggested that DNMT3A(R882H) Tet2(-/-) T-ALLs resemble those of NOTCH1 mutant. Methylation analysis of DNMT3A(R882H) Tet2(-/-) T-ALLs showed a global increase in DNA methylation affecting tumor suppressor genes and local hypomethylation affecting genes involved in the Notch pathway. Our data confirm the transformation potential of DNMT3A(R882H) Tet2(-/-) progenitors and represent the first cooperative model in mice involving Tet2 inactivation driving lymphoid malignancies.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methylation/genetics , DNA-Binding Proteins/genetics , Lymphoproliferative Disorders/genetics , Mutation , Proto-Oncogene Proteins/genetics , Animals , Cell Differentiation , DNA Methyltransferase 3A , Dioxygenases , Genes, Tumor Suppressor , Lymphoproliferative Disorders/etiology , Mice , Receptors, Notch/geneticsABSTRACT
Given the worldwide trend toward the integration of children with special needs into the general school system, and the Program for Educational Modernization (1989-1994) in Mexico, Mexican educators have had to reassess the politics of special education, focusing on different service delivery models. One model, Integrated Groups, which has been functioning since the 1970s and is primarily for children with learning and language disabilities, is described. New legislation recently enacted recognizes and encourages the collaboration of general education and special education to meet the needs of all children. During the school year 1994-1995, the Secretariat of Public Education (SEP; the Mexican centralized public school system) is piloting, in Mexico City, a proposal for the integration of children into the general classroom. This new model of service delivery is designed to provide greater site-based approaches to the education of individuals with learning disabilities.
