Novel transforming genes in murine myeloid leukemia

Abstract

Leukemia is characterised by an accumulation in the bone marrow of non-functional blood cells arrested at a particular stage of differentiation. In the process of normal hematopoiesis, errors may occur as the result of mutations in the DNA of hematopoietic precursor cells. These genetic lesions may lead to activation of protooncogenes, inactivation of tumour suppressor genes or expression of aberrant gene products. The combination of different genetic lesions in a hematopoietic progenitor cell may ultimately result in the development of leukemia. An approach to find leukemia disease genes is the identification and cloning of common virus integration sites in murine leukemias. This approach has proven to be a sensitive tool to identify novel proto-oncogenes as well as tumour suppressor genes. We used the slow transforming retrovirus Cas-Br-M murine leukemia virus (Cas-BrM MuL V) in NIH/Swiss mice to establish a panel of leukemias (Chapter 2). All tumours found in leukemic animals were classified by gross pathology, morphology, and immunophenotype as well as the incidence of known common virus integration sites in murine leukemia virus-induced myeloid malignancies, i.e., Evil [ 1], Evill/C b 2 [2], Evi 12 [3], Flil [ 4] and c-Myb [5]. While most of the immunophenotyped Cas-Br-M MuLV induced tumours were of myeloid origin (58%), also numerous T -cell leukemias (21%) and mixed myeloid/T -cell leukemias (21%) were found. The myeloid leukemias and myeloid compartment of the mixed leukemias were further characterised by immunophenotyping with stem cell-, myeloid- and erythroid-specific antibodies. The known Cas-Br-M MuLV common vims integration sites Evil, Evill/Cb2 and Evil2 were demonstrated in 19%, 12% and 20% of the cases, respectively, whereas no Flil or c-Myb rearrangements were found. Integrations into Evil were restricted to myeloid leukemias, whereas those in Evill/Cb2 and Evil2 were identified in myeloid as well as T -lymphoid leukemias. This panel of well-characterised Cas-Br-M MuL V -induced hematopoietic tumours may be useful for the isolation and characterisation of new proto-oncogenes involved in murine myeloid or T -cell leukemia