Analysis of C/EBP role in leukemogenesis induced by the hybrid protein CALM/AF10

• Grant number: 08/51503-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2008
• End date: May 31, 2010
• Field of knowledge: Biological Sciences - Genetics - Animal Genetics
• Principal Investigator: Eduardo Magalhães Rego
• Grantee: Alexandre Krause
• Host Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil
• Associated research grant: 98/14247-6 - Center for Research on Cell-Based Therapy, AP.CEPID

Abstract

The rare but recurring chomosomal translocation t(10;11)(p13;q14), which results in the CALM/AF10 fusion, is found in patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), acute biphenotypic leukemia (ABL) and in malignant lymphoma (ML). CALM/AF10 - positive leukemias have a bad prognosis like leukemias with fusions involving the MLL gene. This leukemia presents an over expression pattern of the HOXA genes, similar to the MLL - associated leukemias. Mice transplanted with murine bone marrow retrovirally expressing CALM/AF10 die with an aggressive leukemia with a latency of 9 to 14 weeks. In contrast, transgenic mice expressing CALM/AF10 under the control of the LCK or IgH promoter do not show a leukemia phenotype. Gene expression analysis using the Affymetrix platform comparing 10 CALM/AF10 patient samples to ten groups of different leukemia subtypes and normal bone marrow showed a down regulation in the expression of the myeloid transcription factor CCAAT enhancer-binding protein alpha (C/EBP) in CALM/AF10 patients in comparison to all other groups. The aim of this project is to analyze the role of C/EBP in the leukemogenesis induced by the CALM/AF10 fusion using two different animal models: the retroviral expression of CALM/AF10 in primary murine bone marrow cells transplanted into wild type and C/EBP mice and the transgenic model by crossing CALM/AF10 knock-in with C/EBP mice. (AU)