The expression of ETV6/CBFA2 (TEL/AML1) is not sufficient for the transformation of hematopoietic cell lines in vitro or the induction of hematologicdisease in vivo

ETV6/CBFA2 (TEL/AML1) is the most frequent genetic abnormality associated w ith acute lymphoblastic leukemias in children, and is associated with a fav orable prognosis. To investigate the influence of ETV6/CBFA2 on cellular tr ansformation, the fusion gene was cloned into a murine ecotropic retroviral vector and transduced into IL-3-dependent Ba/F3 and 32Dcl.3 and IL-7-depen dent IxN/2b murine hematopoietic cell lines. Different variants of ETV6/CBF A2, corresponding to CBFA2 alternatively spliced variants, and the reciproc al product CBFA2/ETV6, were stably expressed in each of these cell lines. H owever, although Western blot analysis demonstrated expression of each vari ant, none of the stable cell lines expressing CBFA2/ETV6 or the variants co nferred factor-independent growth. We further investigated the effect of ET V6/CBFA2 expression in vivo by generating transgenic mice in which expressi on of the fusion was directed to lymphoid cells using the immunoglobulin he avy chain enhancer/promoter. Four founder mice were identified showing tran smission and expression of the chimeric product. The mice were bred for fiv e generations and followed for more than 24 months. The mice did not develo p a malignant hematologic disorder, nor did they display histopatholagic, m orphologic, or immunophenatypic abnormalities, although ETV6/CBFA2 expressi on was confirmed in each line. We conclude that the expression of ETV6/ CBF A2 alone is not sufficient for induction of growth factor independence in h ematopoietic cell lines or hematologic disease in transgenic mice. (C) 2001 Elsevier Science Inc. All rights reserved.